Muscle diseases

Dr. Omar A. Mahmood

Objectives
• To classify muscle diseases
• To know some types of hereditary and acquired
muscle diseases
• To describe management of some treatable
muscle diseases.
Muscle disease, either hereditary or acquired, is
rare. Most typically, it presents with a proximal
symmetrical weakness.
Diagnosis is dependent on recognition of clinical
clues, such as cardiorespiratory involvement,
evolution, family history, exposure to drugs, the
presence of contractures, myotonia and other
systemic features.
Investigations for muscle diseases:
• Muscle enzymes ; especially CPK
• EMG
• Muscle biopsy
• Gene testing
Fig 1. Normal muscle biopsy (haematoxylin and eosin stain)
Hereditary syndromes include the muscular
dystrophies, muscle channelopathies, metabolic
myopathies (including mitochondrial diseases) and
congenital myopathies.
Muscular dystrophies
Duchenne's Muscular Dystrophy
This X-linked recessive disorder, has an incidence of 30 per
100,000 live-born males. Duchenne's dystrophy is present at
birth, but the disorder usually becomes apparent between ages 3
and 5 years. The boys fall frequently and have difficulty keeping
up with friends when playing. By age 5 years, muscle weakness
is obvious by muscle testing. On getting up from the floor, the
patient uses his hands to climb up himself (Gowers' maneuver).
Contractures of the heel cords become apparent by age 6 years,
when toe walking is associated with a lordotic posture.
By age 12 years, most patients are wheelchair
dependent. Contractures become fixed, and a
progressive scoliosis often develops that may be
associated with pain. The chest deformity with
scoliosis impairs pulmonary function, which is
already diminished by muscle weakness. By age
16–18 years, patients are predisposed to serious,
sometimes fatal pulmonary infections. A cardiac
cause of death is uncommon despite the presence
of a cardiomyopathy in almost all patients.
• Laboratory Features
• Serum CK levels are invariably elevated to between 20 and
100 times normal.
• EMG demonstrates features typical of myopathy.
• The muscle biopsy shows muscle fibers of varying size as well
as small groups of necrotic and regenerating fibers.
Connective tissue and fat replace lost muscle fibers.
• A definitive diagnosis of Duchenne's dystrophy can be
established on the basis of dystrophin deficiency in a biopsy of
muscle tissue or mutation analysis on peripheral blood
leukocytes.
• Treatment
• Glucocorticoids can be used in Duchenne muscular dystrophy but
side-effects should be anticipated and avoided by dose modification.
• Ataluren is a compound given by infusion to affected individuals
that may ‘override’ the stop codon in Duchenne, theoretically
leading to normalisation of muscle proteins and potentially
reducing or arresting functional deteriorations.
• Treatment of associated cardiac failure or arrhythmia (with
pacemaker insertion if necessary) may be required; similarly,
management of respiratory complications (including nocturnal
hypoventilation) can improve quality of life. Improvements in non-
invasive ventilation have led to significant improvements in survival
for patients with Duchenne muscular dystrophy.
• Genetic counselling is important.
 • Becker's Muscular Dystrophy
This less severe form of X-linked recessive
muscular dystrophy results from allelic defects of
the same gene responsible for Duchenne's
dystrophy.
Clinical features
Most patients with Becker's dystrophy first
experience difficulties between ages 5 and 15 years,
although onset in the third or fourth decade or
even later can occur. By definition, patients with
Becker's dystrophy walk beyond age 15. Patients
with Becker's dystrophy have a reduced life
expectancy, but most survive into the fourth or
fifth decade.
The diagnosis of Becker's muscular dystrophy
requires Western blot analysis of muscle biopsy
samples, demonstrating a reduced amount or
abnormal size of dystrophin or mutation analysis
of DNA from peripheral blood leukocytes.
Fig 2. Dystrophin cytoskeleton
Fig 3. Immunohistochemistry of dystrophin antibodies
in 4 different diseases
 • Myotonic Dystrophy
The condition is composed of at least two clinical
disorders with overlapping phenotypes and distinct
molecular genetic defects: myotonic dystrophy type
1 (DM1), and myotonic dystrophy type 2 (DM2).
 • Clinical Features
Affected patients have a typical "hatchet-faced" appearance
due to temporalis, masseter, and facial muscle atrophy and
weakness. Frontal baldness is also characteristic of the
disease. Neck muscles, including flexors and sternocleido-
mastoids, and distal limb muscles are involved early.
Weakness of wrist extensors, finger extensors, and intrinsic
hand muscles impairs function. Ankle dorsiflexor weakness
may cause foot drop. Palatal, pharyngeal, and tongue
involvement produce a dysarthric speech, nasal voice, and
swallowing problems. Some patients have diaphragm and
intercostal muscle weakness, resulting in respiratory
insufficiency.
