Table 1.

Congenital Myasthenic Syndromes: CMS Subtypes and Distinguishing Clinical Features

CMS Subtype 1% of All CMSGene(s) 2Distinguishing Clinical FeaturesResponse to AChE Inhibitors
Acetylcholine receptor (AChR) deficiency50% 3 CHRNA1
AChR deficiency (AR)
  • Early onset
  • Mild to severe
  • Ptosis, EOP; bulbar, arm, leg weakness
Slow-channel CMS (SCCMS)SCCMS (AD)
  • Selective severe neck, wrist, finger extensor weakness
  • Childhood to adult onset
  • Mild to severe
  • Progressive ventilatory insufficiency; may require assisted ventilation
Fast-channel CMS (FCCMS)FCCMS (AR): Mild to severeImprovement
Defect in AChR clustering pathway15%-20% RAPSN Early onset:
  • Hypotonia, respiratory failure at birth
  • Episodic apnea
  • Arthrogryposis multiplex congenita
  • Mild to severe
Late onset:
  • Limb weakness in adolescence or adulthood; as in seronegative myasthenia gravis
10%-15% DOK7 Limb-girdle pattern of predominantly proximal weakness, waddling gait, & ptosis but no EOPDeterioration or ineffective
<1% LRP4 Respiratory failure at birth, delayed motor milestones, ptosis, ophthalmoparesis, limb weaknessSee footnote 4.
<1% MUSK Broad phenotype
  • Prenatal onset w/fetal akinesia deformation sequence
  • Early onset w/ophthalmoplegia & respiratory failure
  • Isolated vocal cord paralysis 5
  • Late-onset limb girdle weakness 6
Deterioration or ineffective
Plectin deficiency<1% PLEC Childhood to adulthood onset:
  • Fatigable proximal myopathy & ptosis
  • W/or w/o skin blistering
Defect in skeletal muscle voltage-gated sodium channel<1% SCN4A Phenotype overlapping w/SCN4A-assoc skeletal muscle sodium channelopathies: periodic paralysis, myotonia, myopathySee footnote 4.
Endplate AChE deficiency10%-15% COLQ
  • Often severe
  • In some w/C-terminal missense pathogenic variants: later presentation, milder clinical course
  • EOP
  • General muscle weakness / severe involvement of axial muscles
  • Slow pupillary light response
Deterioration or ineffective
1%-2%; >14 independent kinships reported COL13A1
  • At birth, respiratory distress & dysphagia; may resolve
  • Recurrent apnea triggered by infections
  • In adulthood, bilateral nonfatigable ptosis & marked axial weakness
  • Sometimes improvement of muscle weakness by adulthood
Likely ineffective
Defects in AChR clustering pathway<1% AGRN
  • Early-onset or late-onset phenotype
  • Persons w/late onset may present w/distal muscle weakness & wasting in addition to myasthenia
Defect in ACh synthesis4%-5% CHAT
  • Hypotonia, respiratory failure at birth
  • Episodic apnea
  • Improvement w/age
Defects in ACh recycling<1% SLC5A7
  • Early onset
  • More severe than CHAT-related CMS
  • Arthrogryposis/joint contractures, apneic crisis at birth, marked ptosis, ophthalmoplegia, & muscle fatigability
  • Some have limited survival, some have milder phenotypes.
  • Some w/learning difficulties
Some improvement
<1% SLC18A3 Similar to SLC5A7Some improvement
Defects in synaptic vesicle docking, priming, fusing, & exocytosis<1% SNAP25 Myasthenia is element of a severe & complex phenotype:
  • Developmental & epileptic encephalopathy of infancy & childhood w/diverse clinical manifestations
  • Severe ID, cerebellar ataxia, brain atrophy
See footnote 4.
<1% VAMP1
  • Early-onset phenotype w/severe congenital hypotonia & muscle weakness, feeding difficulties, delayed motor development, ophthalmoparesis.
  • May have joint contractures or joint laxity
  • May have respiratory insufficiency
Likely improvement 4
<1% SYT2
  • AR: Severe congenital-onset hypotonia & weakness, w/variable degrees of respiratory involvement; mimics severe congenital myopathy
  • AD: Mimics distal hereditary motor neuropathy, slowly progressive distal motor neuropathy, & myasthenic syndrome
See footnote 4.
  • Congenital hypotonia, feeding difficulties, ptosis, & proximal muscle weakness
  • Growth hormone deficiency
  • See footnote 7.
Acetylcholinesterase inhibitors possibly beneficial in infancy 4
Defects in axonal transport of proteins<1% MYO9A
  • Early onset, ptosis, ophthalmoplegia & moderate global weakness, bulbar involvement, respiratory crises
  • Addl CNS symptoms: ID or learning difficulties, nystagmus, oculomotor apraxia
Improvement 4
Defect in mitochondrial citrate carrier<1% SLC25A1
  • Relatively mild CMS phenotype w/ID
  • Subtle mitochondrial abnormalities
Improvement 4
Pre- &
Limb-girdle-myasthenia w/glycosylation deficiency<1% ALG2
Overlap w/CDG syndromesSee footnote 4.
1%-2% DPAGT1
  • "Limb-girdle" pattern of weakness w/predominantly proximal weakness but usually no ptosis or EOP; tubular aggregates on muscle biopsy in some
  • ID may occur in DPAGT1-assoc CMS.
  • GMPPB assoc w/high CK & muscular dystrophy.

ACh = acetylcholine; AChE = acetylcholinesterase; AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorders of glycosylation; CNS = central nervous system; EOP = external ophthalmoplegia; ID = intellectual disability


CMS subtypes are grouped by site of defect and mechanism of neuromuscular junction defect.


Additional genes are published as CMS genes or genes with an underlying pathology of the neuromuscular junction, but to date have been reported in only one or two studies. These genes include: postsynaptic proteins RPH3A, MACF1, and CHD8; synaptic proteins LAMA5, LAMB2, and UNC13A; as well as TOR1AIP1 (encoding the inner nuclear membrane protein, lamin-associated protein 1), and DES (the muscle-specific member of the intermediate filament protein family linking the contractile apparatus to the sarcolemmal cytoskeleton, cytoplasmic organelles, and nucleus). Note: Neuromuscular endplate pathology has been associated with autosomal recessive loss-of-function variants in DES rather than autosomal dominant variants (associated with DES-related myopathies).


CHRNE is by far the most common causative gene among the AChR-subunit genes CHRNA1, CHRNB1, CHRND, and CHRNE.


No or limited data; small number of reported individuals


Additional non-myasthenic features (cystinuria, learning difficulties, endocrinologic defects, hyperphagia with tendency to obesity) may be associated with homozygous deletions of the two contiguous genes PREPL and SLC3A1 on chromosome 2p21 (hypotonia-cystinuria syndrome; OMIM 606407).

From: Congenital Myasthenic Syndromes Overview

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