MOH/P/PAK/216.

11(GU)

Guidelines for Treatment of Lysosomal

Storage Diseases by Enzyme Replacement

Therapy in Malaysia

MEDICAL DEVELOPMENT DIVISION

MINISTRY of HEALTH MALAYSIA
Guidelines for Treatment of Lysosomal Storage Diseases by Enzyme Replacement Therapy In Malaysia

First published in Malaysia in January 2012 by

The Technical Committee on Enzyme Replacement Therapy

in collaboration with
Obstetric & Gynaecological and Paediatric Services Unit,
Medical Services Department Section,
Medical Development Division, Ministry of Health Malaysia.
www.moh.gov.my

A catalogue record of this document is available from the Library and Resource
Unit of the Institute of Medical Research, Ministry of Health;
MOH/P/PAK/216.11(GU)

And also available from the National Library of Malaysia;

ISBN 978-983-44999-9-0

All rights reserved. No part of this publication may be reproduced, stored in a database or
retrieval system, or distributed in any form or any means, without prior written permission of
the Ministry of Health Malaysia.
 CONTENTS

1 Foreword 4
2 Introduction 5
3 Guideline on Gaucher disease 9
4 Guideline on Pompe disease 17
5 Guideline on Mucopolysaccharidosis Type I 25
6 Guideline on Mucopolysaccharidosis Type II 33
7 Guideline on Mucopolysaccharidosis Type VI 41
8 Guideline on Fabry disease 47
9 Appendix 55
A: General conditions for eligibility 56
B: Patient’s consent form (Borang Persetujuan Pesakit) 58
C: Monitoring requirements and data submission form for Gaucher disease 63
D: Monitoring requirements and data submission form for Pompe disease 69
E: Monitoring requirements and data submission form for MPS diseases 80
F: Monitoring requirements and data submission form for Fabry disease 88
G: SF-36 health survey score sheet 96
H: Gross motor function measure score sheet 103
I : Brief pain inventory (short form) 110
J : MRC scale for assessment of muscle power 114
10 Drafting Committee 117
11 Acknowledgement 118

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 3
 FOREWORD

Rare inherited Lysosomal Storage Diseases (LSD) pose diagnostic and therapeutic
challenge. They are also increasingly becoming a health care and economic challenge, mainly
due to the development and availability of enzyme replacement therapy (ERT) for some LSDs.
Currently ERT are available for six LSDs: Mucopolysaccharidosis Type 1(MPS I), MPS II, MPS
VI, Fabry disease, Pompe disease and Gaucher disease.

The Malaysian Government, through the Ministry of Health, has approved the funding
for Enzyme Replacement Therapy Program for LSDs, and provides subsidized access to
expensive and potentially lifesaving drugs for these life-threatening diseases. It would appear
rational to have a national guideline to ensure consistency and a sustainable program. This is
also to ensure careful spending of public funding.

A candidate must fully satisfy the eligibility criteria of the relevant disease as stated in
this guideline before a consideration for the subsidized drugs is to be made. Patient eligibility will
be reviewed in accordance with the frequency stated in this guideline, generally 12 months after
commencing therapy and every 12 months thereafter. Continued eligibility will be subjected to
the evaluation of evidence for

1. clinical improvement in the patient, or

2. stabilisation of the patient’s condition.

We hope this guideline will be a valuable reference document to clinicians, pharmacists,

patients, families as well as the general public.

Y.Bhg. Datuk Dr. Noor Hisham bin Abdullah

Deputy Director General of Health (Medical)
November 2011

4 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
INTRODUCTION
 Lysosomal Storage Diseases (LSD) are a heterogenous group of more than 40 inborn
errors of metabolism that are due to specific defects of lysosomal enzymes, lysosomal membrane
proteins or transporters. All LSDs are inherited autosomal recessively with the exception of MPS
II (Hunter disease) and Fabry Disease that are inherited as X-linked traits. As a group, LSDs
occur in approximately 1 in 5000 to 8000 births.1,2

LSDs in general are progressive multi organ disorder with about 50% having significant
central nervous system involvement. Each LSD comprises a more or less unique clinical
spectrum with patients at the more severe end showing increased morbidity and mortality
whereas patients at the milder end of the spectrum having only subtle clinical signs. Patients
with mild disease may often go unrecognized for many years.

In the past, no specific treatment was available for the affected patients; management
mainly consisted of supportive care and treatment of complications. Allogeneic bone marrow
transplantation (BMT) was the first specific therapeutic approach to be used in LSDs. The vast
majority of clinical experience is in treating patients with mucopolysaccharidoses, particularly
MPS I. Because of the risks associated with the procedure, allogeneic BMT has generally been
used in the more severe, Hurler form of MPS I and the vast majority of children have been
transplanted before the age of three. In the last 2 decades, remarkable progress has been
achieved in the field of LSD with the development of innovative therapies including enzyme
replacement therapies (ERT) and substrate reduction therapy(SRT). Additional therapies such
as chaperone therapy and gene therapy are currently under preclinical investigations. Currently
ERT are available for MPS I, II, VI, Fabry, Pompe and Gaucher diseases. In addition SRT has
been licensed for Gaucher disease.3,4,5

Enzyme replacement therapy for LSD is expensive compared to treatment modalities for
other rare inborn errors of metabolism (dietary therapy, co-factor substitution). The development
of these effective but very expensive therapies presents special problems for health care policy-
makers, who are committed to ensuring access to new therapies which are life saving for
affected patients; but who at the same time are also under pressure to control overall health
care spending. Therefore, a national policy and guideline is deemed necessary to determine
which patients should be treated with this very costly treatment.

The aim of this guideline is to provide guidance judged to be necessary for the selection
of patients for ERT. The candidate must meet all the eligibility criteria and none of the exclusion
criteria in order to be considered for government funded ERT. Government funded ERT will
only be provided where the patient agrees to participate in the evaluation of the efficacy of
the treatment by periodic medical assessment. Continued eligibility will be subjected to clinical
improvement in the patient, and/or stabilisation of the patient’s condition. Separate guidelines
are written for each of the following LSDs:

6 Guidelines for treatment of lysosomal storage diseases

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 • Gaucher disease
• Pompe disease
• Mucopolysaccharidosis type I
• Mucopolysaccharidosis type II
• Mucopolysaccharidosis type VI
• Fabry disease

The committee will review and revise these guidelines periodically in line with any new
medical development and evidence in the field of LSD.

References :-

1. Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S,Niezen-Koning KE, van Diggelen OP.
1999. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet 105:151–156.

2. Lin HY, Lin SP, Chuang CK, Niu DM, ChenMR, Tsai FJ, Chao MC, Chiu PC, Lin SJ, Tsai LP, Hwu WL, Lin JL. 2009.
Incidence of the mucopolysaccharidoses in Taiwan,1984–2004 Am J Med Genet Part A 149A:960–964.

3. Beck M. 2007. New therapeutic options for lysosomal storage disorders: Enzyme replacement, small molecules
and gene therapy. Hum Genet 121:1–22.

4. P.M. Hoogerbrugge, O.F. Brouwer, P. Bordigoni, O. Ringden, P. Kapaun, J.J. Ortega, A.O’Meara, G. Cornu, G.
Souillet, D. Frappaz, et al., Allogeneic bone marrow transplantation for lysosomal storage diseases. The European
Group for Bone Marrow Transplantation, Lancet 345 (1995) 1398–1402 issn: 0140–6736.

5. R.O Brady, Enzyme replacement for lysosomal diseases, Annu. Rev. Med. 57 (2006) 283–296

Guidelines for treatment of lysosomal storage diseases

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GAUCHER DISEASE
INTRODUCTION

Gaucher Disease (GD) is an autosomal recessive disorder, caused by deficiency of the

lysosomal enzyme β-glucosylceramidase. This deficiency results in a decreased breakdown
of the glycosphingolipid and glucocerebroside, which accumulate in the lysosomes of the
monocyte-macrophage system.1,2 The prevalence of type 1 GD is 1:40 000 to 60 000 in the
general population.3

Gaucher Disease encompasses a continuum of clinical findings from a perinatal

lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2,
and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining
prognosis and management. Type 1 Gaucher Disease is characterized by the presence of
clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions,
and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and
the absence of primary central nervous system disease. Types 2 and 3 Gaucher Disease is
characterized by the presence of primary neurologic disease. In the past, they were distinguished
by age of onset and rate of disease progression, but these distinctions are not absolute. Disease
with onset before two years, limited psychomotor development, and a rapidly progressive
course with death by age two to four years is classified as type 2 Gaucher Disease. Individuals
with type 3 Gaucher Disease may have onset before age two years, but often have a more
slowly progressive course and may live into the third or fourth decade. The perinatal-lethal form
is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops
fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves,
mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary
complications have been described in all the clinical subtypes, although varying in frequency
and severity.1,4

DISEASE MANAGEMENT AND ENZYME REPLACEMENT THERAPY

In the past, treatment of Gaucher Disease has focused on symptomatic treatment of

pain, surgical treatment of fractures, infections and avascular necrosis of the bone; surgical
removal of the spleen to relieve thrombocytopenia caused by hypersplenism; and blood
transfusions to correct anaemia. Patients with very severe disease have also been treated by
bone marrow transplantation (BMT). However, this requires the availability of a suitable bone
marrow donor, and the procedure is associated with prolonged hospitalisation and significant
morbidity and mortality.1

An effective treatment of Gaucher Disease has now been available since 1991 in the
form of enzyme replacement therapy (ERT). The two recombinant β-glucosylceramidase enzyme
preparations are currently available commercially and are distinguished according to the cell

10 Guidelines for treatment of lysosomal storage diseases

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type involved in their production: imiglucerase (Cerezyme®, Genzyme) generated in Chinese
hamster ovary cells; velalglucerase alfa (VPRIV®, Shire) from human cell line. Each formulation
is modified to expose the alpha-mannosyl (carbohydrate) residues for enhanced uptake by the
macrophage.5-6 Currently, imiglucerase has been approved by National Pharmaceutical Control
Bureau for treatment of Gaucher Disease in Malaysia.

In clinical studies, ERT is effective for treatment of the haematologic, visceral and bone
complications of the Gaucher Disease. The efficacy of ERT for neurologic complications is not
proven conclusively and still under investigation.7-11 Individuals with chronic neurologic GD
and progressive disease despite ERT may be candidates for BMT or a multi-modal approach
(i.e., combined ERT and BMT). Miglustat, an inhibitor of glucosylceramide synthetase, which is
administered orally, may be an alternative for the treatment of individuals with mild to moderate
Gaucher Disease for whom ERT is not a therapeutic option because of constraints such as
allergy, hypersensitivity, or poor venous access.12

While ERT is effective, such chronic treatment places a burden on the individual patient,
and is costly for society. Therefore, some guidance was judged to be necessary for the selection
of patients for treatment.

ELIGIBILITY CRITERIA FOR ENZYME REPLACEMENT THERAPY

1. Citizen of Malaysia

The patient must be a citizen of Malaysia. Permanent residents are not eligible.

2. Confirmed diagnosis of Gaucher Disease

The diagnosis of Gaucher Disease must have been established by the demonstration of
specific deficiency of β-glucosylceramidase in leukocytes or cultured skin fibroblasts. The
diagnosis can also be confirmed by the presence of glucocerebrosidase gene mutations
known to result in severe deficiency of enzyme activity.

3. Severity of Gaucher Disease

a. ERT is only for Type I Gaucher Disease with clinically significant symptoms.

Guidelines for treatment of lysosomal storage diseases

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 Children (under 18 years of age) Adults (18 Years of Age or Over)

i. Any of the following symptoms :- i. One of the following :-

- Bone pain Symptomatic manifestations of
- Abdominal pain skeletal disease as confirmed by
- Fatigue radiological examination,
- Exertion limitations including :-
- Weakness - Joint deterioration
- Cachexia - Pathological fracture
- Hepatosplenomegaly - Avascular necrosis
- Growth failure - Definite Osteopenia
And - Marrow infiltration
ii. Presents with one or more of the OR
following :- ii. Presents with two or more of
the following :-
- Thrombocytopenia, defined as
- Anemia ≤12.5g/dl for males
platelet count≤ 60 x109/l;
and ≤11.5g/dl for females
- Anemia, defined as Hemoglobin - Platelet count ≤ 120 x109/l
< 2g/dl below the lower limit of
- Hepatomegaly, defined as liver
normal for age and sex;
volume 25% greater than normal
OR - Splenomegaly, defined as
spleen volume 5 times normal
iii. Evidence of skeletal involvement as
or greater
confirmed by radiographic examination,
including :-
- EFD (Erlenmeyer Flask
Deformity)
- Avascular Necrosis of
Bone
- Destructive lesions of
bone

b. Type II and III patients exhibiting primary neurological disease due to Gaucher
disease would not be considered eligible for treatment with ERT. Exception to this
is children with oculomotor apraxia as their only neurological finding.

12 Guidelines for treatment of lysosomal storage diseases

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4. Additional conditions as in Appendix A.

EXCLUSION CRITERIA

1. The treatment of asymptomatic patients is not generally granted unless the disease is of
sufficient severity to suggest a severe course or impending complications (this could be
determined through mutation analysis in the asymptomatic patient), or the presence of a
family history of severe, accelerated course of the disease during childhood.

2. Potentially confounding serious disorders such as Hodgkin’s Disease.

3. The patient should not have any Gaucher Disease related or any other medical condition
that might reasonably be expected to compromise their response to ERT.

4. In some patients with Gaucher disease, secondary pathologic changes, such as avascular
necrosis of bone, may already have occurred that would not be expected to respond to
ERT. In such patients, reversal of the pathology is unlikely. Treatment of patients with
significant secondary pathology would be directed at preventing further progression of
the disease. In these cases, the extent to which symptoms, such as bone pain, are due
to active progression of the disease, rather than the secondary pathology, can only be
established by a trial of therapy.

5. ERT should not be given to a pregnant woman unless it is clearly needed.

DOSING RECOMMENDATIONS

The dose of imiglucerase generally ranges between 15 and 60 units of enzyme per
kilogram body weight by intravenous infusion every 2 weeks. The enzyme dose may be
increased or decreased after initiation of treatment and during the maintenance phase, based
on clinical response – i.e., hematopoietic reconstitution, reduction of liver and spleen volumes,
and stabilization or improvement in skeletal findings.

CONSENT FORMS

Patients or their parents/guardians (if patient is younger than 18 years old) are required
to sign a consent form prior to the start of the subsidized ERT, to be submitted at the time of
application (see Appendix B).

Guidelines for treatment of lysosomal storage diseases

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REVIEW OF THERAPY

Patient who is on subsidized ERT should be reviewed at regular intervals by the ERT
Technical Committee, based on the haematological, biochemical and radiological data that are
to be collected by the treating doctor (see Appendix C).

WITHDRAWAL OF THERAPY

Subsidized imiglucerase treatment could be withdrawn in any of the following situations:

a. the patient fails to comply adequately with treatment (defaults 2 or more infusions
over 6 months period without acceptable reason) or monitoring requirements, taken
to evaluate the effectiveness of the therapy

b. if therapy fails to relieve the symptoms that originally resulted in the patient being
approved for subsidized treatment

c. young children with severe visceral manifestations of Gaucher disease may be

considered for therapy prior to the possible development of primary neurological
complications, with the understanding of the treating doctor and parents/guardians
that there should be close neurodevelopmental follow-up. Development of the
following features consistent with a neuronopathic form of Gaucher Disease would
result in therapy being withdrawn :-

- Opisthotonus

- Seizures

- Bulbar dysfunction (manifested by swallowing difficulties)

- Deteriorating intellectual function (determined by age-appropriate psychometric

testing)

- Deterioration in motor skills

d. development of a life threatening complication, which would compromise the

effectiveness or benefit from continued ERT, including severe infusion-related
adverse reactions or antibody-related reactions which are not preventable or
controlled by appropriate pre-medication and/or adjustment of infusion rates

14 Guidelines for treatment of lysosomal storage diseases

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REFERENCES

1. Grabowski GA, Kolodny EH, Weinreb NJ, Rosenbloom BE, Prakash-Cheng A, Kaplan P, Charrow J, Rastores
GM, Mistry PK. Gaucher disease: phenotypic and genetic variation. In: Scriver CR, Beaudet AL, Sly WS,
Valle D, Vogelstein B, eds.The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York:
McGraw-Hill; Chap 146.1. Available at www.ommbid.com.

