Congenital Myasthenic Syndromes

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

‡ 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

iagnosis 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 deficiency
Pupillary hyporeflexia Progressive myopathy

Hand & Neck muscle 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.

High serum concentrations of AChR binding Ab  Temporary reversal of weakness :S/c or I/V inj. edrophonium chloride, 0.15 mg/kg

‡ 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


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
Affected siblings 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

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 one one one

(alpha) subunits 

In the foetus a subunit replaces the

‡ Extra-junctional receptors, or on the preterminal bulb and are called pre-junctional receptors.

-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 , , and subunits: severe phenotypes ‡ -subunit mutations :mild ‡ Relatively nonprogressive ‡ Even improve slightly with age.

Arthrogryposis Multiplex

‡ Congenital AChR deficiency should be suspected in infants 

Hypotonia Arthrogryposis multiplex Skeletal deformities Ptosis, weak cry, cough, feeding difficulties, respiratory insufficiency Congenital myopathy or dystrophy MND Inherited neuropathies CNS disorders

‡ D/D

‡ 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
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

‡ 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 (Selcen et al, 2007) deficiency ‡ 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

‡ 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


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

Familial infantile myasthenia
(Conomy et al, 1975)

Congenital myasthenic syndrome with episodic apnea (Kraner et al, 2003)

Mutations in the CHAT gene 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

‡ 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 MuSKantibody 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.

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