Congenital Myasthenic Syndromes

L.J.Basumatary
MD, DM Neurology Resident
Gauhati Medical College & Hospital
Guwahati

[email protected]
• CMS : mutations that alter the expression and function of
– ion channels,
– receptors,
– enzymes, or
– other accessory molecules needed to maintain the safety margin of
NMT
• Important cause of seronegative myasthenia.
• Advances in molecular genetics and correlation of molecular
biology with microphysiology, morphologic studies, clinical
electrophysiology, and clinical observations have led to a
better understanding of the pathophysiology of CMS
• Many CMS can be Dx and in many cases given specific Rx,
based on the results of clinical information and Edx
evaluation
• Heterogeneous group of NM disorders caused
by genetic defects of endplate molecules
involved in NM transmission
(Engel and Sine, 2005)
• Present in infancy, childhood or later.

• May resemble
 Neonatal or adult-onset myasthenia gravis (MG)
 Lambert-Eaton syndrome (LES).
Differential diagnosis

 Seronegative myasthenia gravis

 Myopathy
 Peripheral neuropathy
 Motor neuron diseases
 PREVALENCE

 Unknown

 Underdiagnosis
 Incomplete characterization
 Misdiagnosis
 Classification of CMS

• Presynaptic CMS

 CMS with episodic apnea (disorder of ACh

resynthesis and packaging)
 CMS with deficiency of synaptic vesicles
 CMS resembling Lambert-Eaton syndrome
 CMS with nystagmus and ataxia (deficient action
potential-dependent release of ACh)
Synaptic CMS

 Congenital endplate acetylcholinesterase deficiency

 Postsynaptic CMS AChR deficiency
(recessive AChR subunit mutations)

• Altered AChR channel kinetics

 Slow-channel CMS
 Low-affinity fast-channel CMS
 High-conductance fast-channel CMS
 CMS with AChR deficiency and short channel open
time
 CMS with plectin deficiency
• Poorly characterized CMS
 WORKUP AND DIAGNOSTIC STUDIES

• Suspected in any person presenting with

 Fatigable ocular
 Bulbar
 Limb weakness during infancy or early childhood
 With a positive family history
• Decremental response in the CMAP:
RNS low frequency (2 Hz) is strongly s/o impaired
NM transmission, but may only be present in a few
muscle groups.

• SFEMG : abnormal jitter and blocking.

• AChR antibody : Negative

Diagnosis of a particular CMS may be made
based on
 C/F
 Electrophysiologic testing
 Response to Rx
• Prominent weakness
 Cervical
 Wrist
 Finger extensor muscles

• Repetitive CMAPs in response to a single

nerve stimulus :
 Slow channel CMS
 Endplate AChE deficiency
Endplate AChE deficiency
 Lack of response to AChE inhibitors
 Delayed pupillary light reflex

Recurrent apneic episodes

 Defective ACh resynthesis and packaging

CMS with plectin deficiency

 Epidermolysis bullosa
 Congenital AChE SCCMS
deficiency
Pupillary hyporeflexia Hand & Neck muscle
Progressive myopathy weakness
Progressive myopathy
 Presynaptic CMS

Defect in Acetylcholine Resynthesis or Packaging

 AR
 Familial infantile myasthenia
 Typically manifest at birth
 Hypotonia
 Bulbar and respiratory weakness
 Ptosis
 Extraocular muscle weakness{mild}
• Respiratory insufficiency with Rec. apnea
• Death
• Improve with age (majority)
• May persist into adulthood and may cause
respiratory failure precipitated by infections,
fever etc

• Rx
– Anticholinesterase drugs
 Transitory Neonatal Myasthenia

• Approx. 15% of newborns of myasthenic mothers

(Hoff et al, 2003)
• Passive transfer of antibody directed against fetal
AChR
• Fetal AChR is structurally different from adult AChR.
• The severity of symptoms
 Correlates with the ratio of fetal to adult AChR antibodies
in the mother
 Not with the severity or duration of weakness in the
mother.
 Clinical Features: TNM

 Hypotonic in utero
 Arthrogryposis
 Feeding difficulties
 Generalized hypotonia
 Eager to feed, but the ability to suck fatigues quickly
 Onset within hours of birth but delay until the 3rd D
PP.
 Weakness of cry and lack of facial expression: 50%
 Limitation of EOM & Ptosis: 15%
• Respiratory insufficiency : Uncommon

• Weakness becomes progressively worse in the

first few days and then improves.