2. Grabowski GA, Horowitz M. Gaucher’s disease: molecular, genetic and enzymological aspects. Baillieres
Clin Haematol.1997;10:635–56.

3. Meikle PJ, Hopwood JJ, ClagueAE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–
54.

4. Grabowski GA, Andria G, Baldellou A, Campbell PE, Charrow J, Cohen IJ, Harris CM, Kaplan P, Mengel E,
Pocovi M, Vellodi A. Pediatric non-neuronopathic Gaucher disease: presentation, diagnosis and assessment.
Consensus statements.Eur J Pediatr. 2004;163:58–66.

5. Pastores GM (2003) Enzyme therapy for the lysosomal storage disorders: principles, patents, practice and
prospects. Expert Opin Ther Patents 13:1157-72.

6. Zimran A, Altarescu G, Philips M, Attias D, Jmoudiak M, Deeb M, Wang N, Bhirangi K, Cohn GM, Elstein
D. Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher
disease: 48-month experience.Blood. 2010;115:4651–6.

7. Weinreb NJ, Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, Rosenbloom BE, Scott
CR, Wappner RS, Zimran A. Effectiveness of enzyme replacement therapy in 1028 patients with type 1
Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med. 2002;113:112–
9.

8. Mistry PK, Cappellini MD, Lukina E, Ozsan H, Mach Pascual S, Rosenbaum H, Helena Solano M, Spigelman
Z, Villarrubia J, Watman NP, Massenkeil G. A reappraisal of Gaucher disease-diagnosis and disease
management algorithms. Am J Hematol. 2011;86:110–5.

9. Baldellou A, Andria G, Campbell PE, Charrow J, Cohen IJ, Grabowski GA, Harris CM, Kaplan P, McHugh
K, Mengel E, Vellodi A. Paediatric non-neuronopathic Gaucher disease: recommendations for treatment and
monitoring. Eur J Pediatr.2004;163:67–75.

10. Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, Prakash-Cheng A, Rosenbloom BE,
Scott CR, Wappner RS, Weinreb NJ. Enzyme replacement therapy and monitoring for children with type 1
Gaucher disease: consensus recommendations. J Pediatr. 2004;144:112–20.

11. Hughes D, Cappellini MD, Berger M, Van Droogenbroeck J, de Fost M, Janic D, Marinakis T, Rosenbaum
H, Villarubia J, Zhukovskaya E, Hollak C. Recommendations for the management of the haematological and
onco-haematological aspects of Gaucher disease. Br J Haematol. 2007;138:676–86.

12. Pastores GM, Elstein D, Hrebicek M, Zimran A. Effect of miglustat on bone disease in adults with type 1
Gaucher disease: a pooled analysis of three multinational, open-label studies. Clin Ther. 2007;29:1645–54.

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 15
 Website resources

1. Dr A Vellodi, Dr JE Wraith, Dr K McHugh and Mr A Cooper for the National Specialist Commissioning
Advisory Group (NSCAG).guidelines for the management of Paediatric Gaucher disease in the united
kingdom (August 2005). www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/
digitalasset/dh_4118411.pdf

2. P Deegan, D Hughes, A Mehta, TM Cox. UK National Guideline for Adult Gaucher Disease (April 2005). www.
specialisedservices.nhs.uk/.../Guidelines_for_Adult_Gauchers_Disease.pdf

3. Department of Health and Ageing, Australia Guidelines for the treatment of Gaucher Disease through the Life
Saving Drugs Program (September 2009). www.commcarelink.health.gov.au/.../Guidelines%20Gaucher%20
Disease.pdf

4. Canadian guidelines for treatment of Gaucher Disease by enzyme replacement with imiglucerase
or substrate reduction therapy with miglustat (Version 8; March 26, 2007) www.garrod.ca/data/.../
RevisedGaucherGuidelinesV8Mar26-07.pdf

16 Guidelines for treatment of lysosomal storage diseases

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POMPE DISEASE
INTRODUCTION

Pompe Disease is a rare autosomal recessive disease caused by the deficiency of acid
α-glucosidase (GAA), which is needed for the degradation of lysosomal glycogen. The disease
causes lysosomal glycogen to accumulate in various tissues, particularly muscle, resulting in
progressive muscle dysfunction.1 Incidence data for Pompe Disease is limited with reports
ranging from 1 in 14,000 to 1 in 300,000 depending upon ethnicity or the geographic area
studied.2

Clinically, Pompe Disease encompasses a range of phenotypes. The infantile

form presents with a generalized muscle weakness, hypotonia and a severe hypertrophic
cardiomyopathy followed by death from cardio-respiratory failure or respiratory infection usually
by age 1 year. Late onset Pompe Disease (juvenile and adult-onset) primarily presents with
skeletal and respiratory muscle weakness with minimal to no cardiac involvement and longer
survival.

Symptoms with late onset Pompe Disease may start at any age and rate of disease
progression is variable. It is associated with significant morbidity, and as the disease advances
patients often become wheelchair bound and require artificial ventilation due to respiratory
insufficiency. Most patients with infantile-onset disease have undetectable to minimal GAA
activity, whereas those with the late-onset phenotype tend to have a limited amount of residual
GAA activity.1,3,4

DISEASE MANAGEMENT AND ENZYME REPLACEMENT THERAPY

(ERT)

Until 2006, there has been no specific treatment for Pompe Disease, other than
supportive care such as symptomatic treatment of cardiomyopathy and respiratory support. A
high-protein, low-carbohydrate diet or, alternatively, a diet rich in L-alanine has shown benefit in
some but not all patients with late-onset Pompe Disease.

Since 1999 enzyme therapy with recombinant human alpha-glucosidase was investigated
as treatment for the disease. In 2006, enzyme replacement therapy with Chinese hamster ovary
cell derived recombinant human acid alpha glucosidase (alglucosidase alfa, Genzyme) was
approved by both the European Union and the US Food and Drug Administration for treatment
of patients with this otherwise devastating and lethal disease. It degrades glycogen by catalyzing
the hydrolysis of alpha 1, 4 and alpha 1, 6 glycosidic linkages of lysosomal glycogen. Till
now, ERT using alglucosidase alfa is the only approved specific treatment available for Pompe
Disease. Alglucosidase alfa has been approved by National Pharmaceutical Control Bureau for
treatment of Pompe Disease in Malaysia.

18 Guidelines for treatment of lysosomal storage diseases

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 A majority of infants in whom ERT was initiated before the age of six months and
before the need for ventilatory assistance demonstrated improved survival, ventilator-
independent survival, and acquisition of motor skills, and reduced cardiac mass compared to
untreated controls.5,6,7 The individual response to enzyme replacement therapy may vary due to
development of rhGAA specific antibodies, age of presentation and progression of disease. The
development of rhGAA antibodies may be more frequent in patients with absent GAA protein
or cross-reacting immunological material (CRIM). The absence of CRIM (CRIM negative) may
have an impact on the prognosis of patients with infantile disease. In patients with late-onset
disease, ERT may stabilize ventilatory function and motor ability, measured by six-minute walk
and upright pulmonary function testing.8,9

While ERT is effective, such chronic treatment places a burden on the individual patient,
and is costly for society. Therefore, some guidance was judged to be necessary for the selection
of patients for treatment.

DEFINITION OF INFANTILE AND LATE-ONSET DISEASE

Infantile disease:

All patients become symptomatic and diagnosed in the first two years of life with a
documented deficiency of acid alpha-glucosidase measured in lymphocytes, muscle, skin
fibroblasts. This will include “classic” infantile patients presenting with severe cardiomyopathy
in the first few months of life and also variant patients who present outside the first year of life
but suffering from early onset cardiomyopathy.

Late-onset disease:

All patients become symptomatic and diagnosed over the age of 2 years with a
documented deficiency of acid alpha-glucosidase measured in lymphocytes, muscle or skin
fibroblasts.

Guidelines for treatment of lysosomal storage diseases

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ELIGIBILITY CRITERIA FOR ENZYME REPLACEMENT THERAPY (ERT)

1. Citizen of Malaysia

The patient must be a citizen of Malaysia. Permanent residents are not eligible.

2. Confirmed diagnosis of Pompe Disease

The diagnosis of Pompe disease must have been established by one of the following
methods:

a. demonstration of specific deficiency of acid alpha-glucosidase measured in dry

blood spots, lymphocytes, skin fibroblasts or muscle;

b. the presence of acid alpha-glucosidase gene mutations known to result in severe

deficiency of enzyme activity.

3. Severity of Pompe disease

Infantile disease

a. All patients with infantile disease with cardiomyopathy, muscle weakness and/or
respiratory compromise are eligible for ERT except for patients who are already on
long term invasive ventilation for respiratory failure or in such an advance stage of
disease that will not benefit from treatment.

b. CRIM status: patients who are CRIM negative are not excluded from ERT but may
need a modified plan for enzyme therapy.

Late-onset disease

Late-onset patient with muscle weakness and/or respiratory compromise, leading

to an impaired quality of life are eligible for ERT except for patients who are already
on long term invasive ventilation for respiratory failure or in a too advance stage of the
disease prior to starting ERT.

4. Additional conditions as in Appendix A.

20 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
EXCLUSION CRITERIA

1. Patients with another life-threatening disease where prognosis is unlikely to be influenced

by enzyme replacement therapy would not be considered eligible for treatment with ERT.

2. The presence of severe or irreversible muscle/cardiac end organ damage that is not likely
to improve with ERT.

3. Refusal of the patients or caretakers to comply with the following:-

a. To be compliant with the lifelong therapy, as recommended by the ERT committee,

currently in the form of two weekly intravenous infusion.

b. To comply with the requirement to undergo regular follow up, evaluation and,
monitoring procedures as stated in the ERT guidelines.

DRUG DOSAGE

Recommended dose regimen for alglucosidase alfa is 20 mg/kg/every other week via
intravenous infusion.

CONSENT FORMS

Patients or their parents/ guardians are required to sign a consent form prior to the start
of the subsidized ERT, to be submitted at the time of application (see Appendix B).

MONITORING OF THERAPY

Patient who is on subsidized ERT are monitored at regular intervals by the Technical
Committee on ERT, basing on the data that are to be collected by the treating doctor (see
Appendix D).

Guidelines for treatment of lysosomal storage diseases

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WITHDRAWAL OF THERAPY

Subsidized ERT treatment could be withdrawn in any of the following situations: -

a. patient fails to comply adequately with treatment (defaults 2 or more infusions

over 6 months period without acceptable reason) or monitoring taken to evaluate
the effectiveness of the therapy

b. if therapy fails to relieve the symptoms of the disease that originally resulted in
the patient being approved for subsidized treatment

c. evidence of disease progression despite regular therapy including the development

of the need for 24 hour invasive ventilation indicating that the cardiorespiratory
failure is progressive

d. the muscle tone is so poor that there is no useful movement or motor development

e. development of a life threatening complication, which would compromise the

effectiveness or benefit from continued ERT, including severe infusion-related
adverse reactions or antibody-related reactions which are not preventable or
controlled by appropriate pre-medication and/or adjustment of infusion rates

22 Guidelines for treatment of lysosomal storage diseases

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REFERENCES

1. Hirschhorn R, Reuser AJJ. Glycogen storage disease type II: (acid maltase) deficiency. In: Scriver CR,
Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease
(OMMBID). New York: McGraw-Hill. Chap 135. Available at www.ommbid.com.

2. Lin CY, Hwang B, Hsiao KJ, Jin YR. Pompe’s disease in Chinese and prenatal diagnosis by determination of
alpha-glucosidase activity. J Inherit Metab Dis. 1987;10:11–7

3. van den Hout HM, Hop W, van Diggelen OP, Smeitink JA, Smit GP, Poll-The BT, Bakker HD, Loonen MC, de
Klerk JB, Reuser AJ, van der Ploeg AT. The natural course of infantile Pompe’s disease: 20 original cases
compared with 133 cases from the literature. Pediatrics. 2003;112:332–40.

4. Hagemans ML, Winkel LP, Van Doorn PA, et al. Clinical manifestation and natural course of late-onset
Pompe’s disease in 54 Dutch patients. Brain 2005;128(Pt 3):671–7.

5. Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits
in infantile-onset Pompe disease. Neurology 2007;68(2):99–109.

6. Kishnani PS, Corzo D, Leslie ND, Gruskin D, Van der Ploeg A, Clancy JP, Parini R, Morin G, Beck M, Bauer
MS, Jokic M, Tsai CE, Tsai BW, Morgan C, O’Meara T, Richards S, Tsao EC, Mandel H. Early treatment with
alglucosidase alpha prolongs long-term survival of infants with Pompe disease. Pediatr Res. 2009;66:329–35.

7. Nicolino M, Byrne B, Wraith JE, Leslie N, Mandel H, Freyer DR, Arnold GL, Pivnick EK, Ottinger CJ,
Robinson PH, Loo JC, Smitka M, Jardine P, Tatò L, Chabrol B, McCandless S, Kimura S, Mehta L, Bali D,
Skrinar A, Morgan C, Rangachari L, Corzo D, Kishnani PS. Clinical outcomes after long-term treatment with
alglucosidase alfa in infants and children with advanced Pompe disease. Genet Med. 2009;11:210–9.

8. Strothotte S, Strigl-Pill N, Grunert B, Kornblum C, Eger K, Wessig C, Deschauer M, Breunig F, Glocker FX,
Vielhaber S, Brejova A, Hilz M, Reiners K, Müller-Felber W, Mengel E, Spranger M, Schoser B. Enzyme
replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2:
12-month results of an observational clinical trial. J Neurol. 2010;257:91–7.

9. van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, Herson S, Kishnani
PS, Laforet P, Lake SL, Lange DJ, Leshner RT, Mayhew JE, Morgan C, Nozaki K, Park DJ, Pestronk A,
Rosenbloom B, Skrinar A, van Capelle CI, van der Beek NA, Wasserstein M, Zivkovic SA. A randomized study
of alglucosidase alfa in late-onset Pompe’s disease.N Engl J Med. 2010;362:1396–406.

10. American College of Medical Genetics. Pompe disease diagnosis and management guideline. Available
at www.acmg.net(pdf). 2006

11. Pompe Disease Diagnostic Working Group; Methods for a prompt and reliable laboratory diagnosis of Pompe
disease: report from an international consensus meeting. Mol Genet Metab. 2008;93:275–81.

12. Kishnani PS, Goldenberg PC, DeArmey SL, Heller J, Benjamin D, Young S, Bali D, Smith SA, Li JS, Mandel
H, Koeberl D, Rosenberg A, Chen YT. Cross-reactive immunologic material status affects treatment outcomes
in Pompe disease infants.Mol Genet Metab. 2010;99:26–33.