Myotonia, which usually appears by age 5 years, is
demonstrable by percussion of the thenar
eminence, the tongue, and wrist extensor muscles.
Myotonia causes a slow relaxation of hand grip
after a forced voluntary closure.
Cardiac disturbances occur commonly in patients
with DM1. ECG abnormalities include first-degree
heart block and more extensive conduction system
involvement. Complete heart block and sudden
death can occur. Other associated features include
intellectual impairment, hypersomnia, posterior
subcapsular cataracts, gonadal atrophy, insulin
resistance, and decreased esophageal and colonic
motility.
DM2, has a distinct pattern of muscle weakness
affecting mainly proximal muscles. Other features
of the disease overlap with DM1, including
cataracts, testicular atrophy, insulin resistance,
constipation, hypersomnia, and cognitive defects.
• Diagnosis
• The diagnosis of myotonic dystrophy can usually be
made on the basis of clinical findings.
• Serum CK levels may be normal or mildly elevated.
• EMG evidence of myotonia is present in most cases
of DM1 but may be more patchy in DM2.
• Muscle biopsy shows muscle atrophy, which
selectively involves type 1 fibers in 50% of cases, and
ringed fibers in DM1 but not in DM2.
• DM1 is caused by expansion of a CTG trinucleotide
repeat in a serine-threonine protein kinase gene
(named DMPK) on chromosome 19q13.3.
• Treatment
• Phenytoin and mexiletine are the preferred agents for
myotonia.
• A cardiac pacemaker should be considered for patients with
unexplained syncope, advanced conduction system
abnormalities with evidence of second-degree heart block, or
trifascicular conduction disturbances with marked
prolongation of the PR interval.
• Molded ankle-foot orthoses help stabilize gait in patients with
foot drop.
• Excessive daytime somnolence with or without sleep apnea is
not uncommon. Sleep studies, noninvasive respiratory
support ;biphasic positive airway pressure (BiPAP), and
treatment with modafinil may be beneficial.
Metabolic myopathies
This group of diseases is divisible into three major
categories:
• Disorders of carbohydrate metabolism,
• Disorders of lipid metabolism, and
• Disorders of mitochondrial function.
• Disorders of Carbohydrate Metabolism
Myophosphorylase deficiency(Mc Ardle disease):
Onset of symptoms is during the first 10 years of life.
As children, patients may complain of being tired and
unable to keep up with their playmates. Fatigue and
pain begin within the first few minutes of exercise,
particularly if it is strenuous. If exercise is continued,
pain develops within the muscle, which at first is deep
and aching but gives way to the rapid development of a
painful tightening of the muscle. The muscle is hard
and contracted, and any attempt to straighten it results
in great pain.
The muscle contracture may last for several hours
and can be differentiated from a muscle cramp on
two counts: the EMG is electrically silent, and the
duration of the contracture is far longer than that
of a physiological cramp. Another aspect of Mc
Ardle disease is the development of the second-
wind phenomenon. If, with the onset of fatigue,
the patient slows down but does not stop, the
abnormal sensation may disappear, and thereafter
the muscle may function more normally.
 • Acid maltase deficiency (Pompe’s disease)
Three clinical forms of acid maltase deficiency can be
distinguished:
• The infantile form is the most common, with onset of
symptoms in the first 3 months of life. Infants develop severe
muscle weakness, cardiomegaly, hepatomegaly, and
respiratory insufficiency. Glycogen accumulation in motor
neurons of the spinal cord and brainstem contributes to
muscle weakness. Death usually occurs by 1 year of age.
• In the childhood form, the picture resembles muscular
dystrophy. Delayed motor mile-stones result from proximal
limb muscle weakness and involvement of respiratory
muscles. The heart may be involved, but the liver and brain
are unaffected.
• The adult form usually begins in the third or
fourth decade but can present as late as the
seventh decade. Respiratory failure and
diaphragmatic weakness are often initial
manifestations, heralding progressive proximal
muscle weakness. The heart and liver are not
involved.
Pompe’s disease is inherited as an autosomal
recessive disorder caused by mutations of the α-
glucosidase gene. Enzyme replacement therapy
(ERT) with IV recombinant human α-glucosidase
has been shown to be beneficial in infantile-onset
Pompe’s disease.
• Mitochondrial myopathies
Mitochondria are present in all tissues and dysfunction
causes widespread effects, on vision (optic atrophy, retinitis
pigmentosa, cataracts), hearing (sensorineural deafness),
and the endocrine, cardiovascular, gastro-intestinal and
renal systems. Any combination of these should raise the
suspicion of a mitochondrial disorder, especially if there is
evidence of maternal transmission. Genetic abnormalities
or mutations in mitochondrial DNA may affect single
individuals and single tissues (most commonly muscle).