• Duration of symptoms is 18 Ds (5 D- 2 mn)

• Complete recovery

• TNM does not develop into MG later in life.

 Diagnosis
 High serum concentrations of AChR binding Ab

 Temporary reversal of weakness :S/c or I/V inj.

edrophonium chloride, 0.15 mg/kg
 Management
• Plasma exchange
 Severe generalized weakness
 Respiratory distress

• Mild form: 0.l% Neostigmine IM inj before

feeding
• Progressively reduce the dose
• An alternative route :
– NG tube at a dose 10 x that of the parenteral
 CLINICAL MANIFESTATIONS of CMS

 Depend on the age at presentation

 H/o ↓ Fetal movements

• Fluctuating and Fatigable Weakness
 Crises triggered by exertion or intercurrent illness
• Hypotonia and Generalized Weakness
 Delayed motor development
 Muscle hypotrophy
• Cranial Muscle Weakness
 Ptosis and EO muscle weakness (pupil abnormalities
in AChE deficiency)
 Facial weakness
 Chewing and feeding difficulties
 High-arched palate
• Respiratory Insufficiency
 CNS signs secondary to episodic hypoxic injury
• Skeletal Deformities
 Facial dysmorphism
 Arthrogryposis multiplex
 Scoliosis
• Family History
 Affectedsiblings in AR disorders (M/C)
 Generational transmission in SCCMS AD inheritance
 Spontaneous abortions or SIDS
Benefit From AChE Inhibitors

 All except AChE deficiency & SCCMS

• When CMS presents during late childhood or
in adulthood, the Sx is difficult to differentiate
clinically from autoimmune MG or myopathy
• SCCMS is most likely to present at this age
because it is the only CMS that follows an AD
pattern of inheritance.
• A family h/o of affected relatives in other
generations is common in SCCMS
• Skeletal deformities:
– scoliosis or lordosis
 C/F of CMS in Late
Childhood and Adults

• Fluctuating and Fatigable Weakness

– Crises triggered by exertion or intercurrent illness
• Generalized/ Cranial Muscle Weakness
• Respiratory Insufficiency
• Skeletal Deformities
• Personal H/o of NM Problems in Infancy or Early
Childhood
• Family History
• Benefit From AchE Inhibitors
– All except AchE deficiency and SCCMS
Classification of Congenital
Myasthenic Syndromes (Based on 271
Index Cases Evaluated at Mayo Clinic)
(Engel et al, 2003; Engel and Sine, 2005)

Continuum Lifelong Learning

Neurol 2009;15(1)
 Postsynaptic Defects (79%)

Reduced AChR expression (with or without minor AChR kinetic

abnormality)
 AChR mutations (isolated or with plectin deficiency)
 Rapsyn mutations

DOK-7 mutations (formerly limb–girdle myasthenia)

AChR kinetic abnormality

 Slow-channel syndrome
 Fast-channel syndrome

Sodium-channel mutations
Synaptic Defect (Basal Lamina) (14%)
 Endplate AchE deficiency
Presynaptic Defects (7%)

 ChAT deficiency
 Paucity of synaptic vesicles
 Congenital Lambert-Eaton–like syndrome
 Other unclassified presynaptic defects
 Acetyl-coA  Pyruvate (mitochondria )
+
Choline  ECF (50%) + acetylcholine breakdown
Choline acetlytransferase
Acetylcholine

Acetylcholinesterase (AChE)

Choline + Acetate
 Acetylcholine Receptors
 Nicotinic acetylcholine receptors
 Average 50 million
 5 polypeptide subunits that form a ring structure
around a central, funnel-shaped pore
 Adult receptor
 2 identical α (alpha) subunits
 one β
 one δ
 one ε
 In the foetus a γ subunit replaces the ε
• Extra-junctional receptors, or on the pre-
terminal bulb and are called pre-junctional
receptors.
α-subunit of the AchR
Escobar syndrome
 Arthrogryposis multiplex
 Pterygia
 Respiratory distress
 a/w mutations of the g-subunit

(Hoffman et al, 2006)

 Rapsyn mutations

• Rapsyn
– receptor associated protein at synapse
• Mediates agrin and MuSK-induced clustering
of AChRs on the crests of the postsynaptic
folds of the NMJ
(Ramarao et al, 2001)
C/F Rapsyn mutations