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 23
 Website resources

1. J.E. Wraith, P. Lee, A. Vellodi, M.A. Cleary, U. Ramaswami, Edmund Jessop. Guidelines for the Investigation
and Management of Infantile Pompe disease (2 August 2006) www.dh.gov.uk/en/Publicationsandstatistics/
Publications/PublicationsPolicyAndGuidance/DH_4137654

2. P.B. Deegan,T.M. Cox, S Waldek, R Lachmann, Uma Ramaswami, Edmund Jessop. Guidelines for the
Investigation and Management of Late Onset Acid Maltase Deficiency (Type II Glycogen Storage Disease /
Pompe Disease) (Version 3 August 2007). http://www.specialisedservices.nhs.uk/library/23/Guidelines_for_
Late_Onset_Pompe_Disease.pdf

3. Department of Health and Ageing, Australia. Guidelines for the treatment of infantile-onset Pompe disease
through the life saving drugs program . www.health.gov.au/internet/.../Infantile-Onset%20Pompe%20dis-
ease.doc

24 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
MUCOPOLYSACCHARIDOSIS
TYPE I
INTRODUCTION

Mucopolysaccharidosis Type I (MPS I) is a recessively inherited, progressive lysosomal

storage disorder due to the deficiency of an enzyme known as α-L-iduronidase. The disease
causes widespread intracellular accumulation of the glycosaminoglycans (GAG) in tissues
throughout the body. Tissues which are affected include skeleton, cartilage, liver, spleen,
ligaments, joints, heart valves, airways, corneas and in some forms, the brain.1

Patients with MPS I are classified into three clinical syndromes based on their symptoms
and the severity of their symptoms – Hurler, Hurler-Scheie and Scheie. Hurler syndrome is the
most severe clinical phenotype; Hurler-Scheie syndrome is an intermediate clinical phenotype;
and Scheie syndrome is a milder clinical phenotype.1,2

Hurler syndrome (MPS IH) is characterized by facial and skeletal deformities, cardiac
disease, respiratory difficulties and mental retardation/ regression. In Scheie syndrome (MPS
IS), joint stiffness, aortic valve disease and corneal clouding are the leading symptoms. Patients
with Scheie syndrome are of normal intelligence and may have a near normal life-span. Hurler-
Scheie syndrome (MPS IH-S) is an intermediate clinical phenotype and clinical features include
short stature, coarse facies, corneal clouding, joint stiffness, deafness, valvular heart disease
and there is usually little or no intellectual dysfunction.1,2 MPS I is seen in all populations at a
frequency of approximately 1:100,000 for the severe form and 1:500,000 for the attenuated
form.3

DISEASE MANAGEMENT AND ENZYME REPLACEMENT THERAPY

The treatment of MPS I has mostly been symptomatic, involving orthopaedic,

otolaryngological, cardiac, ophthalmological and neurosurgical interventions. Bone marrow
transplantation (BMT) or hematopoietic stem cell transplantation (HSCT) has been used
successfully in patients with MPS IH and has been shown to maintain intellectual function
in many patients. While such transplants greatly improve many of the symptoms of MPS I,
significant skeletal problems still develop.4,5

In 2003, enzyme replacement therapy (ERT) with Chinese hamster ovary cell derived
recombinant human α-L-iduronidase ( Laronidase, Genzyme), was approved by both the
European Union and the US Food and Drug Administration for long term treatment of patients
with MPS I. Laronidase has been approved by National Pharmaceutical Control Bureau for
treatment of MPS I in Malaysia.

26 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
 In clinical studies, Laronidase has been shown to improve respiratory function, distance
walked in 6 minutes, range of movements of joints, sleep disordered breathing and result in a
reduction of urinary GAGs. Some tissues such as bone respond poorly to ERT. No benefit to
the brain or nervous system has been demonstrated.6-10 Therefore, BMT/HSCT will still be
the treatment of choice for patients with MPS IH. This procedure should be performed within
the first years of life to prevent irreversible damage to the brain; however, ERT may also be of
importance for young patients with MPS IH, as it may improve general lung and heart function,
making BMT/HSCT easier to tolerate.5

In view of the very high cost of treatment, wide variation in the extent of ERT benefit,
and the risk and inconvenience associated with the need for frequent intravenous injections;
guidelines are necessary for the selection of patients for treatment with the newly available
intervention.

ELIGIBILITY CRITERIA FOR ENZYME REPLACEMENT THERAPY (ERT)

1. Citizen of Malaysia

The patient must be a citizen of Malaysia. Permanent residents are not eligible.

2. Confirmed diagnosis of MPS I

The diagnosis of MPS I must have been established by the demonstration of specific
deficiency of α-L-Iduronidase measured in lymphocytes or skin fibroblasts. The diagnosis
can also be confirmed by the presence of mutations in the α-L-Iduronidase gene known
to result in severe deficiency of enzyme activity.

3. Severity of disease

a. Patient has little or no cognitive impairment (IQ >70).

b. Patient should have a minimal level of disease severity in order to be considered

for ERT. At least one or more of the following should be present :-

i. Sleep Disordered Breathing

Patients with an apnoea/hypopnoea incidence of > 5 events/hour of total sleep

time or more than 2 severe episodes of desaturation (oxygen saturation <80%) in
an overnight sleep study

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 27
 ii. Respiratory Function Tests

Patients with FVC less than 80% of predicted value for height

iii. Cardiac

Myocardial dysfunction as indicated by a reduction in ejection fraction to less than

56% (Normal Range 56-78%) OR a reduction in fractional shortening to <25%
(normal range 2546%)

iv. Joint Contractures

Patients developing restricted range of movement of joints of greater than 10

degrees from normal in shoulders, neck, hips, knees, elbows or hands

Patients with little or no cognitive impairment (MPS IS or I H-S) who fail to meet above
criteria should be followed up in a systematic way with annual assessments designed to
detect deterioration in their clinical condition. In this way they may be identified as suitable
for treatment with ERT at a later date.

As Laronidase has only been shown to improve the non-neurological features of MPS I,
there is no indication for long term treatment in MPS IH patients who have not had or are not
planning to have a bone marrow transplant. BMT/HSCT transplant remains the treatment
of choice for MPS IH.

4. Option of BMT/HSCT

All patients who are less than 2 years old and have normal IQ [>70] should be offered
work up for BMT/HSCT if there is suitable donor.

5. Additional conditions as in Appendix A.

28 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
EXCLUSION CRITERIA

1. Patients with another life-threatening disease where prognosis is unlikely to be influenced

by enzyme replacement therapy would not be considered eligible for treatment with ERT.

2. The presence of severe or irreversible end organ damage that is not likely to improve with
ERT.

3. Patients with evidence of significant learning difficulties and/or progressive

neuropsychological deterioration.

4. Refusal of the patients or caretakers to comply with the following:-

a. To be compliant with the lifelong therapy, as recommended by the ERT committee,

currently in the form of weekly intravenous infusion.

b. To comply with the requirement to undergo regular follow up, evaluation and,
monitoring procedures as recommended by the ERT committee, for the purpose of
evaluating treatment efficacy and complication of the disease.

DRUG DOSAGE

Recommended dose regimen for Loranidase is 100U/kg/week via intravenous infusion.

CONSENT FORMS

Patients or their parents/ guardians are required to sign a consent form prior to the start
of the subsidized ERT, to be submitted at the time of application (see Appendix B).

MONITORING OF THERAPY

Patient who is on subsidized ERT are monitored at regular intervals by the Technical
Committee on ERT, basing on the data that are to be collected by the treating doctor (see
Appendix E).

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 29
WITHDRAWAL OF THERAPY

Subsidized ERT treatment could be withdrawn in any of the following situations:-

a. If the patient develops progressive neurological decline.

b. If the patient fails to comply with the therapy, follow up, evaluation and assessment
procedure as recommended by the ERT guidelines.

c. If the patient develops another unrelated life threatening diseases/ conditions

or severe diseases/condition that is likely to shorten his/her Iife span and life
quality, in which he/she will not gain benefit from ERT for MPS I disease.

d. If the patient develops a life threatening complication, which would compromise

the effectiveness or benefit from continued ERT, including severe infusion-related
adverse reactions or antibody-related reactions which are not preventable or
controlled by appropriate pre-medication and/or adjustment of infusion rates

e. If the patient develops irreversible or severe life threatening complications of MPS

I that will not benefit from further ERT. For example: cardiac failure secondary to
severe mitral regurgitation.

30 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
REFERENCES

1. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B
(eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 136.
Available at www.ommbid.com.

2. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J
Pediatr.2004;144:S27–34.

3. Lowry RB, Applegarth DA, Toone JR, MacDonald E, Thunem NY. An update on the frequency of mucopolysaccharide
syndromes in British Columbia. Hum Genet. 1990;85:389–90.

4. Braunlin EA, Stauffer NR, Peters CH, Bass JL, Berry JM, Hopwood JJ, Krivit W. Usefulness of bone marrow
transplantation in the Hurler syndrome. Am J Cardiol. 2003;92:882–6.

5. Cox-Brinkman J, Boelens JJ, Wraith JE. Haematopoietic cell transplantation (HCT) in combination with enzyme
replacement therapy (ERT) in patients with Hurler syndrome. Bone Marrow Transplant. 2006;38:17–21.

6. Wraith EJ, Hopwood JJ, Fuller M, Meikle PJ, Brooks DA. Laronidase treatment of mucopolysaccharidosis
I. BioDrugs.2005;19:1–7.

7. Coppa GV, Buzzega D, Zampini L, Maccari F, Galeazzi T, Pederzoli F, Gabrielli O, Volpi N. Effect of 6 years of
enzyme replacement therapy on plasma and urine glycosaminoglycans in attenuated MPS I patients. Glycobiology.
2010 Oct;20(10):1259-73

8. Tylki-Szymanska A, Marucha J, Jurecka A, Syczewska M, Czartoryska B. Efficacy of recombinant human alpha-

L-iduronidase (laronidase) on restricted range of motion of upper extremities in mucopolysaccharidosis type I
patients. J Inherit Metab Dis. 2010 Apr;33(2):151-7

9. Clarke LA, Wraith JE, Beck M, Kolodny EH, Pastores GM, Muenzer J, Rapoport DM, Berger KI, Sidman
M, Kakkis ED, Cox GF. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I.
Pediatrics. 2009 Jan;123(1):229-40.

10. Wraith JE. The first 5 years of clinical experience with laronidase enzyme replacement therapy for
mucopolysaccharidosis I. Expert Opin Pharmacother. 2005 Mar;6(3):489-506.

Website resources

1. J.E. Wraith, A. Vellodi, M.A. Cleary, U. Ramaswami, C. Lavery Edmund Jessop. Guidelines for the Investigation
and Management of Mucopolysaccharidosis type I. www.specialisedservices.nhs.uk/.../Guidelines_for_
Mucopolysaccharidosis_Type_I.pdf

2. Department of Health and Ageing, Australia. Guidelines for the treatment of Mucopolysaccharidosis type I (MPS
I) disease through life saving drugs programe. www.health.gov.au/internet/main/publishing.nsf/Content/.../
MPS%20I.doc

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 31
MUCOPOLYSACCHARIDOSIS
TYPE II
INTRODUCTION

Mucopolysaccharidosis Type II (MPS II, Hunter disease) is caused by a deficiency

of the lysosomal enzyme iduronate-2-sulphatase, which catalyzes a step in the stepwise
degradation of the glycosaminoglycans, heparin sulphate (HS) and dermatan sulphate (DS).
The enzyme deficiency will lead to progressive accumulation of partially degraded HS and DS
in the lysosomes of cells in almost all tissues and organs. Tissues which are markedly affected
include the liver and spleen and, to a lesser extent, skin, bone, cartilage, ligaments, heart valves,
airways, meninges, and corneas.1,2 Several surveys suggest MPS II has an incidence between
1:100,000 and 1:170,000 male births.3,4

MPS II is a rare X-linked disorder which typically affects the males but has also rarely
been reported in females. The disease is progressive and eventually results in death, most
commonly due to respiratory or/and cardiac failure. However, the severity varies and could
range from the mild to severe. The severe form of MPS II is more common, has an early age
of onset, usually between 1-4 years of age, and involves the central nervous system leading
to intellectual impairment and progressive neurodegeneration. Other clinical features include
coarse facies, growth retardation, joint stiffness, communicating hydrocephalus, chronic
diarrhoea, sensorineural deafness, compression of the cervical cord, chronic respiratory disease,
degeneration of the retina and cardiac valvular disease. The course is rapidly progressive and
leads to death usually between 10 and 20 years of age.1,2,5

The attenuated form of MPS II has a later onset and has a slower rate of progression.
There is little or no involvement of the central nervous system so intelligence is preserved. The
somatic features are similar to, but milder than the severe form. Short stature, joint stiffness,
early-onset osteoarthritis, carpal tunnel syndrome, cardiac valvular disease, cervical cord
compression and sensorineural hearing loss are common features. Survival to the fifth or sixth
decade occurs although deaths from the late teenage years have been reported.1

DISEASE MANAGEMENT AND ENZYME REPLACEMENT THERAPY (ERT)

Treatment of MPS II has generally been symptomatic, involving orthopaedic,

otolaryngological, cardiac, respiratory and neurosurgical interventions. Unlike MPS I,
Haematopietic stem cell transplant (HSCT) does not prevent neurodegeneration and is not
recommended for the treatment of MPS II.2,5

In 2006, a recombinant form of human iduronate 2-sulfatase (idursulfase, Genzyme)

has been approved in the United States and the European Union for the treatment of MPS II.
Idursulfase has been approved by National Pharmaceutical Control Bureau for treatment of
MPS I in Malaysia.

34 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
 In clinical studies, idursulfase has been shown to improve respiratory function, distance
walked in 6 minutes, , liver and spleen size and produce significant reductions in urinary GAGs.
Idursulfase does not cross the blood-brain barrier and there is no evidence to support and no
expectation that the neurological features will be improved by ERT.5-10

In view of the very high cost of treatment, wide variation in the extent of ERT benefit,
and the risk and inconvenience associated with the need for frequent intravenous injections;
guidelines are necessary for the selection of patients for this intervention.

ELIGIBILITY CRITERIA FOR ENZYME REPLACEMENT THERAPY (ERT)

1. Citizen of Malaysia

The patient must be a citizen of Malaysia. Permanent residents are not eligible.

2. Confirmed diagnosis of MPS I

The patient has been confirmed to have the disease by the demonstration of absent
or deficient Iduronate-2-Sulphatase activity in any of the following tissues/body fluid:
serum, leucocytes and fibroblast. The diagnosis can also be confirmed by the presence
of iduronate-2-sulphatase gene mutations known to result in severe deficiency of enzyme
activity.

3. Severity of disease

a. Patient has little or no cognitive impairment (IQ >70).

b. Patient should have a minimal level of disease severity in order to be considered

for ERT. At least one or more of the following should be present:-

i. Sleep Disordered Breathing

Patients with an apnoea/hypopnoea incidence of > 5 events/hour of total

sleep time or more than 2 severe episodes of desaturation (oxygen saturation
<80%) in an overnight sleep study

ii. Respiratory Function Tests

Patients with FVC less than 80% of predicted value for height

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 35
 iii. Cardiac

Myocardial dysfunction as indicated by a reduction in ejection fraction to less

than 56% (Normal Range 56-78%) OR a reduction in fractional shortening to
<25% (normal range 2546%)

iv. Joint Contractures

Patients developing restricted range of movement of joints of greater than 10

degrees from normal in shoulders, neck, hips, knees, elbows or hands

Patients with little or no cognitive impairment who fail to meet above criteria should be
followed up in a systematic way with annual assessments designed to detect deterioration
in their clinical condition. In this way they may be identified as suitable for treatment with
ERT at a later date.

Uncertainty around neurological involvement

The Committee recognizes that it is often difficult to distinguish between the severe
and attenuated forms of MPS II early in life. Where the clinical assessment suggests
mild/early neurological involvement, and potential but not conclusive severe CNS form
of MPS II, the Committee may consider a trial of treatment, with frequent review of MRI
and neuropsychological assessments, to be performed by a qualified neuropsycholo-
gist. The identification of evidence of neurological impairment will lead to the withdrawal
of therapy. The Committee are aware that this will be a very difficult process for families
and recommends the discussion of these issues prior to the commencement of therapy.

4. Additional conditions as in Appendix A.

36 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
EXCLUSION CRITERIA

1. Patients with another life-threatening disease where prognosis is unlikely to be influenced

by enzyme replacement therapy would not be considered eligible for treatment with ERT.

2. The presence of severe or irreversible end organ damage that is not likely to improve with
ERT.

3. Patients with evidence of significant learning difficulties and/or progressive

neuropsychological deterioration.

4. Refusal of the patients or caretakers to comply with the following:-

a. To comply with the lifelong weekly intravenous infusion therapy as recommended

by the ERT committee’.

b. To comply with the requirement to undergo regular follow up, evaluation and,
monitoring procedures as recommended by the ERT committee, for the purpose of
evaluating treatment efficacy and complication of the disease.

DRUG DOSAGE

Recommended dose regimen for idursulfase is 0.5 mg/kg weekly via intravenous infusion.

CONSENT FORMS

Patients or their parents/ guardians are required to sign a consent form prior to the start
of the subsidized ERT, to be submitted at the time of application (see Appendix B).

MONITORING OF THERAPY

Patient who is on subsidized ERT are monitored at regular intervals by the Technical
Committee on ERT, basing on the data that are to be collected by the treating doctor (see
Appendix E).