Thus, patients may present with exercise intolerance,
myalgia and sometimes recurrent myoglobinuria .
Diagnosis is based on clinical appearances,
supported by muscle biopsy appearance (usually
with ‘ragged red’ and/or cytochrome oxidase
negative fibres), and specific mutations either on
blood or, more reliably, muscle testing.
Fig 4. Ragged red fibers in Gomori trichome stain
Periodic paralyses
The periodic paralysis syndromes, which may be
familial (dominant inheritance), are characterized
by episodes of flaccid weakness or paralysis with
preserved ventilation that may be associated with
abnormalities of the serum potassium level.
Strength is normal between attacks.
 • Hypokalemic periodic paralysis
In the hypokalemic form, attacks tend to occur on
awakening, after exercise, or after a heavy meal, and
may last or several days. The disorder is due to a
mutation in gene encoding skeletal muscle calcium
channel. Acetazolamide (250-750 mg daily) or oral
potassium supplements may prevent attacks, as also
may a low salt and low carbohydrate diet. Ongoing
attacks may be arrested by potassium chloride given
orally or even intravenously. All patients with
suspected hypokalemic periodic paralysis should be
screened for thyroid disease, as it may be associated
with hyperthyroidism.
 • Hyperkalemic periodic paralysis
Attacks associated with hyperkalemia also tend to
come on after exercise but are usually much
briefer, lasting less than 1 hour. Severe attacks may
be terminated by intravenous calcium gluconate (1-
2 g), intravenous diuretics (furosemide 20-40 mg),
or glucose, and daily acetazolamide or
chlorothiazide may help prevent further episodes.
Many families with this disorder have mutations in
the gene encoding voltage-gated sodium channel.
Acquired myopathies
These include the inflammatory myopathies, or
myopathy associated with a range of metabolic and
endocrine disorders or drug and toxin exposure
Fig 5. Acquired myopathy
Inflammatory myopathies
The inflammatory myopathies represent the
largest group of acquired and potentially treatable
causes of skeletal muscle weakness. They are
classified into three major groups: polymyositis
(PM), dermatomyositis (DM), and inclusion body
myositis (IBM).
• Polymyositis
It is a subacute inflammatory myopathy affecting adults, and
rarely children, who do not have any of the following: rash,
involvement of the extraocular and facial muscles, family history
of a neuromuscular disease, history of exposure to myotoxic
drugs or toxins, endocrinopathy, neurogenic disease, muscular
dystrophy, biochemical muscle disorder (deficiency of a muscle
enzyme), or IBM as excluded by muscle biopsy analysis. As an
isolated entity, Polymyositis is a rare (and over diagnosed)
disorder; more commonly, Polymyositis occurs in association
with a systemic autoimmune or connective tissue disease, or
with a known viral or bacterial infection. Drugs, especially d-
penicillamine, statins, or zidovudine (AZT), may also trigger an
inflammatory myopathy similar to PM.
• Dermatomyositis
DM is a distinctive entity identified by a characteristic rash
accompanying, or more often preceding, muscle weakness. The rash
may consist of a blue-purple discoloration on the upper eyelids with
edema (heliotrope rash), a flat red rash on the face and upper trunk,
and erythema of the knuckles with a raised violaceous scaly eruption
(Gottron's sign).The erythematous rash can also occur on other body
surfaces, including the knees, elbows, malleoli, neck and anterior chest
(often in a V sign), or back and shoulders (shawl sign), and may
worsen after sun exposure. In some patients, the rash is pruritic,
especially on the scalp, chest, and back. Dilated capillary loops at the
base of the fingernails are also characteristic. The cuticles may be
irregular, thickened, and distorted, and the lateral and palmar areas of
the fingers may become rough and cracked, with irregular, "dirty“
horizontal lines, resembling mechanic's hands.
• Inclusion Body Myositis
In patients 50 years of age, IBM is the most common of the
inflammatory myopathies. It is often misdiagnosed as PM and is
suspected only later when a patient with presumed PM does not
respond to therapy. Weakness and atrophy of the distal muscles,
especially foot extensors and deep finger flexors, occur in almost all
cases of IBM and may be a clue to early diagnosis. Some patients
present with falls because their knees collapse due to early quadriceps
weakness. Others present with weakness in the small muscles of the
hands, especially finger flexors, and complain of inability to hold
objects. On occasion, the weakness and accompanying atrophy can be
asymmetric and selectively involve the quadriceps, iliopsoas, triceps,
biceps, and finger flexors, resembling a lower motor neuron disease.
Dysphagia is common, occurring in up to 60% of IBM patients, and
may lead to episodes of choking.
Treatment:
• Glucocorticoids.
• Other immunosuppressive drugs.
• immunomodulation.
References
• Davidsons principles and practice of
medicine,23 rd edition.
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