• Varies considerably
• Mutations of the α , β , and –subunits: severe
phenotypes
• ε -subunit mutations :mild
• Relatively nonprogressive
• Even improve slightly with age.
Arthrogryposis Multiplex
 Diagnosis

• Congenital AChR deficiency should be suspected in infants

 Hypotonia
 Arthrogryposis multiplex
 Skeletal deformities
 Ptosis, weak cry, cough, feeding difficulties, respiratory
insufficiency
• D/D
 Congenital myopathy or dystrophy
 MND
 Inherited neuropathies
 CNS disorders
• RNS at slow rates (2 Hz to 3 Hz) :
– decrement of the CMAP
• The decrement is partially repaired
– cholinesterase inhibitors or
– 3,4-diaminopyridine
(Engel, 2007)
• In moderate to severe cases,
– the decrement worsens with higher rates of RNS
(10 Hz to 50 Hz).
• Needle EMG and SFEMG :
– congenital AChR deficiency are nonspecific.
• Muscle biopsy:
– nonspecific in congenital AChR deficiency with
type II fiber atrophy as the predominant feature
(Engel et al, 2003)
• CMS caused by AChR deficiency
– Difficult to differentiate clinically and EDx from
seronegative autoimmune MG
• Specific diagnosis:
– Intercostal muscle Bx
– Genetic analysis
 Natural history and treatment

• CMS associated with AChR deficiency

 Relatively nonprogressive
 May improve slightly with age
 Typically responds to symptomatic Rx with
pyridostigmine and/or 3,4-DAP
(Engel, 2007)
• Ephedrine
• Immunotherapy has no effect
 DOK-7 Mutations
Dok-7
 Muscle cytoplasmic protein
 Activates MuSK
 Critical in endplate development and AChR aggregation
(Muller et al, 2007)

• Distinctive clinical phenotype of relatively isolated

proximal limb weakness (limb-girdle myasthenia)

• C/F largely indistinguishable from patients with AChR

deficiency (Selcen et al, 2007)
• EDx studies are indistinguishable from
patients with other causes of congenital AChR
deficiency (Selcen et al, 2007)
• Response to AChEIs
– variable, with some patients improving but many
demonstrating no response.
• Ephedrine and 3,4-DAP produce modest
benefits
(Muller et al,2007; Selcen et al, 2007)
 Slow-channel CMS [SCCMS]
• M/C CMS
• Kinetic abnormality of the AChR (Engel and Sine, 2005)
• Increase the rate of channel opening
• Slow the rate of closure
• ↑ affinity of the Receptor for Ach
• Slows the decay of endplate currents
• Permits cationic overload of the synaptic region of the
muscle fiber.
• AD, [recessive mutations reported]
(Croxen et al, 2002; Engel et al, 1996)
• Mutations of the transmembrane segments
tend to produce a more severe phenotype than
those of the extracellular domain.
ACh receptor subunit mutations
SCCMS
 C/F SCCMS
• Variable expression, wide spectrum
• Infancy or early childhood to seventh decade.
• Characteristic Features
 Muscles of the neck
 Distal regions of the upper limbs
 Intrinsic hand muscles
 Digit extensors are weak and atrophic
• Worsening of the symptoms with
administration of ChE-I helps differentiate
SCCMS from autoimmune MG and other CMS
(except congenital AChE deficiency).
• Mutational analysis
• Muscle biopsy
 Degeneration of the postsynaptic folds
 Subsarcoplasmic regions of the muscle fiber in the
endplate region
 Endplate myopathy

Engel et al, 2003

 Natural history and treatment

• Without Rx, the condition worsens over years as the endplate

myopathy progresses.

• ChE-I typically worsen symptoms

 prolonging endplate currents
 promoting further desensitization of the receptor.

• Quinidine & Fluoxetine

– ↓ duration of AChR channel
– Effective Rx SCCMS

Harper et al, 2003; Harper and

Engel,1998
 Congenital fast-channel myasthenic
syndrome

• Mirror image of the SCCMS

• Fast-channel mutations shorten the duration

of AChR channel openings
 ↓ Receptor’s affinity for ACh
 Impairing channel-gating efficiency
 Destabilizing channel kinetics

Brownlow et al, 2001; Ohno et al, 1996;

Shen et al, 2002
• Presents in infancy or early childhood
• Ptosis , ophthalmoparesis
• Dysphagia, dysarthria
• Exertional weakness of axial & limb muscles
• Responds favorably
– ChE-I
– 3,4-diaminopyridine
(Engel,
2007)
 Natural history & Rx FCCMS
• Static or slowly progressive
• Rx
 3,4-diaminopyridine (enhances release of ACh)
 pyridostigmine (reduces metabolism of Ach)