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 37
WITHDRAWAL OF THERAPY

Subsidized ERT treatment could be withdrawn in any of the following situations: -

a. If the patient develops progressive neurological decline. This would indicate that
the child has the severe form of Hunter disease

b. b.If the patient fails to comply with the therapy, follow up, evaluation and assessment
procedure as recommended by the ERT guidelines.

c. c.If the patient develops another unrelated life threatening diseases/ conditions or
severe diseases/condition that is likely to shorten his/her Iife span and life quality,
in which he/she will not gain benefit from ERT for MPS II disease.

d. d.If the patient develops a life threatening complication, which would compromise
the effectiveness or benefit from continued ERT, including severe infusion-related
adverse reactions or antibody-related reactions which are not preventable or
controlled by appropriate pre-medication and/or adjustment of infusion rates

e. e.If the patient develops irreversible or severe life threatening complications of MPS
II that will not benefit from further ERT. For example: cardiac failure secondary to
severe mitral regurgitation.

38 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
REFERENCES

1. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B
(eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 136.
Available at www.ommbid.com.

2. Wraith JE, Scarpa M, Beck M, Bodamer OA, De Meirleir L, Guffon N, Meldgaard Lund A, Malm G, Van der
Ploeg AT, Zeman J. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for
treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008;167(3):267–77.

3. Baehner F, Schmiedeskamp C, Krummenauer F, Miebach E, Bajbouj M, Whybra C, Kohlschutter A, Kampmann C,

Beck M. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis. 2005;28:1011–
7.

4. Nelson J, Crowhurst J, Carey B, Greed L. Incidence of the mucopolysaccharidoses in Western Australia. Am J Med
Genet A. 2003;123A(3):310–3.

5. Muenzer J, Beck M, Eng CM, Escolar ML, Giugliani R, Guffon NH, Harmatz P, Kamin W, Kampmann C, Koseoglu
ST, Link B, Martin RA, Molter DW, Muñoz Rojas MV, Ogilvie JW, Parini R, Ramaswami U, Scarpa M, Schwartz
IV, Wood RE, Wraith E. Multidisciplinary management of Hunter syndrome. Pediatrics. 2009;124(6):e1228–39.

6. Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, Vellodi A, Martin R, Ramaswami U, Gucsavas-
Calikoglu M, Vijayaraghavan S, Wendt S, Puga AC, Ulbrich B, Shinawi M, Cleary M, Piper D, Conway AM, Kimura
A. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter
syndrome). Genet Med.2006;8:465–73

7. Schulze-Frenking G, Jones SA, Roberts J, Beck M, Wraith JE. Effects of enzyme replacement therapy on growth
in patients with mucopolysaccharidosis type II. J Inherit Metab Dis. 2011;34:203–8. Wraith JE, Beck M, Giugliani
R, Clarke J, Martin R, Muenzer J., HOS Investigators. Initial report from the Hunter Outcome Survey. Genet
Med. 2008;10:508–16.

8. Muenzer J, Gucsavas-Calikoglu M, McCandless SE, et al. A phase 1/11 clinical trial of enzyme replacement
therapy in mucopolysaccharidosis 1/(Hunter syndrome). Mol Genet Metab 1997;90:329-37

9. Manara R, Rampazzo A, Cananzi M, Salviati L, Mardari R, Drigo P, Tomanin R, Gasparotto N, Priante E, Scarpa M.
Hunter syndrome in an 11-year old girl on enzyme replacement therapy with idursulfase: brain magnetic resonance
imaging features and evolution. J Inherit Metab Dis. 2010

Website resources

1. Department of Health and Ageing, Australia. Guidelines for the treatment of MucopolysacharidosisType II (MPS II)
disease through life saving drugs programe.

www.health.gov.au/internet/main/publishing.nsf/.../lsdp.../MPS%20II.doc

3. A. Vellodi, J.E. Wraith, M.A. Cleary, U. Ramaswami, C. Lavery, Edmund Jessop. Guidelines for the Investigation
and Management of Mucopolysaccharidosis type II.

www.specialisedservices.nhs.uk/.../Guidelines_for_Mucopolysaccharidosis_Type_II.pdf

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 39
MUCOPOLYSACCHARIDOSIS
TYPE VI
INTRODUCTION

Mucopolysaccharidosis Type VI (MPS VI) or also known as Maroteaux–Lamy syndrome

is an autosomal recessive lysosomal storage disorder (LSD) that results from a deficiency in the
lysosomal enzyme, N-acetylgalactosamine-4-sulphatase ( also known as arylsulphatase B). This
enzyme deficiency leads to the intracellular accumulation and urinary excretion of undegraded/
partially degraded dermatan sulphate and chondroitin sulphate glycosaminoglycans.1

MPS VI patients can present with a spectrum of clinical phenotypes. The classical
symptoms of MPS VI include short stature, hepatosplenomegaly, dysostosis multiplex, joint
stiffness, corneal clouding, cardiac abnormalities, and facial dysmorphia. Severely affected
patients suffer early onset symptoms with rapid disease progression, while patients at the
attenuated end of the clinical spectrum have a later onset and variable clinical presentation. In
the severe form of MPS VI, death usually occurs in the early teenage years due to respiratory
and cardiac problems, while in patients with the attenuated form, lifespan can be up to 50 or
more years in some cases. In contrast to many of the MPS disorders, MPS VI is not typically
associated with progressive impairment of mental status, although physical limitations may
impact learning and development. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160
live births.1,2

DISEASE MANAGEMENT AND ENZYME REPLACEMENT THERAPY (ERT)

In the past, limited treatment options for MPS VI led many clinicians to adopt a palliative
approach and focus primarily on management of individual disease complications such as
physical therapy to minimize joint contractures and stiffness and improve muscle strength,
spinal fusion for spinal cord compression or progressive kyphosis, hernia repair, tonsillectomy
and adenoidectomy for airway obstruction or eustachian tube dysfunction.

Historically, HSCT had been the only specific therapy available for MPS VI. Successful
HSCT has benefited a small number of patients with MPS VI. In 2006, enzyme replacement therapy
(ERT) with Chinese hamster ovary cell derived recombinant human N-acetylgalactosamine-
4-sulphatase (Recombinant Human Arylsulfatase B or rhASB; Galsulfase; Biomarin), was
approved by both the European Union and the US Food and Drug Administration for long term
treatment of patients with MPS VI. In clinical studies, Galsulfase has been shown to improve
respiratory function, distance walked in 6 minutes, liver and spleen size and produce significant
reductions in urinary GAGs,.

While ERT is effective, such chronic treatment places a burden on the individual patient,
and is costly for society. Therefore, some guidance is judged to be necessary for the selection
of patients for treatment.

42 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
ELIGIBILITY CRITERIA FOR ENZYME REPLACEMENT THERAPY (ERT)

1. Citizen of Malaysia

The patient must be a citizen of Malaysia. Permanent residents are not eligible.

2. Confirmed diagnosis of MPS VI

The diagnosis of MPS I has been established by the demonstration of specific

deficiency of N-acetylgalactosamine-4-sulphatase (arylsulphatase B) measured in
lymphocytes or skin fibroblasts. The diagnosis can also be confirmed by the presence of
N-acetylgalactosamine-4-sulphatase/ arylsulphatase B gene mutations known to result in
severe deficiency of enzyme activity.

3. Severity of the disease

Patient should have a minimal level of disease severity in order to be considered for ERT.
At least one or more of the following should be present:-

a. Sleep Disordered Breathing

Patients with an apnoea/hypopnoea incidence of > 5 events/hour of total sleep

time or more than 2 severe episodes of desaturation (oxygen saturation <80%) in
an overnight sleep study

b. Respiratory Function Tests

Patients with FVC less than 80% of predicted value for height

c. Cardiac

Myocardial dysfunction as indicated by a reduction in ejection fraction to less than

56% (Normal Range 56-78%) OR a reduction in fractional shortening to <25%
(normal range 2546%)

d. Joint Contractures

Patients developing restricted range of movement of joints of greater than 10

degrees from normal in shoulders, neck, hips, knees, elbows or hands

Patients who fail to meet above criteria should be followed up in a systematic way with
annual assessments designed to detect deterioration in their clinical condition. In this way
they may be identified as suitable for treatment with ERT at a later date.

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 43
 Special circumstance
Hydrocephalus:

To date there is limited data on the response of hydrocephalus to enzyme re-

placement therapy. Each case will be considered on its merits. In general,
enzyme replacement therapy would be recommended in addition to surgery
rather than as an alternative to surgery.

Spinal cord compression:

Some patients receiving enzyme replacement therapy have developed spinal

cord compression. Although each case will be considered on its merits, surgery
remains the preferred treatment for this complication.

4. Additional conditions as in Appendix A.

EXCLUSION CRITERIA

1. Patients with another life-threatening disease where prognosis is unlikely to be influenced

by enzyme replacement therapy would not be considered eligible for treatment with ERT.

2. The presence of severe or irreversible end organ damage that is not likely to improve with
ERT.

3. Patients with evidence of significant learning difficulties.

4. Refusal of the patients or caretakers to comply with the following:-

a. To comply with the lifelong weekly intravenous infusion therapy as recommended

by the ERT guidelines.

b. To comply with the requirement to undergo regular follow up, evaluation and,
monitoring procedures as recommended by the ERT guidelines, for the purpose of
evaluating treatment efficacy and complication of the disease.

44 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
DRUG DOSAGE

Recommended dose regimen for Galsulfase is 1mg/kg weekly via intravenous infusion.

CONSENT FORMS

Patients or their parents/ guardians are required to sign a consent form prior to the start
of the subsidized ERT, to be submitted at the time of application (see Appendix B).

MONITORING OF THERAPY

Patient who is on subsidized ERT are monitored at regular intervals by the Technical
Committee on ERT, basing on the data that are to be collected by the treating doctor (see
Appendix E).

WITHDRAWAL OF THERAPY

Subsidized ERT treatment could be withdrawn in any of the following situations: -

a. If the patient develops progressive neurological decline.

b. If the patient fails to comply with the therapy, follow up, evaluation and assessment
procedure as recommended by the ERT guidelines.

c. If the patient develops another unrelated life threatening diseases/conditions or

severe diseases/condition that is likely to shorten his/her Iife span and life quality,
in which he/she will not gain benefit from ERT for MPS VI disease.

d. If the patient develops a life threatening complication, which would compromise

the effectiveness or benefit from continued ERT, including severe infusion-related
adverse reactions or antibody-related reactions which are not preventable or
controlled by appropriate pre-medication and/or adjustment of infusion rates

e. If the patient develops irreversible or severe life threatening complications of MPS

VI that will not benefit from further ERT. For example: cardiac failure secondary to
severe mitral regurgitation.

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 45
REFERENCES

1. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B
(eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 136.
Available at www.ommbid.com.

2. Valayannopoulos V, Nicely H, Harmatz P, Turbeville S. Mucopolysaccharidosis VI. Orphanet J Rare Dis. 2010 Apr
12;5:5. Review.

3. Turbeville S, Nicely H, Rizzo JD, Pedersen TL, Orchard PJ, Horwitz ME, Horwitz EM, Veys P, Bonfim C, Al-Seraihy
A. Clinical outcomes following hematopoietic stem cell transplantation for the treatment of mucopolysaccharidosis
VI. Mol Genet Metab. 2011 Feb;102(2):111-5.

4. Harmatz P. Enzyme replacement therapy with galsulfase for mucopolysaccharidosis VI: clinical facts and figures.
Turk J Pediatr. 2010 Sep-Oct;52(5):443-9. Review

5. Lin HY, Chen MR, Chuang CK, Chen CP, Lin DS, Chien YH, Ke YY, Tsai FJ, Pan HP, Lin SJ, Hwu WL, Niu DM,
Lee NC, Lin SP. Enzyme replacement therapy for mucopolysaccharidosis VI-experience in Taiwan. J Inherit Metab
Dis. 2010 Oct 6. [Epub ahead of print]

6. Auclair D, Hopwood JJ, Brooks DA, Lemontt JF, Crawley AC: Replacement therapy in Mucopolysaccharidosis
type VI: advantages of early onset of therapy. Mol Genet Metab 2003, 78:163-174.

7. Harmatz P, Giugliani R, Schwartz I, Guffon N, Teles EL, Miranda MC, et al. Enzyme replacement therapy for
mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recom-
binant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on,
open-label extension study. J Pediatr 2006, 148:533-539.

8. Harmatz P, Giugliani R, Schwartz IV, Guffon N, Teles EL, Miranda MC, et al.: Long-term follow-up of endurance and
safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical
studies of recombinant human N-acetylgalactosamine 4-sulfatase. Mol Genet Metab 2008, 94:469-475.

9. Harmatz P, Yu ZF, Giugliani R, Schwartz IV, Guffon N, Teles EL, et al. Enzyme replacement therapy for muco-
polysaccharidosis VI: evaluation of long-term pulmonary function in patients treated with recombinant human N-
acetylgalactosamine 4-sulfatase. J Inherit Metab Dis 2010, 33(1):51-60.

10. R Giugliani, P Harmatz, JE Wraith. Management Guidelines for Mucopolysaccharidosis VI. Pediatrics 2007;120(2)
doi:10.1542/peds.2006-2184

Website resources

1. J.E. Wraith, A. Vellodi, M.A. Cleary, U. Ramaswami, C. Lavery, Edmund Jessop. Guidelines for the Investiga-
tion and Management of Mucopolysaccharidosis type VI. www.specialisedservices.nhs.uk/.../Guidelines_for_Mu-
copolysaccharidosis_Type_VI.pdf

2. Department of Health and Ageing, Australia. Guidelines for the treatment of Mucopolysaccharidosis Type VI (MPS
VI) disease through life saving programme. www.health.gov.au/internet/main/publishing.nsf/.../lsdp.../MPS%20VI.
doc

46 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
FABRY DISEASE
INTRODUCTION

Fabry Disease is an X-linked disorder caused by the deficiency of the lysosomal

enzyme αGalactosidase A (α-Gal A). The deficiency of the enzyme causes accumulation
of globotriaosylceramide (GL-3) and related glycolipids in tissues and body fluids. GL-3
accumulation affects many cell types, including vascular endothelium, various renal cell types,
and epithelial and smooth-muscle cells of the cardiovascular and renal systems.1

The classic form, occurring in males with less than 1% α-Gal A enzyme activity, usually
has its onset in childhood or adolescence with periodic crises of severe pain in the extremities
(acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas),
hypohidrosis, characteristic corneal and lenticular opacities, and proteinuria. Gradual
deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in
the third to fifth decade. In middle age, most males successfully treated for ESRD develop
cardiovascular and/or cerebrovascular disease, a major cause of morbidity and mortality.1,2

Males with greater than 1% α-Gal A activity may have either (1) a cardiac
variant phenotype that usually presents in the sixth to eighth decade with left ventricular
hypertrophy, mitral insufficiency and/or cardiomyopathy, and proteinuria, but without ESRD;
or (2) a renal variant phenotype associated with ESRD but without the skin lesions or pain.1,2,3

Heterozygous females typically have milder symptoms at a later age of onset than
males. Rarely, they may be relatively asymptomatic throughout a normal life span or may have
symptoms as severe as those observed in males with the classic phenotype.4

DISEASE MANAGEMENT AND ENZYME REPLACEMENT THERAPY (ERT)

Prior to the introduction of enzyme replacement therapy, treatment of Fabry Disease

was symptomatic and included dialysis, renal transplantation, and neurotropic analgesics. ERT
was evaluated in clinical trials during the late 1990s leading to the commercial availability of
two enzyme formulations: agalsidase beta/Fabrazyme (Genzyme) and agalsidase alfa (Shire
Human Genetic Therapies). Agalsidase alfa is produced using a genetically engineered human
fibroblast cell line; whereas agalsidase beta is produced using a Chinese hamster ovary cell
line. Biochemical comparison studies have shown that both preparations are structurally and
functionally very similar. Fabrazyme has been approved by National Pharmaceutical Control
Bureau for ERT of Fabry Disease in Malaysia.

Clinical studies have demonstrated that ERT may prevent irreversible end-organ
damage in Fabry Disease from chronic GL-3 deposition. ERT has been shown to decrease pain
and to stabilize renal function.5-14

48 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
ELIGIBILITY CRITERIA FOR ENZYME REPLACEMENT THERAPY (ERT)

1. Citizen of Malaysia

The patient must be a citizen of Malaysia. Permanent residents are not eligible.

2. Confirmed diagnosis of Fabry disease

a. In males, the diagnosis must have been established by the demonstration of

specific deficiency of alpha galactosidase A measured in lymphocytes, plasma
or cultured cells.sThe diagnosis can also be confirmed by the presence of alpha
galactosidase A gene mutations known to result in severe deficiency of enzyme
activity.

b. In females, DNA analysis is essential as enzymatic levels of the female heterozygote

may lie within the normal range. In cases where DNA analysis is

non-conclusive examination of urine for globotriaosylceramide (GL-3) and cornea

for verticillata may assist in the diagnosis.

3. Severity of disease

Patients must meet the criteria of at least one of the following four Fabry related diseases:-

a. Fabry-related renal disease

All patients:

Confirmation by renal biopsy is recommended to:

i. provide prognostic information;

ii. exclude other causes of nephropathy;

iii. demonstrate evidence of focal glomerular sclerosis or fibrosis greater,

then that expected for age, once other causes of nephropathy have been
excluded; and

iv. document significant histological changes related to Fabry disease.

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 49
 Male Fabry patients:

i. proteinuria >300mg/24 hours with clinical evidence of progression; or

ii. abnormal albumin excretion rate (> 20µg/min ) as determined by 2 separate

samples, at least 24 hours apart; or

iii. albumin:creatinine ratio greater than upper limit of normal, in 2 separate

samples, at least 24 hours apart.

Female Fabry patients:

i. proteinuria >300mg/24 hours with clinical evidence of progression.

b. Fabry-related cardiac disease

i. Left ventricular hypertrophy, as evidenced by cardiac MRI or

echocardiogram data, in the absence of hypertension or other causes. If
hypertension is present, it should be treated optimally for at least 6 months
prior to the submission of an ERT application through this criterion.

ii. Significant life threatening arrhythmia or conduction defect.

iii. Valvular thickening/insufficiency.

c. Fabry-related ischaemic vascular disease

i. Stroke or transient ischaemic attacks (minumum 3 documented TIAs) at

age less than 50 with no other cause identified.

ii. Documented progression of white matter microvascular disease with MRI

with no other cause identified.

d. Fabry-related neuropathic pain

i. Uncontrolled chronic pain despite the use of maximum doses of analgesics

and no other cuase identified.

50 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
4. Additional conditions as in Appendix A.

EXCLUSION CRITERIA

1. Patients with another life-threatening disease where prognosis is unlikely to be influenced

by enzyme replacement therapy would not be considered eligible for treatment with ERT.

2. The presence of severe or irreversible end organ damage that is not likely to improve with
ERT.

3. Patients with evidence of significant learning difficulties.

4. Refusal of the patients or caretakers to comply with the following:-

a. Totcomply with the lifelong 2 weekly intravenous infusion therapy, as recommended

by the ERT committee.

b. To comply with the requirement to undergo regular follow up, evaluation and,
monitoring procedures as recommended by the ERT guidelines, for the purpose of
evaluating treatment efficacy and complication of the disease.

DRUG DOSAGE

Recommended dose regimen for agalsidase beta is 1mg/kg intravenously every two
weeks.

Adjunctive therapies: ERT must be supplemented by optimal treatment with

analgesics, reno-protective, cardio-protective and vasculo-protective medications as indicated.

CONSENT FORMS

Patients or their parents/ guardians are required to sign a consent form prior to the start
of the subsidized ERT, to be submitted at the time of application (see Appendix B).

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 51
MONITORING OF THERAPY

Patient who is on subsidized ERT are monitored at regular intervals by the Technical
Committee on ERT, basing on with the data that are to be collected by the treating doctor (see
Appendix F).

WITHDRAWAL OF THERAPY

Subsidized ERT treatment could be withdrawn in any of the following situations:

a. If the patient develops progressive neurological decline.

b. If the patient fails to comply with the therapy, follow up, evaluation and assessment
procedure as recommended by the ERT guidelines.

c. If the patient develops another unrelated life threatening diseases/ conditions or

severe diseases/condition that is likely to shorten his/her Iife span and life quality,
in which he/she will not gain benefit from ERT for Fabry disease.

d. If the patient develops a life threatening complication, which would compromise

the effectiveness or benefit from continued ERT, including severe infusion-related
adverse reactions or antibody-related reactions which are not preventable or
controlled by appropriate pre-medication and/or adjustment of infusion rates

e. If the patient develops irreversible or severe life threatening complications of Fabry

Disease that will not benefit from further ERT.

52 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
REFERENCES

1. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL,
Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New
York: McGraw-Hill. Chap 150. Available at www.ommbid.com.

2. Ries M, Gupta S, Moore DF, Sachdev V, Quirk JM, Murray GJ, Rosing DR, Robinson C, Schaefer E, Gal A,
Dambrosia JM, Garman SC, Brady RO, Schiffmann R. Pediatric Fabry disease. Pediatrics. 2005;115:e344–55.

3. Linhart A, Kampmann C, Zamorano JL, Sunder-Plassmann G, Beck M, Mehta A, Elliott PM. Cardiac manifestations
of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J. 2007;28:1228–35.

4. Deegan PB, Baehner AF, Barba Romero MA, Hughes DA, Kampmann C, Beck M. Natural history of Fabry disease
in females in the Fabry Outcome Survey. J Med Genet. 2006;43:347–52.

5. Hoffmann B, Beck M, Sunder-Plassmann G, Borsini W, Ricci R, Mehta A. Nature and prevalence of pain in Fabry
disease and its response to enzyme replacement therapy--a retrospective analysis from the Fabry Outcome
Survey. Clin J Pain.2007a;23:535–42.

6. Hoffmann B, Schwarz M, Mehta A, Keshav S. Fabry Outcome Survey European Investigators; Gastrointestinal
symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy. Clin
Gastroenterol Hepatol.2007b;5:1447–53.

7. Hoffmann B, Garcia de Lorenzo A, Mehta A, Beck M, Widmer U, Ricci R. Effects of enzyme replacement therapy
on pain and health related quality of life in patients with Fabry disease: data from FOS (Fabry Outcome Survey). J
Med Genet.2005;42:247–52.

8. Mignani R, Panichi V, Giudicissi A, Taccola D, Boscaro F, Feletti C, Moneti G, Cagnoli L. Enzyme replacement therapy
with agalsidase beta in kidney transplant patients with Fabry disease: a pilot study. Kidney Int. 2004;65:1381–5.

9. Schiffmann R, Askari H, Timmons M, Robinson C, Benko W, Brady RO, Ries M. Weekly enzyme replacement
therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing. J
Am Soc Nephrol.2007;18:1576–83.

10. Schiffmann R, Kopp JB, Austin HA, Sabnis S, Moore DF, Weibel T, Balow JE, Brady RO. Enzyme replacement
therapy in Fabry disease: a randomized controlled trial. JAMA. 2001;285:2743–9.

11. Schwarting A, Sunder-Plassmann G, Mehta A, Beck M. Fabry Disease: Perspectives from 5 Years of FOS.
In: Mehta A, Beck M, Sunder-Plassmann G, eds. Effect of enzyme replacement therapy with agalsidase alfa
on renal function in patients with Fabry disease: data from FOS – the Fabry Outcome Survey. Oxford: Oxford
PharmaGenesis; 2006: Chapter 38.

12. Thurberg BL, Rennke H, Colvin RB, Dikman S, Gordon RE, Collins AB, Desnick RJ, O’Callaghan M.
Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme
replacement therapy. Kidney Int.2002;62:1933–46.

13. Vedder AC, Linthorst GE, Houge G, Groener JE, Ormel EE, Bouma BJ, Aerts JM, Hirth A, Hollak CE. Treatment
of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg. PLoS
ONE. 2007;2:e598.

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 53
14. Weidemann F, Breunig F, Beer M, Sandstede J, Turschner O, Voelker W, Ertl G, Knoll A, Wanner C, Strotmann JM.
Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective
strain rate imaging study. Circulation. 2003;108:1299–301.

Website resources

1. Department of Health and Ageing, Australia. Guidelines for the treatment of Fabry disease through life saving
drugs programe.

www.health.gov.au/internet/main/publishing.nsf/.../Fabry%20Disease1.doc

2. D.A.Hughes, U. Ramaswam, P Elliott, P.Deegan, P. Lee, S.Waldek, G Apperley, T.Cox and A.B.Mehta for the
National Specialist Commissioning Advisory Group (NSCAG). Guidelines for the diagnosis and management of
Anderson-Fabry Disease. www.dh.gov.uk › Home › Publications

3. Lorne A. Clarke, Joe T.R.Clarke, Sandra Sirrs, Michael L West, R. Mark Iwanochko, JohnR. Wherrett, Cheryl R.
Greenberg, Alicia K.J. Chan, Robin Casey. Fabry Disease: Recommendations for Diagnosis, Management, and
Enzyme Replacement Therapy in Canada. www.garrod.ca/data/.../CanadianFabryGuidelinesNov05.pdf

54 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
APPENDIX
 APPENDIX A

general conditions
for eligibility
 GENERAL CONDITIONS FOR ELIGIBILITY

1. Patients to be considered for financial support from the Malaysian government (Ministry
of Health) or its related health agencies (eg Ministry of Higher Education and Ministry of
Defence) for ERT treatment must be willing to participate in the long term evaluation of the
efficacy of treatment via periodic medical assessment as required by the ERT Guidelines.

2. If, depending on the natural course of the disease, there is no evidence of: (a) substantial
clinical improvement in the patient, or (b) stabilization of the patient’s condition as assessed
not later than 12 months after commencing therapy with the subsidized drug, then the
patient’s continued eligibility for financial assistance under these arrangements will be
reviewed.

3. Where the patient fails to comply adequately with the treatment or measures taken to
evaluate the effectiveness of the treatment, financial assistance under these arrangements
will be withdrawn.

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 57
 APPENDIX B

BORANG PERSETUJUAN
PESAKIT
 BORANG PERSETUJUAN PESAKIT

NAMA PESAKIT: ...........................................................................................................................................

NOMBOR KP: ................................................................TARIKH LAHIR: ....................................................

HOSPITAL: ......................................... NOMBOR PENDAFTARAN HOSPITAL: .........................................

Nama rawatan yang dicadangkan:

Enzyme replacement therapy (ERT) untuk penyakit: (pilih yang berkenaan)

Pompe [ ] Gaucher [ ] Fabry [ ] MPS I [ ] MPS II [ ] MPS VI [ ]

A. Kenyataan pengamal perubatan:

Saya telah menerangkan rawatan yang dicadangkan kepada pesakit. Secara khususnya, saya
telah menerangkan isu-isu seperti berikut:

1. Kebaikan dan sasaran rawatan yang diingini: (pilih yang berkenaan)

[ ] Penyakit otot jantung (cardiomyopathy) pulih

[ ] Bebas daripada bantuan alat pernafasan invasif

[ ] Penyakit otot skeletal menjadi stabil atau pulih

[ ] Bengkak hati dan limpa susut ke tahap yang minimal

[ ] Masalah kekurangan sel-sel darah pulih

[ ] Penyakit buah pinggang menjadi stabil atau pulih

[ ] Peningkatan jarak di dalam ujian six-minute walk

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 59
 [ ] Peningkatan fungsi paru-paru (increased forced vital capacity)

[ ] Lain-lain: ...............................................................................................................

2. Risiko rawatan yang mungkin terjadi:

• Anaphylaxis

• Kesan alergi seperti ruam, gatal dan deman yang berkaitan dengan infusi ubat

• Kegagalan dalam mencapai sasaran rawatan yang diingini

3. Prosedur rawatan akan dijalankan: (pilih yang berkenaan)

[ ] seminggu sekali

[ ] dua minggu sekali

Bertempat di Hospital ..................................................................................................

Selain rawatan ERT, pesakit mungkin memerlukan rawatan multidisiplinary yang lain
seperti berikut:

.....................................................................................................................................

.....................................................................................................................................

.....................................................................................................................................

4. Ujian pemantauan:

• akan dijalankan secara berkala

• ianya bertujuan memantau keberkesanan rawatan

60 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
5. Rawatan mungkin ditarik balik atau ditamatkan jika:

• tidak hadir tanpa sebab untuk rawatan sebanyak 2 kali dalam tempoh 6 bulan

• tidak hadir tanpa sebab untuk ujian pemantauan sehingga menjejaskan penilaian
keberkesanan rawatan

• tidak hadir tanpa sebab untuk rawatan multidisiplinary yang lain

• rawatan tidak mendatangkan kebaikan yang diingini

• terdapat tanda-tanda kemerosotan fungsi otak

Tandatangan: ....................................................................

Tarikh: ................................................................................

Nama: ................................................................................

Jawatan: ............................................................................

B. Kenyataan penterjemah (sekiranya berkenaan)

Saya telah menterjemahkan segala maklumat seperti di atas kepada pesakit ini dengan sedaya
upaya saya dan dengan cara di mana saya percaya ianya dapat difahami oleh pesakit.

Tandatangan: ............................................................................

Nama: .......................................................................................

Tarikh: .......................................................................................

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 61
C. Kenyataan pesakit

Sila baca borang ini dengan teliti. Sila juga baca helaian pertama borang persetujuan ini yang telah
menghuraikan segala kebaikan, risiko, prosedur rawatan dan pemantauan yang telah dicadangkan. Seki-�����
ranya anda ada apa-apa soalan, sila kemukakan kepada kami. Kami di sini untuk membantu anda.

1. Saya telah membaca helaian pertama borang ini dan telah faham YA TIDAK

kebaikan serta risiko rawatan yang dicadangkan.

2. Saya bersetuju menjalani rawatan yang dicadangkan. YA TIDAK

3. Saya telah dimaklumkan tentang prosedur rawatan yang perlu dipatuhi. YA TIDAK

4. Saya telah dimaklumkan tentang prosedur pemantauan yang perlu YA TIDAK

dipatuhi.
5. Saya telahpun dimaklumkan bahawa rawatan akan ditarik balik jika saya YA TIDAK

gagal mematuhi prosedur rawatan dan pemantauan yang ditetapkan.

6. Saya telahpun dimaklumkan bahawa rawatan akan ditarik balik jika saya YA TIDAK

gagal mencapai kebaikan atau sasaran rawatan yang dikehendaki.

Tandatangan: ............................................................................

Nama: .......................................................................................

Tarikh: .......................................................................................

(Untuk pesakit di bawah 18 tahun, ibubapa/penjaga akan mewakilinya untuk menandatangani borang
persetujuaan ini)

D. Saksi

Seorang saksi perlu tandatangani di bawah ini sekiranya beliau telah menyaksikan pesakit
menandatangan di atas.

Tandatangan: ............................................................................

Nama: .......................................................................................

Tarikh: .......................................................................................

Jawatan: ...................................................................................

62 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
 APPENDIX C
MONITORING REQUIREMENT
AND DATA SUBMISSION FORM
FOR GAUCHER DISEASE
 MONITORING REQUIREMENTS AND DATA SUBMISSION FORM

FOR GAUCHER DISEASE

Baseline and monitoring requirement (Gaucher disease)

Subsequently
3 6 12
Baseline 12-24
months months months 6 monthly
monthly
Hemoglobin X X X X X
Platelet Count X X X X X
Total white count X
Chitotriosidase X X X X X
Liver function X X
Coagulation profile X
Calcium/Phosphorus X X
Liver Volume
(Volumetric MRI or
CT) X X X
Spleen Volume
(Volumetric MRI or
CT) X X X
X-ray: AP view of
entire femora and
lateral view of spine X X1 X1
MRI (coronal; T1 &
T2-weighted) of entire
femora X X1 X1
DEXA: lumbar spine
and non-dominant
femoral neck X X X
Chest X-ray X X X
ECG/Echocardiogram X X X
Quality of Life and
Health- Related assess-
ments: X X X

SF-36 Health Survey

PedsQLTM Measurement
Model

1
if treated for bone involvement

64 Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia
 ENZYME REPLACEMENT THERAPY PROGRAM FOR LSD

DATA SUBMISSION FORM (GAUCHER DISEASE)

Patient details:

Patient’s name: .....................................................................................................................................

Date of birth: ......................................................... IC Number: ...........................................................

Contact No:............................................................ Gender: Male [ ] Female [ ]

Address: ................................................................................................................................................

Doctor’s details:

Doctor’s name: .....................................................................................................................................

Phone number:......................................................... Fax number:.........................................................

Hospital address: ..................................................................................................................................

Treatment details:

Has received ERT before: No [ ] Yes [ ]

If yes,

Date ERT started: ......................................................................

Product: .....................................................................................

Dose: .........................................................................................

Frequency: ................................................................................