• Cases of pure kinetic abnormalities and

relatively normal expression AChRs respond
best to Rx
 Sodium-channel CMS

• A single case of Na-channel myasthenic

syndrome has been described a/w two
recessive mutations in the skeletal muscle
sodium-channel gene SCN4A
(Tsujino, 2003)
SYNAPTIC BASAL LAMINA-ASSOCIATED DEFECTS

• Congenital Acetylcholinesterase Deficiency

• Recessive mutations of COLQ Gene
responsible for synthesis of ColQ
• Triple stranded collagenous tail of the
heteromeric AChE molecule at the motor
endplate
(Ohno et al, 2000)
• ColQ
– Anchoring the globular catalytic subunits of AChE
to the basal lamina of the postsynaptic membrane
 ColQ

Semin Neurol 2004;24(1):111–123.

Absence or dysfunction of endplate AChE
 ↑ exposure of ACh to its receptor
 ↑ Endplate currents
 Receptor desensitization
 Depolarization block of the muscle membrane at
physiologic rates of contraction.

↑ endplate currents lead to cationic overload

and an endplate myopathy (SSCMS)
 C/F ColQ

• Infancy or early childhood

• Generalized weakness
• Underdevelopment of muscles
• Slowed pupillary responses to light
• No response or clinical worsening with ChE-I
• Skeletal deformities
– Lordosis or scoliosis

Hutchinson et al, 1993

Nerve conduction studies

• one or more R- CMAPs with single stimuli

• SCCMS is the only other congenital disorder

associated with repetitive CMAPs

• Can be differentiated from ChE by observing the

effect of IV edrophonium or prostigmine on the
number and size of repetitive potentials
• Administration of ChE-I has no effect because there is
little or no cholinesterase to inhibit.

• ChE-I increase the number and size of repetitive CMAPs in

SCCMS.

• The R-CMAPs increase in size and number following

administration of edrophonium in SCCMS but not in AChE
deficiency.

• AChE deficiency: AR
• SCCMS: AD
 Natural history and treatment

• Infantile cases are typically quite severe, and mild to

moderately severe cases tend to progress over time as
the endplate myopathy worsens.

• No effective long-term Rx

• ChE-I do not help and may make symptoms worse.

• Ephedrine produces subjective benefit in some patients

Engel, 2007; Milone and Engel, 1996
PRESYNAPTIC DEFECTS CAUSING CMS

Congenital Choline Acetyltransferase Deficiency

Δ Familial infantile myasthenia (Conomy et al, 1975)
Δ Congenital myasthenic syndrome with episodic apnea
(Kraner et al, 2003)

Δ Mutations in the CHAT gene

Δ Absence or impaired function of ChAT

↓ Ach release with eventual failure of NM
transmission.
 Severe cases ACh is depleted rapidly

 Characteristic sudden crises

 generalized weakness, dysphagia, and respiratory
insufficiency

 Less in adolescence and adulthood

 Family h/o ‘‘SIDS’’ particularly affecting

previously born siblings
Clues to the diagnosis ChAT deficiency
Episodic acute prolonged crises
↓ in the number and severity of crises with age
Decremental response on RNS during a crisis

Progressive pattern of decrement

 Autoimmune MG
 Congenital AChR deficiency
 More severe and recovers more slowly
(over 10 -15 min) in ChAT deficiency
 Natural history and treatment

• If patients with endplate ChAT deficiency survive

infancy and childhood, the symptoms generally
improve gradually with age.

• Adults are often minimally disabled by their

symptoms and respond modestly to
pyridostigmine

• 3,4-DAP may produce transient benefit

Engel, 2007
 CONCLUSIONS

• CMS are a heterogeneous group of disorders

resulting from genetically determined defects in
NMT

• A CMS should be suspected in any patient with

fatigable ocular, bulbar, or limb weakness presenting
in infancy or early childhood, or in older patients
who are anti-AChR and anti–MuSK-antibody negative
and fail to respond to immunosuppressant Rx
• Certain clinical features, such as a delayed
pupillary light reflex, prominent weakness of
finger/wrist extensors, scoliosis, or a repetitive
CMAP, may aid in making a diagnosis in certain
cases

• Definitive diagnosis in many cases requires

detailed morphologic, microphysiologic, and
genetic studies.
Thank you