Guidelines for treatment of lysosomal storage diseases

by enzyme replacement therapy in malaysia 65
 Clinical data:

Confirmation of disease:

Enzyme Assay ..............................................................................................................

Genotype ......................................................................................................................

Histology ......................................................................................................................

(Please attach a copy of the result for the initial submission)

Height: .................. cm (.................. %)

Weight: .................. kg (.................. %)

Head Circumference: .................. cm (.................. %)

Haematology: (Please provide serial results)

Date

Hb (g/L)
Platelet count (109/L)

History of blood transfusion? No [ ] Yes [ ] Date: ............................................

History of platelet transfusion? No [ ] Yes [ ] Date: .........................................

Visceral involvement:

Liver: : (measured in midclavicular line)

Span: ............................ cm Below costal margin:............................ cm Date: ............................

Volume: ............................cc Date: ............................

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Spleen:( measured in midclavicular line)

Span: ............................ cm Below costal margin: ............................ cm Date: ................................

Volume: ............................cc Date: ............................

Splenectomy  Yes  No If yes, provide date: ......................................

Liver dysfunction: No [ ] Yes [ ] Please provide details .....................................................................

Abdominal discomfort: No [ ] Yes [ ]

Skeletal Involvement:

Skeletal MRI report attached: Yes [ ] No [ ]

Please provide information to describe the patient’s experience with any of the following.

Severe bone crisis: ................................................................................................................................

Destruction of joints: ..............................................................................................................................

Spontaneous fractures: .........................................................................................................................

Chronic bone pain: ................................................................................................................................

Disease biomarker:

Date
Chitotriosidase

nmol/mL/hr

Quality of Life and Health- Related assessments report atached: Yes [ ] No [ ]

(SF-36 Health Survey/PedsQLTM Measurement Model)

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 Other Complications: .............................................................................................................................

Other medical problems: .......................................................................................................................

Current medications: .............................................................................................................................

Compliant: Yes [ ] No [ ] Hypersensitivity: Yes [ ] No [ ]

Other comments: ...................................................................................................................................

****Please provide ciopies of sonography/MRI/other relevant reports/CD

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 APPENDIX D
MONITORING REQUIREMENT
AND DATA SUBMISSION FORM
FOR POMPE DISEASE
 MONITORING REQUIREMENTS AND SUBMISSION FORM FOR POMPE DISEASE

Baseline and monitoring requirements (Infantile Pompe Disease)

1 2 3 6 12 After 12
Baseline month months months months months months

Echocardiogram1 X X X X X X 6 monthly
Electrocardiography X X X X X X 6 monthly
Chest x-ray X X X as required
Biochemical Tests (CK, X X X X X X 6 monthly
AST, LDH, ALT,urine
tetraglucoside)
Sleep study/ overnight X X as required
oxygen saturation
Respiratory X X X X X X 6 monthly
assessment2
Developmental X X X X 6 monthly
assessment
Gross Motor Func- X X X X 6 monthly
tion measure (GMF),
Walton-Gardner
Medwin Score
Swallowing X X X X 6 monthly
assessment
Audiology X X annually
CRIM status X
Antibody Levels X annually
Growth: height, X X X X X X 6 monthly
weight and head
circumference

1
measuring left ventricular mass index (LVMI), fractional shortening and ejection fraction

2
Respiratory rate, oxygen saturation on room air, requirement for non-invasive/ invasive respiratory support

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 Baseline and monitoring requirements (Late-Onset Pompe Disease)

Baseline 1 month 3 months 6 months 12 months After 12

months

6-minute Walk Test1 X X X X X 6 monthly

Arm function test X X X X X 6 monthly
Walton-Gardner X X X X X 6 monthly
Medwin score
Time function tests3 X X X X X 6 monthly

1
Guidelines for the Six-Minute Walk Test: Please refer Am J Respir Crit Care Med Vol 166. pp 111–
117, 2002

2
by speech therapist

3
modified Gowers’ maneuver, 10-meter walk, 4-stair climb.

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 ENZYME REPLACEMENT THERAPY PROGRAM FOR LSD

DATA SUBMISSION FORM (INFANTILE POMPE DISEASE)

Patient details:

Patient’s name: ......................................................................................................................................

Date of birth: ......................................................... IC Number: ............................................................

Contact No: ........................................................... Gender: Male [ ] Female [ ]

Address: ................................................................................................................................................

Doctor’s details:

Doctor’s name: ......................................................................................................................................

Phone number: ....................................................... Fax number: ........................................................

Hospital address: ...................................................................................................................................

Treatment details:

Has received ERT before: No [ ] Yes [ ]

If yes,

Date ERT started: ......................................................................

Product: .....................................................................................

Dose: .........................................................................................

Frequency: ................................................................................

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Clinical data:

Confirmation of disease:

Enzyme Assay .......................................................................................................................................

Genotype ...............................................................................................................................................

Histology ................................................................................................................................................

Height: ................................. cm ( ...................%)

Weight: ................................. kg ( ...................%)

Head Circumference: .................................cm ( ...................%)

Respiratory:

Ventilation: No [ ] Non-invasive [ ] Invasive [ ] Details: .............................................................

Tracheostomy: No [ ] Yes [ ]

Sleep study report attached:  Yes [ ] No [ ]

Obstructive episodes (number/hour): ......................... Lowest saturation: ............................................

Number of desaturations <80%: ............................................................................................................

Blood gas - pCO2, pH, bicarbonate: .....................................................................................................

Apnoea Hypopnoea Index: ....................................................................................................................

Cardiology:

Pediatric cardiology assessment attached:  Yes [ ] No [ ]

Echocardiogram attached: Yes [ ] No [ ]

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Date

Left ventricular mass

index
Fractional shortening
Ejection fraction

Valvular Pathology: ................................................................................................................................

Electrocardiography attached:  Yes [ ] No [ ]

Chest x-ray attached:  Yes [ ] No [ ]

Haematology/Biochemistry:

Date

Haemoglobin (g/L)
Platelets (109/L)
Creatine Kinase (CK)
Alanine Amino Transferase (ALT)
Aspartate Amino Transferase (AST)
Lactate Dehydrogenase (LDH)

Developmental Assessement Report attached: Yes [ ] No [ ]

Gross Motor Function Measure Report attached: Yes [ ] No [ ]

Walton-Gardner Medwin Score Report attached: Yes [ ] No [ ]

Swallowing Assessment: .......................................................................................................................

Swallowing Assessment test results attached: Yes [ ] No [ ]

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Hearing Test:

Date: ................................................ NORMAL/ABNORMAL

If abnormal:

Sensorineural: Max loss-Left ear: ............................................. Right ear: ...........................................

Shape audiogram: .....................................................................

Conductive: Max loss – Left ear:............................................... Right ear: ...........................................

Shape audiogram: .................................................................................................................................

Neurological Examination:

Date R Upper Limb L Upper Limb R Lower Limb L Lower Limb

Reflexes
Tone
Power (?/5)
Plantar

Neurological Evaluation Report attached: Yes [ ] No [ ]

Other Medical Problems:

...............................................................................................................................................................

...............................................................................................................................................................

Current medication: ...............................................................................................................................

Compliant: Yes [ ] No [ ]

Hypersensitivity: Yes [ ] No [ ]

Other comments: ...................................................................................................................................

****Please provide ciopies of sonography/echocardiography/MRI/other relevant reports/CD

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 ENZYME REPLACEMENT THERAPY PROGRAM FOR LSD

DATA SUBMISSION FORM (LATE ONSET POMPE DISEASE)

Patient details:

Patient’s name: ......................................................................................................................................

Date of birth: ........................................................... IC Number: ..........................................................

Contact No:............................................................. Gender: Male [ ] Female [ ]

Address: ................................................................................................................................................

Doctor’s details:

Doctor’s name: ......................................................................................................................................

Phone number: ...........................................................Fax number:.......................................................

Hospital address: ...................................................................................................................................

Treatment details:

Has received ERT before: No [ ] Yes [ ]

If yes,

Date ERT started: ......................................................................

Product: .....................................................................................

Dose: .........................................................................................

Frequency: ................................................................................

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Clinical data:

Confirmation of disease:

Enzyme Assay .......................................................................................................................................

Genotype ...............................................................................................................................................

Histology ................................................................................................................................................

(Please attach a copy of the result for the initial submission)

Height: ................................. cm ( ...................%)

Weight: ................................. kg ( ...................%)

BMI: .....................................................................

Respiratory:

Ventilation: No [ ] Non-invasive [ ] Invasive [ ] Details: ...........................................................

Tracheostomy: No [ ] Yes [ ]

Sleep study with a report of Apnoea Hypopnoea Index: Date .............................................................

(No. / hour): ....................................... Lowest saturation .......................................%

No. desaturations <80%: .......................................

FVC: Date .............................................................

(if old enough to co-operate): ................................... (mls) ...............................(%for age and height);

FEV 1: ........................... (mls) ........................... (%for age and height)

6 minute walk test: ........................... metres (if old enough)

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 Mean performance time for:

Modified Gowers’ maneuver: ....................................................... seconds

10-meter walk: ............................................................................. seconds

4-stair climb: ............................................................................... seconds

Arm function test report attached: Yes [ ] No [ ]

Range of Movement of Joints evaluation report attached: Yes [ ] No [ ]

Neurological Examination:

Date R Upper Limb L Upper Limb R Lower Limb L Lower Limb

Reflexes
Tone
Power (?/5)
Plantar

Neurological Evaluation Report attached: Yes [ ] No [ ]

Swallowing Assessment: ......................................................................................................................

Swallowing Assessment test results attached:  Yes [ ] No [ ]

Hearing Test:

Date: ..................................................................... NORMAL/ABNORMAL

If abnormal:

Sensorineural: Max loss-Left ear: ......................................... Right ear: ..............................................

Shape audiogram: ..................................................................................................................................

Conductive: Max loss – Left ear: .............................................. Right ear: ...........................................

Shape audiogram: ....................................................................

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Haematology/Biochemistry:

Date

Haemoglobin (g/L)
Platelets (109/L)
Creatine Kinase (CK)
Alanine Amino Transferase (ALT)
Aspartate Amino Transferase
(AST)
Lactate Dehydrogenase (LDH)

Walton-Gardner Medwin Score Report attached: Yes [ ] No [ ]

SF-36 Health Survey Report attached Yes [ ] No [ ]

Other Medical Problems:

...............................................................................................................................................................

...............................................................................................................................................................

Current medication:

...............................................................................................................................................................

...............................................................................................................................................................

Compliant: Yes [ ] No [ ]

Hypersensitivity: Yes [ ] No [ ]

Other comments: ...................................................................................................................................

****Please provide ciopies of sonography/echocardiography/MRI/other relevant reports/CD

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 APPENDIX E
MONITORING REQUIREMENT
AND DATA SUBMISSION FORM
FOR MUCOPOLYSACCHARIDOSIS
DISEASE
 MONITORING REQUIREMENTS AND SUBMISSION FORM

FOR MUCOPOLYSACCHARIDOSIS DISEASE

Baseline and monitoring requirement (MPS Disease)

Baseline 6 mths 12 mths 6mthly Annually Biannually

Height X X X X X X
Weight X X X X X X
Head Circumference X X X X X X
Hepatomegaly 1 X X X X X

Splenomegaly1 X X X X X
Sleep Study/Over- X X X X
night O2 saturation
Pulmonary function X X X X
test
Echocardiogram2 X X X X X
Ophthalmological X X X X
Examination X
Skeletal Survey X
MRI craniocervical X X X X
junction/spine
Six minute walk test X X X X X X
IQ / Neuropsychologi- X X X X
cal tests
Full Neurological X X X X X X
Examination
Audiology X X X X
Urinary GAGs - X X X X
quantitative X
ROM of joints3 X X X X X
Quality of Life and
Health- Related
assessments: X X X X
SF-36 Health
SurveyPedsQLTM
Measurement Model
1
Ultrasound. Just clinical once normal.
2
Including ejection fraction and fractional shortening
3
Shoulder Flex/Ext & abduction; Elbow Flex/Ext; Wrist Flex/Ext; Hip Flex/Ext; Knee Flex/Ext; Ankle Flex/Ext

and Hand clawing nil/mild/mod/severe

Guidelines for the Six-Minute Walk Test: Please refer Am J Respir Crit Care Med Vol 166.

pp 111–117, 2002

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 DATA SUBMISSION FORM (MPS DISEASE)

Patient details:

Patient’s name: ......................................................................................................................................

Date of birth: ........................................................... IC Number: ..........................................................

Contact No: ........................................................... Gender: Male [ ] Female [ ]

Address: ................................................................................................................................................

Diagnosis: MPS I [ ] MPSII [ ] MPS VI [ ]

Doctor’s details:

Doctor’s name: ......................................................................................................................................

Phone number: .......................................................... Fax number: ......................................................

Hospital address: ...................................................................................................................................

Treatment details:

Has received ERT before: No [ ] Yes [ ]

If yes,

Date ERT started: ......................................................................

Product: .....................................................................................

Dose: .........................................................................................

Frequency: ................................................................................

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Clinical data:

Confirmation of disease:

Enzyme Assay .......................................................................................................................................

Genotype ...............................................................................................................................................

Urine glycoamineglycans analyses .......................................................................................................

(Please attach a copy of the result for the initial submission)

Height: ................................. cm ( ...................%)

Weight: ................................. kg ( ...................%)

Head circumference: ............................ cm ( ............................%)

Liver size:( measured in midclavicular line)

Span: ............................cm Below costal margin: ............................cm

Spleen size:( measured in midclavicular line)

Span: ............................ cm Below costal margin: ............................ cm

Sleep study with a report of Apnoea Hypopnoea Index: Date ........................................................

(No. / hour): ............................ Lowest saturation ............................ %

No. desaturations <80%: ......................................................................

FVC: Date ............................................................................................

(if old enough to co-operate): ............................(mls) ............................ (%for age and height);

FEV 1: ............................(mls) ............................ (%for age and height)

Echocardiogram: Ejection Fraction: ........................% or Fraction Shortening: .......................%

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 Left ventricular hypertrophy (thickness): ................................... Date ..................................................

Valvular pathology: ................................................................................................................................

Valvular stenosis/regurgitation (grade): .................................................................................................

Opthalmological examination:

Corneal clouding Yes /No; Date ............................................................................................................

If patient able to co-operate then measure intraocular pressure ...................................... mm Hg, and

ERG .......................................................................................... Date ...................................................

VEP.......................................................................................... Date ....................................................

Psychometric Testing:

Bayley Scale of Infant Development or Griffiths Mental Development Scale

WIPPSI: Full Scale ..................; Verbal..................; Performance ....................... Date: .....................

WISC: Full Scale .....................; Verbal..................; Performance......................... Date: ......................

(Please attach report)

Skeletal Survey including flexion and extension view of neck: Attach report

6 minute walk test:............................ metres (if old enough)

Range of Movement of Joints:

Normal Left Right

FOOT +20

Dorsiflexion
Plantar flexion 45
Inversion 30
Eversion 25

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KNEE 120-130

Flexion
Extension 0
HIP 115-125

Flexion
Extension -15
Abduction 45
Adduction 20-30
Internal Rotation 30-45
External 30-45

Rotation
WRIST 90

Flexion
Extension 70
Ulnar deviation 35
Radial deviation 25
ELBOWS 145

Flexion
Extension 0
Pronation 90
Supination 90
SHOULDER

Flexion 180
Extension 0
Abduction 180
Internal rotation 65-90
External rotation 90
NECK 45

Flexion
Extension 45
Rotation 60-75
Lateral flexion 45-60

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 Carpal Tunnel Syndrome: Yes [ ] Suspicious [ ] No [ ]

If suspicious: result of nerve conduction studies: Normal [ ] Abnormal [ ]

Hearing Test:

Date: ...................................... NORMAL [ ] ABNORMAL [ ]

If abnormal:

Sensorineural:

Max loss - Left ear: ........................ Right ear: ........................ Shape audiogram: ...............................

Conductive:

Max loss – Left ear: ........................ Right ear: ........................ Shape audiogram: ..............................

Neurological Examination:

Date R Upper Limb L Upper Limb R Lower Limb L Lower Limb

Reflexes
Tone
Power (?/5)
Plantar

Urinary GAGs (quantitative): ........................ gm/mol creat; Date ........................

SF-36 Health Survey /PedsQLTM Measurement Model Report attached Yes [ ] No [ ]

Surgery, if any: (date/ Procedure) ........................................................................................................

...............................................................................................................................................................

Other Medical Problems: (date of onset/Problem/active or inactive)

...............................................................................................................................................................

...............................................................................................................................................................

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Other medication:

...............................................................................................................................................................

Compliant: Yes [ ] No [ ] Hypersensitivity: Yes [ ] No [ ]

Other comments: ................................................................................................................................

...............................................................................................................................................................

**** Please provide ciopies of skeletal radiography/sonography/MRI/other relevant reports/CD/

photos

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 APPENDIX F
MONITORING REQUIREMENT AND
DATA SUBMISSION FORM
FOR FABRY DISEASE
 MONITORING REQUIREMENTS AND SUBMISSION FORM FOR FABRY DISEASE

Baseline and monitoring requirement (Fabry Disease)

Baseline 6 monthly 12 - 24 monthly

Height/Weight X X

Medical history1 X X

Physical examination1 X X

Blood pressure X X
Serum Creatinine, blood urea and X X
electrolytes
Urinalysis X X
24 hour urine for protein (or urine X X

protein/creatinine ratio)
GFR2 X X

Renal biopsy X 3

Electrocardiogram X X

Echocardiography X X

Eye examination X X

Audiology X X

MRI brain X if required

Pain, Quality of Life and Health-
Related assessments:
X X
SF-36 Health Survey

Brief Pain Inventory (Short Form)

PedsQLTM Measurement Model

1
Clinical assessments focussed on the core Fabry related disease manifestations

2
GFR can be estimated using equations such as the MDRD equation for adults and Schwartz
formula for children

3
If treated for renal indication

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 DATA SUBMISSION FORM (FABRY DISEASE)

Patient details:

Patient’s name: ......................................................................................................................................

Date of birth: ........................................................... IC Number: ..........................................................

Contact No:............................................................. Gender: Male [ ] Female [ ]

Address .................................................................................................................................................

Doctor’s details:

Doctor’s name: ......................................................................................................................................

Phone number: .......................................................... Fax number: ......................................................

Hospital address: ...................................................................................................................................

Treatment details:

Has received ERT before: No [ ] Yes [ ]

If yes,

Date ERT started: ......................................................................

Product: .....................................................................................

Dose: .........................................................................................

Frequency: ................................................................................

90 Guidelines for treatment of lysosomal storage diseases

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 Clinical data:

Confirmation of disease:

Enzyme Assay .......................................................................................................................................

Genotype ...............................................................................................................................................

Histology.................................................................................................................................................

(Please attach a copy of the result for the initial submission)

Height: ................................. cm ( ...................%)

Weight: ................................. kg ( ...................%)

Blood pressure: Systolic: ................................. Diastolic: .................................

SF-36 Health Survey /PedsQLTM Measurement Model Report attached Yes [ ] No [ ]

Laboratory data (Please provide serial results)

Date
Haemoglobin g/L
Platelets x109/L
White Cell Count x109/L
Total Bilirubin µmol/L
Alkaline Phosphatase u/L
GGT u/L
ALT u/L
Total cholesterol mmol/L
HDL-cholesterol
LDL-cholesterol
Triglyceride mmol/L
Blood Urea mmol/L
Plasma Creatinine µmol/L
Proteinuria mg/24 hours
Urine Alb:Cr ratio
GFR (method)
mL/min/1.73m²

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 Cardiovascular findings

Hypertension: Yes: .......................................... No: ........................................ Date: ...........................

Echo:

Date: ......................................... Ventricular wall thickness: .......................................................... mm

Other: ....................................................................................................................................................

ECG:

Date: ........................................ Normal: ........................................ Abnormal: .....................................

PR interval: ........................................ mm

PQ interval (if available):

Other arrhythmia: ..................................................................................................................................

Stress test:

Date:........................................ Normal: ........................................ Abnormal: ......................................

Findings: ................................................................................................................................................

Cardiac MRI: Yes: .......................................... No: ........................................ Date: ............................

Findings: ................................................................................................................................................

Cardiac Biopsy: Yes: ....................................... No: ........................................ Date: ...........................

Findings: ................................................................................................................................................

Electrophysiological Study: Yes: ............................ No: ............................... Date: .............................

Findings:................................................................................................................................................

History of arrythmia: Yes: ........................... No: ........................... Date of onset: ................................

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Type: .....................................................................................................................................................

Treatment required: ...............................................................................................................................

History of acute myocardial infarction: Yes: ........................No: ........................ Date: ..........................

Investigations / Interventions: ................................................................................................................

Other cardiac event?: Yes: ............................... No: ................................ Date: ..............................

Findings: ...............................................................................................................................................

Cerebrovascular findings

MRI date: .................................................... Location: .......................................................................

Findings: ................................................................................................................................................

Neurology

Clinical examination:

Sensory (Please tick)

Sensation Normal Abnormal Sensory level

(if abnormal)
Light touch
Temperature
Vibration
Joint position sens
Sweating
Heat/cold tolerance
Pain sensatio

Other sensory abnormalities: ................................................................................................................

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 Motor examination/coordination

Test Normal Abnormal

Heel/toe
Romberg

Other gait/motor abnormalities: .............................................................................................................

Has this patient a history of transient ischemic attacks: Yes: ......... No: ......... Date: ...................

Has this patient had a CVA: Yes: .................. No: .................. Date: .................................................

If yes, please provide details:

...............................................................................................................................................................

Pain : Yes: .................................... No: .....................................................

If yes, Chronic: .................................... Episodic: ....................................

Pain score: Brief Pain Inventory BPI– 9: ...............................................................................................

Vertigo : Yes: ....................................... No: ............................................

If yes, Chronic: .................................... Episodic: ....................................

Hearing test:

Date: .................................... Normal: .................................... Abnormal: ............................................

Abnormalities : Left ear: ......................................................

Right ear: ....................................................

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Renal findings

Dialysis : Yes: ................................ No: ................................ Date: ..................................................

Renal transplant : Yes: ................................No: ................................ Date: .......................................

Other findings: .......................................................................................................................................

Lung function tests

Result Date
FEV1
FVC
VC
FEF 50
FEF 25-75

Ophthalmic evaluation: ......................................................................................................................

Gastrointestinal findings

Abdominal pain: Yes: ................................No: ................................

Diarrhoea: Yes: ................................ No: ........................................ Details (include frequency):

Past medical history: ..........................................................................................................................

Previous medication: ..........................................................................................................................

Current medication: ............................................................................................................................

Compliant: Yes [ ] No [ ] Hypersensitivity: Yes [ ] No [ ]

Other comments: ..........................................................................................................................

**** Please provide ciopies of skeletal radiography/sonography/MRI/other relevant reports/CD/

photos

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 APPENDIX G
SF-36 HEALTH SURVEY
 SF-36 Health Survey

NAMA PESAKIT: …………………………………………………………………………………....................

NOMBOR KP: ……………………………............. TARIKH LAHIR: ……………………………...............

HOSPITAL: ………………………………………………………………………………................................

NOMBOR PENDAFTARAN HOSPITAL: ……………………………………………………………............

INSTRUCTIONS: This survey asks your views about your health. This information will help to keep
track of how you feel and how well you are able to do your usual activities. Please answer every
question by marking the answer as indicated. If you are unsure about how to answer a question,
please give the best answer you can. When you have completed, please return the questionnaire in
the envelope provided.

1. In general, would you say your health is:

(circle one)

Excellent? ………………………………………………………………………………….. 1

Very good? …………………………………………………………………………………. 2

Good? …………………………………………………………………………………. 3

Fair? …………………………………………………………………………………. 4

Poor? …………………………………………………………………………………. 5

2. Compared to one year ago, how would you rate your health in general now?

(circle one)

Much better now than one year ago. ………………………………………………………. 1

Somewhat better than one year ago. ………………………………………………………. 2

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 About the same as one year ago. ………………………………………………………. 3

Somewhat worse than one year ago. ………………………………………………………. 4

Much worse now than one year ago. ………………………………………………………. 5

3. The following questions are about activities you might do during a typical day. Does your
health now limit you in these activities? If so, how much?

(circle one number on each line)

Activities Yes, limited a lot Yes, limited a little No, not limited at all
Vigorous activities, 1 2 3
such as running, lift-
ing heavy objects,
participating in strenuous
sports.

Moderate activities, such as 1 2 3

moving a table, pushing a,
vacuum cleaner,bowling or
playing golf

Lifting or carrying groceries 1 2 3

Climbing several flights of 1 2 3
stairs
Climbing one flight of stairs 1 2 3
Bending, kneeling or 1 2 3
stooping
Walking more than a mile 1 2 3
[~1.5km]
Walking half a mile 1 2 3
Walking one hundred yards 1 2 3
Bathing or dressing yourself 1 2 3

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 4. During the past 4 weeks, have you had any of the following problems with your work or
other regular daily activities as a result of your physical health?

(circle one number on each line)

Yes No
Cut down on the amount of time you 1 2
spent on work or other activities
Accomplished less than you would like 1 2
Were limited in the kind of work or 1 2
other activities
Had difficulty performing the work or 1 2
other activities (for example, it took
extra effort)

5. During the past 4 weeks, have you had any of the following problems with your work or
other regular daily activities as a result of any emotional problems (such as feeling depressed
or anxious)?

(circle one number on each line)

Yes No
Cut down on the amount of time you 1 2
spent on work or other activities
Accomplished less than you would like 1 2
Didn’t do work or other activities as 1 2
carefully as usual

6. During the past 4 weeks, to what extent has your physical health or emotional problems
interfered with your normal social activities with family, friends, neighbours or groups?

(circle one)

Not at all …………………………………………………………………………………… 1

Slightly …………………………………………………………………………………… 2

Moderately …………………………………………………………………………………… 3

Quite a bit …………………………………………………………………………………… 4

Extremely …………………………………………………………………………………… 5

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 7. How much bodily pain have you had during the past 4 weeks?

(circle one)

None …………………………………………………………………………………..…. 1

Very mild …………………………………………………………………………………….. 2

Mild …………………………………………………………………………………...... 3

Moderate ………………………………………………………………………………..….... 4

Severe …………………………………………………………………………………….. 5

Very severe …………………………………………………………………………………….. 6

8. During the past 4 weeks, how much did pain interfere with your normal work (including
both work outside the home and housework)?

(circle one)

Not at all …………………………………………………………………………………..... 1

A little bit …………………………………………………………………………………...... 2

Moderately …………………………………………………………………………………...... 3

Quite a bit …………………………………………………………………………………..... 4

Extremely …………………………………………………………………………………...... 5

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 9. These questions are about how you feel and how things have been with you during the
past 4 weeks. For each question please give the one answer that comes closest to the way you
have been feeling. How much of the time during the past 4 weeks.

All of Most of the A good bit of Some of A little of None of the

the time time the time the time the time time

Did you feel 1 2 3 4 5 6

full of life?
Have you been 1 2 3 4 5 6
a very nervous
person?
Have you felt 1 2 3 4 5 6
so down in the
dumps that
nothing could
cheer you up?
Have you 1 2 3 4 5 6
felt calm and
peaceful?
Did you have a 1 2 3 4 5 6
lot of energy?
Have you felt 1 2 3 4 5 6
downhearted
and low?
Did you feel 1 2 3 4 5 6
worn out?
Have you 1 2 3 4 5 6
been a happy
person?
Did you feel 1 2 3 4 5 6
tired?

10. During the past 4 weeks, how much of the time has your physical health or emotional
problems interfered with your social activities (like visiting friends, relatives, etc.)?

(circle one)

All of the time ………………………………………………………………………………….. 1

Most of the time …………………………………………………………………………………... 2

Some of the time …………………………………………………………………………………... 3

A little of the time …………………………………………………………………………………... 4

None of the time …………………………………………………………………………………... 5

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 11. How TRUE or FALSE is each of the following statements to you?

(circle one number on each line)

Definitely Mostly true Don’t know Mostly false Definitely

true false
I seem to get 1 2 3 4 5
ill more easily
than other
people

I am as 1 2 3 4 5
healthy as
anybody
I know

I expect my 1 2 3 4 5
health to
get worse

My health is 1 2 3 4 5
excellent

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 APPENDIX H
GROSS MOTOR FUNCTION
MEASURE (GMFM)
SCORE SHEET
 GROSS MOTOR FUNCTION MEASURE (GMFM) SCORE SHEET

(GMFM-88 and GMFM-66 scoring) Version 1.

Patient’s Name: …………………………………………………………………………………..….......................

Assessment Date: …………………………………………………………………………………..…...................

Date of Birth: …………………………………………………………………………………..…...........................

Chronological Age: …………………………………………………………………………………..…..................

Evaluator’s Name: …………………………………………………………………………………..…...................

GMFCS Level1: I [ ] II [ ] III [ ] IV [ ] V [ ]

Testing Conditions (eg, room, clothing, time, others present):

…………………………………………………………………………………..….................................................

…………………………………………………………………………………..….................................................

The GMFM is a standardized observational instrument designed and validated to measure change in
gross motor function over time in children with cerebral palsy. The scoring key is meant to be a general
guideline. However, most of the items have specific descriptors for each score. It is imperative that the
guidelines contained in the manual be used for scoring each item.

SCORING KEY 0 = does not initiate

1 = initiates

2 = partially completes

3 = completes

NT = Not tested [used for the GMAE scoring*]

It is now important to differentiate a true score of “0” (child does not initiate) from an item which is Not
Tested (NT) if you are interested in using the GMFM-66 Ability Estimator Software.

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*The GMFM-66 Gross Motor Ability Estimator (GMAE) software is available with the GMFM manual
(2002). The advantage of the software is the conversion of the ordinal scale into an interval scale. This will
allow for a more accurate estimate of the child’s ability and provide a measure that is equally responsive to
change across the spectrum of ability levels. Items that are used in the calculation of the GMFM-66 score
are shaded and identified with an asterisk (*). The GMFM-66 is only valid for use with children who have
cerebral palsy.

1
GMFCS level is a rating of severity of motor function. Definitions are found in Appendix I of the GMFM
manual (2002).

Check (√ ) the appropriate score: if an item is not tested (NT), circle the item number in the right
column

Item A: LYING & ROLLING SCORE NT

1 SUP, HEAD IN MIDLINE: TURNS HEAD WITH EXTREMITIES SYMMETRICAL 0 1 2 3 1

*2 SUP: BRINGS HANDS TO MIDLINE, FINGERS ONE WITI H THE OTHER 0 1 2 3 2
3 SUP: LIFTS HEAD 45° 0 1 2 3 3
4 SUP: FLEXES R HIP AND KNEE THROUGH FULL RANGE 0 1 2 3 4
5 SUP: FLEXES L HIP AND KNEE THROUGH FULL RANGE 0 1 2 3 5
*6 SUP: REACHES OUT WITH R ARM, HAND CROSSES MIDLINE TOWARD TOY 0 1 2 3 6
*7 SUP: REACHES OUT WITH L ARM, HAND CROSSES MIDLINE TOWARD TOY 0 1 2 3 7
8 SUP: ROLLS TO PR OVER R SIDE 0 1 2 3 8
9 SUP: ROLLS TO PR OVER L SIDE 0 1 2 3 9
*10 PR: LIFTS HEAD UPRIGHT 0 1 2 3 10
11 PR ON FOREARMS: LIFTS HEAD UPRIGHT, ELBOWS EXT., CHEST RAISED 0 1 2 3 11
12 PR ON FOREARMS: WEIGHT ON R FOREARM, FULLY EXTENDS OPPOSITE 0 1 2 3 12
ARM FORWARD
13 PR ON FOREARMS: WEIGHT ON L FOREARM, FULLY EXTENDS OPPOSITE 0 1 2 3 13
ARM FORWARD
14 PR: ROLLS TO SUP OVER R SIDE 0 1 2 3 14
15 PR: ROLLS TO SUP OVER L SIDE 0 1 2 3 15
16 PR: PIVOTS TO R 90° USING EXTREMITIES 0 1 2 3 16
17 PR: PIVOTS TO L 90° USING EXTREMITIES 0 1 2 3 17

TOTAL DIMENSION A

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 Item B: SITTING SCORE NT

*18 SUP, HANDS GRASPED BY EXAMINER: PULLS SELF TO SITTING WITH 0 1 2 3 18

HEAD CONTROL
19 SUP: ROLLS TO R SIDE, ATTAINS SITTING 0 1 2 3 19
20 SUP: ROLLS TO L SIDE, ATTAINS SITTING 0 1 2 3 20
21 SIT ON MAT, SUPPORTED AT THORAX BY THERAPIST: LIFTS HEAD 0 1 2 3 21
UPRIGHT, MAINTAINS 3 SECONDS
*22 SIT ON MAT, SUPPORTED AT THORAX BY THERAPIST: LIFTS HEAD 0 1 2 3 22
MIDLINE, MAINTAINS 10 SECONDS
*23 SIT ON MAT, ARM(S) PROPPING: MAINTAINS, 5 SECONDS 0 1 2 3 23
*24 SIT ON MAT: MAINTAINS, ARMS FREE, 3 SECONDS 0 1 2 3 24
*25 SIT ON MAT WITH SMALL TOY IN FRONT: LEANS FORWARD, TOUCHES 0 1 2 3 25
TOY, RE-ERECTS WITHOUT ARM PROPPING
*26 SIT ON MAT: TOUCHES TOY PLACED 45° BEHIND CHILD’S R SIDE, 0 1 2 3 26
RETURNS TO START
*27 SIT ON MAT: TOUCHES TOY PLACED 45° BEHIND CHILD’S L SIDE, 0 1 2 3 27
RETURNS TO START
28 R SIDE SIT: MAINTAINS, ARMS FREE, 5 SECONDS 0 1 2 3 28
29 L SIDE SIT: MAINTAINS, ARMS FREE, 5 SECONDS 0 1 2 3 29
*30 SIT ON MAT: LOWERS TO PR WITH CONTROL 0 1 2 3 30
*31 SIT ON MAT WITH FEET IN FRONT: ATTAINS 4 POINT OVER R SIDE 0 1 2 3 31
*32 SIT ON MAT WITH FEET IN FRONT: ATTAINS 4 POINT OVER L SIDE 0 1 2 3 32
33 SIT ON MAT: PIVOTS 90°, WITHOUT ARMS ASSISTING 0 1 2 3 33
*34 SIT ON BENCH: MAINTAINS, ARMS AND FEET FREE, 10 SECONDS 0 1 2 3 34
*35 STD: ATTAINS SIT ON SMALL BENCH 35
*36 ON THE FLOOR: ATTAINS SIT ON SMALL BENCH 0 1 2 3 36
*37 ON THE FLOOR: ATTAINS SIT ON LARGE BENCH 0 0 2 3 37

TOTAL DIMENSION B

Item C: CRAWLING & KNEELING SCORE NT

38 PR: CREEPS FORWARD 1.8m (6’) 0 1 2 3 38

*39 4 POINT: MAINTAINS, WEIGHT ON HANDS AND KNEES, 10 SECONDS 0 1 2 3 39
*40 4 POINT: ATTAINS SIT ARMS FREE 0 1 2 3 40
*41 PR: ATTAINS 4 POINT, WEIGHT ON HANDS AND KNEES 0 1 2 3 41
*42 4 POINT: REACHES FORWARD WITH R ARM, HAND ABOVE SHOULDER 0 1 2 3 42
LEVEL
*43 4 POINT: REACHES FORWARD WITH L ARM, HAND ABOVE SHOULDER 0 1 2 3 43
LEVEL
*44 4 POINT: CRAWLS OR HITCHES FORWARD 1.8m (6’) 0 1 2 3 44

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*45 4 POINT: CRAWLS RECIPROCALLY FORWARD 1.8m (6’) 0 1 2 3 45
*46 4 POINT: CRAWLS UP 4 STEPS ON HANDS AND KNEES/FEET 0 1 2 3 46
47 4 POINT: CRAWLS BACKWARDS DOWN 4 STEPS ON HANDS AND 0 1 2 3 47
KNEES/FEET
*48 SIT ON MAT: ATTAINS HIGH KN USING ARMS, MAINTAINS, ARMS FREE, 0 1 2 3 48
10 SECONDS ..
49 HIGH KN: ATTAINS HALF KN ON R KNEE USING ARMS, MAINTAINS, 0 1 2 3 49
ARMS FREE, 10 SECONDS
50 HIGH KN: ATTAINS HALF KN ON L KNEE USING ARMS, MAINTAINS, 0 1 2 3 50
ARMS FREE, 10 SECONDS
*51 HIGH KN: KN WALKS FORWARD 10 STEPS, ARMS FREE 0 1 2 3 51

TOTAL DIMENSION C

Item D: STANDING SCORE NT

*52 ON THE FLOOR: PULLS TO STD AT LARGE BENCH 0 1 2 3 52

*53 STD: MAINTAINS, ARMS FREE, 3 SECONDS 0 1 2 3 53
*54 STD: HOLDING ON TO LARGE BENCH WITH ONE HAND, LIFTS R FOOT, 0 1 2 3 54
3 SECONDS
*55 STD: HOLDING ON TO LARGE BENCH WITH ONE HAND, LIFTS L FOOT, 0 1 2 3 55
3 SECONDS
*56 STD: MAINTAINS, ARMS FREE, 20 SECONDS 0 1 2 3 56
*57 STD: LIFTS L FOOT, ARMS FREE, 10 SECONDS 0 1 2 3 57
*58 STD: LIFTS R FOOT, ARMS FREE, 10 SECONDS 0 1 2 3 58
*59 SIT ON SMALL BENCH: ATTAINS STD WITHOUT USING ARMS 0 1 2 3 59
*60 HIGH KN: ATTAINS STD THROUGH HALF KN ON R KNEE, WITHOUT 0 1 2 3 60
USING ARMS
*61 HIGH KN: ATTAINS STD THROUGH HALF KN ON L KNEE, WITHOUT 0 1 2 3 61
USING ARMS
*62 STD: LOWERS TO SIT ON FLOOR WITH CONTROL, ARMS FREE 0 1 2 3 62
*63 STD: ATTAINS SQUAT, ARMS FREE 0 1 2 3 63
*64 STD: PICKS UP OBJECT FROM FLOOR, ARMS FREE, RETURNS TO 0 1 2 3 64
STAND

TOTAL DIMENSION D

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 Item E: WALKING, RUNNING & JUMPING SCORE NT

*65 STD, 2 HANDS ON LARGE BENCH: CRUISES 5 STEPS TO R. 0 1 2 3 65

*66 STD, 2 HANDS ON LARGE BENCH: CRUISES 5 STEPS TO L 0 1 2 3 66
*67 STD, 2 HANDS HELD: WALKS FORWARD 10 STEPS 0 1 2 3 67
*68 STD, 1 HAND HELD: WALKS FORWARD 10 STEPS 0 1 2 3 68
*69 STD: WALKS FORWARD 10 STEPS 0 1 2 3 69
*70 STD: WALKS FORWARD 10 STEPS, STOPS, TURNS 180°, RETURNS 0 1 2 3 70
*71 STD: WALKS BACKWARD 10 STEPS 0 1 2 3 71
*72 STD: WALKS FORWARD 10 STEPS, CARRYING A LARGE OBJECT WITH 0 1 2 3 72
2 HANDS
*73 STD: WALKS FORWARD 10 CONSECUTIVE STEPS BETWEEN PARALLEL 0 1 2 3 73
LINES 20cm (8”) APART
*74 STD: WALKS FORWARD 10 CONSECUTIVE STEPS ON A STRAIGHT LINE 0 1 2 3 74
2cm (3/4”) WIDE
*75 STD: STEPS OVER STICK AT KNEE LEVEL, R FOOT LEADING 0 1 2 3 75
*76 STD: STEPS OVER STICK AT KNEE LEVEL, L FOOT LEADING 0 1 2 3 76
*77 STD: RUNS 4.5m (15’), STOPS & RETURNS 0 1 2 3 77
*78 STD: KICKS BALL WITH R FOOT 0 1 2 3 78
*79 STD: KICKS BALL WITH L FOOT 0 1 2 3 79
*80 STD: JUMPS 30cm (12”) HIGH, BOTH FEET SIMULTANEOUSLY 0 1 2 3 80
*81 STD: JUMPS FORWARD 30 cm (12”), BOTH FEET SIMULTANEOUSLY 0 1 2 3 81
*82 STD ON R FOOT: HOPS ON R FOOT 10 TIMES WITHIN A 60cm (24”) 82
CIRCLE
*83 STD ON L FOOT: HOPS ON L FOOT 10 TIMES WITHIN A 60cm (24”) 0 1 2 3 83
CIRCLE
*84 STD, HOLDING 1 RAIL: WALKS UP 4 STEPS, HOLDING 1 RAIL, 0 0 2 3 84
ALTERNATING FEET
*85 STD, HOLDING 1 RAIL: WALKS DOWN 4 STEPS, HOLDING 1 RAIL, 0 1 2 3 85
ALTERNATING FEET
*86 STD: WALKS UP 4 STEPS, ALTERNATING FEET 0 1 2 3 86
*87 STD: WALKS DOWN 4 STEPS, ALTERNATING FEET 87
*88 STD ON 15cm (6”) STEP: JUMPS OFF, BOTH FEET SIMULTANEOUSLY 0 1 2 3 88

TOTAL DIMENSION E

Was this assessment indicative of this child’s “regular” performance? YES[ ] NO[ ] COMMENTS:

…………………………………………………………………………………………
…………………………………………………………………………………………
…………………………………………………………………………………………
…………………………………………………………………………………………
……………………………………………………..................................................

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 GMFM RAW SUMMARY SCORE

DIMENSION CALCULATION OF DIMENSION % SCORES GOAL AREA

(indicated with √ check)

A. Lying & Rolling Total Dimension A = x 100% = % A.[ ]

51 51

B. Sitting Total Dimension B = x100% = % B.[ ]

60 60

C. Crawling & Kneeling Total Dimension C = x100% = % C.[ ]

42 42

D. Standing Total Dimension D = ´x100% = % D.[ ]

39 39

E. Walking, Running & Total Dimension E = x´100% = % E.[ ]

Jumping 72 72

TOTAL SCORE = %A + %B + %C + %D + %E
Total # of Dimensions

= + + + +
5
= __________________________
5

= __________________________%

GOAL TOTAL SCORE = Sum of % scores for each dimension identified as a goal area
# of Goal areas

= %

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 APPENDIX I
BRIEF PAIN INVENTORY
(SHORT FORM)
 Brief Pain Inventory (Short Form)

Patient’s Name: ………………………………………………………………………………..….........................

Patient’s IC: ……………………………………………………………………………..…...................................

Date completed: ……………………………………………………………………………..…...........................

1. Throughout our lives, most of us have had pain from time to time (such as minor headaches,

sprains and toothaches). Have you had pain other than these everyday kinds of pain today?

Yes [ ] No [ ]

2. On the diagram, shade in the areas where you feel pain. Put an “X” on the area that hurts the

most.

Front Back

Right Left Left Right

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3. Please rate your pain by circling the one number that best describes your pain at its worst in
the last 24 hours.

0 1 2 3 4 5 6 7 8 9 10

No Pain Pain as bad as you can imagine

4. Please rate your pain by circling the one number that best describes your pain at its least in
the last 24 hours.

0 1 2 3 4 5 6 7 8 9 10

No Pain Pain as bad as you can imagine

5. Please rate your pain by circling the one number that best describes your pain on the average.

0 1 2 3 4 5 6 7 8 9 10

No Pain Pain as bad as you can imagine

6. Please rate your pain by circling the one number that tells you how much pain you have right
now.

0 1 2 3 4 5 6 7 8 9 10

No Pain Pain as bad as you can imagine

7. What treatments or medications are you receiving for your pain?

……………………………………………………………………………..…..................................................

8. In the last 24 hours, how much relief have pain treatments or medications provided? Please
circle the one percentage that most shows how much relief you have received.

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

No Relief Complete Relief

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9. Circle the one number that describes how, during the past 24 hours, pain has interfered with
your:

A. General Activity

0 1 2 3 4 5 6 7 8 9 10

Does not interfere Completely interfere

B. Mood

0 1 2 3 4 5 6 7 8 9 10

Does not interfere Completely Interfere

C. Walking Ability

0 1 2 3 4 5 6 7 8 9 10

Does not interfere Completely interfere

D. Normal Work (includes both work outside the home and housework)

0 1 2 3 4 5 6 7 8 9 10

Does not interfere Completely interfere

E. Relations with other people

0 1 2 3 4 5 6 7 8 9 10

Does not interfere Completely interfere

F. Sleep

0 1 2 3 4 5 6 7 8 9 10

Does not interfere Completely interfere

G. Enjoyment of life

0 1 2 3 4 5 6 7 8 9 10

Does not interfere Completely interfere

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 APPENDIX J
MRC SCALE FOR
ASSESSMENT OF MUSCLE
POWER
 MRC SCALE FOR ASSESSMENT OF MUSCLE POWER

Each muscle group is graded as follows:

0 - no movement
1 - flicker is perceptible in the muscle
2 - movement only if gravity eliminated
3 - can move limb against gravity
4 - can move against gravity & some resistance exerted by examiner
5 - normal power

MODIFIED WALTER GARDNER MEDWIN SCORE

Grade 0 = Pre-Clinical. All activities.

Grade 1 = Walks normally. Unable to run freely.

Grade 2 = Detectable defect in posture or gait. Climbs stairs without using banister.

Grade 3 = Detectable defect in posture or gait. Climbs stairs only with banisters.

Grade 4 = Walks without assistance. Unable to climb stairs.

Grade 5 = Walks normally. Unable to rise from chair.

Grade 6 = Walks only with callipers or other aids.

Grade 7 = Unable to walk. Sits erect in a chair. Able to roll wheelchair and eat and drink
normally.

Grade 8 = Sits unsupported in a chair. Unable to roll wheelchair or unable to drink from a
glass unassisted.

Grade 9 = Unable to sit erect without support or unable to eat or drink without assistance.

Grade 10 = Confined to bed. Requires help for all activities.

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 ARM FUNCTION TEST

Grade 1 = Starting with arms at sides, the patient is capable to abduct the arms in a full circle
until the handbacks touch above the head.

Grade 2 = Can raise arms above only by flexing the elbow (i.e., shortening the circumference
of the movement) or using accessory muscles.

Grade 3 = Cannot raise hands above head but can raise an 8 oz. glass/cup of water to mouth
(using both hands if necessary). When raising glass to mouth, the patient may not
lower his head to reach the glass.

Grade 4 = Can raise hands to mouth but cannot raise an 8 oz. glass/cup of water to mouth.

Nothing = Cannot raise hands to mouth at all.

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 DRAFTING COMMITTEE

ADVISOR
Y.Bhg Dato’ Dr Azmi Shapie
Director
Medical Development Division
Ministry of Health

AUTHORS
Dr Keng Wee Teik
Consultant Clinical Geneticist
Kuala Lumpur Hospital

Professor Dr Thong Meow Keong

Consultant Clinical Geneticist
University Malaya Medical Centre

Dr Ngu Lock Hock

Consultant Clinical Geneticist
Kuala Lumpur Hospital

Associate Professor Zarina Abd Latif

Consultant Clinical Geneticist
National University of Malaysia Medical Centre

Dr Rowani Mohd Rawi

Consultant Clinical Geneticist
Hospital University Science Malaysia

SECRETARIAT

Dr Noor Aziah Zainal Abidin Dr Jafanita Jamaludin

Senior Principal Assistant Director Principal Assistant Director
O & G /Pediatric Services Division O & G /Pediatric Services Division
Medical Development Division Medical Development Division
Ministry of Health Ministry of Health

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 ACKNOWLEDGEMENT

Medical Services Development Section would like to express our

gratitude and appreciation to :-

Y.Bhg. Datuk Dr. Noor Hisham bin Abdullah, Deputy Director General of
Health (Medical) and Y.Bhg. Dato’ Dr. Azmi bin Shapie, Director of Medical
Development Division, Ministry of Health Malaysia for their
continuing support and services rendered;

All members of the committee for their contributions in drawing up the guideline;

And last but not least to all those who provided valuable input and
feedback to make this publication a success.

118 Guidelines for treatment of lysosomal storage diseases

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Medical Development Division

Block E1, Parcel E, Federal Government Administrative Centre,

62590 Putrajaya, Malaysia.
(T) 603-8883 1047 (F) 603-8883 1427

Kementerian Kesihatan Malaysia

(Ministry of Health

http://www.moh.gov.my