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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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Congenital Myasthenic Syndromes Overview

Synonym: Congenital Myasthenia

, MD, , PhD, and , MD.

Author Information and Affiliations

Initial Posting: ; Last Update: December 23, 2021.

Estimated reading time: 29 minutes

Summary

The purpose of this overview is to increase the awareness of clinicians regarding congenital myasthenic syndromes (CMS) and their genetic causes and management.

Goal 1.

Briefly describe the clinical characteristics of CMS.

Goal 2.

Review the subtypes and genetic causes of CMS.

Goal 3.

Review the differential diagnosis of CMS.

Goal 4.

Provide an evaluation strategy to identify the genetic cause of CMS in a proband.

Goal 5.

Review management of CMS following diagnosis: evaluations, treatment (based on genetic cause when possible) and surveillance.

Goal 6.

Inform genetic counseling of family members of a proband with CMS

1. Clinical Characteristics of Congenital Myasthenic Syndromes

Clinical Features

An individual with a congenital myasthenic syndrome (CMS) typically presents with a history of fatigable weakness involving ocular, bulbar, and limb muscles with onset at or shortly after birth or in early childhood, usually in the first two years. Rarely, onset is in the second to third decade of life [McMacken et al 2017, Engel et al 2018, Kao et al 2018, Rodríguez Cruz et al 2018, Finsterer 2019, Vanhaesebrouck & Beeson 2019].

In its classic presentation, CMS is limited to weakness of the skeletal muscles. Cardiac and smooth muscle are not involved. Cognitive skills, coordination, sensation, and tendon reflexes are normal. However, in some newly identified CMS subtypes, myasthenia is only one element of a more severe and complex clinical spectrum.

Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement.

An absence of major pathology is noted on skeletal muscle biopsy despite considerable muscle weakness ‒ except for GMPPB-related CMS, where a dystrophic pattern is found on biopsy (see Table 1).

Neonatal presentation. Some myasthenic symptoms are present at birth.

  • Respiratory insufficiency with sudden, episodic apnea and cyanosis are common findings in neonates.
  • Neonates with CMS can have multiple joint contractures (often described as arthrogryposis multiplex congenita) resulting from a lack of fetal movement in utero.
  • Other major findings in the neonatal period may include feeding difficulties, poor suck and cry, choking spells, eyelid ptosis, and facial, bulbar, and generalized weakness. Stridor in infancy may be an important clue to CMS.
  • In some individuals, long face, narrow jaw, and a high-arched palate have been reported.

Childhood presentation. Individuals with onset later in childhood show abnormal muscle fatigability, with difficulty in running or climbing stairs.

  • Motor milestones may be delayed.
  • Affected individuals present with fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness. Ptosis may involve one or both eyelids.
  • Facial and bulbar weakness with nasal speech and difficulties in coughing and swallowing may be present.
  • Spinal deformity or muscle atrophy may occur.

Limb-girdle presentation. Some individuals display a characteristic "limb-girdle" pattern of weakness with ptosis and a waddling gait, usually without ophthalmoparesis ("limb-girdle myasthenia") [O'Connor et al 2018].

Prognosis. Severity and course of disease are highly variable and depend on the underlying genetic defect [Della Marina et al 2020]. Findings range from minor symptoms (e.g., mild exercise intolerance) to progressive disabling weakness. Minor myasthenic symptoms may be exacerbated by sudden onset of severe weakness or respiratory insufficiency precipitated by fever, infections, or excitement, especially in individuals with CMS with episodic apnea or endplate rapsyn deficiency.

Laboratory and Test Findings

Laboratory findings

  • Serum creatine kinase (CK) concentration may be normal or slightly elevated (usually ≤10-fold normal value). CK levels may be higher only in GMPPB-related CMS.
  • Anti-AChR and anti-MuSK antibody testing (serum) is negative.
    Note: (1) Absence of anti-AChR, anti-MuSK, and anti-LRP4 antibodies in serum can help distinguish CMS from myasthenia gravis (MG), but does not exclude seronegative types of MG which lack those antibodies.
  • With the exception of GMPPB-related CMS, major pathology in a skeletal muscle biopsy specimen is absent despite considerable muscle weakness

EMG testing. EMG testing is helpful to establish a defect in neuromuscular transmission.

  • In the majority of CMS subtypes, a decremental EMG response of the compound muscle action potential (CMAP) can be evoked on low-frequency (2-3 Hz) stimulation.
    • Generally, individuals should be tested for a decremental EMG response of CMAP on low-frequency (2- to 3-Hz) stimulation.
    • In some cases, 2- to 3-Hz stimulation elicits no decremental response from rested non-weak muscle, but elicits a significant decremental response after five to ten minutes of stimulation at 10 Hz.
    • If CMAP amplitude is normal in two distal and two proximal muscles, facial muscles should be tested.
    • Alternatively, or in addition, a single-fiber EMG is a good determinant of a neuromuscular transmission defect.
    • A single nerve stimulus may elicit a repetitive CMAP (the "double response to single nerve stimulus") in individuals with endplate acetylcholinesterase (AChE) deficiency or slow-channel CMS, or in those taking high doses of AChE inhibitors.
  • By contrast with the majority of CMS, some presynaptic subtypes (e.g., PREPL-, SNAP25B-, SYT2-, UNC13A-, and VAMP1-associated CMS) may show increment of CMAP amplitude with high-frequency repetitive nerve stimulation.

AChE inhibitors. In some subtypes of CMS, a positive response to acetylcholinesterase (AChE) inhibitors may occur. Response to AChE inhibitors is usually assessed by a controlled/supervised trial of oral AChE inhibitors and monitoring of fatigable muscle weakness and obvious clinical symptoms (e.g., ptosis, bulbar weakness).

2. Subtypes and Genetic Causes of Congenital Myasthenic Syndromes

Table 1.

Congenital Myasthenic Syndromes: CMS Subtypes and Distinguishing Clinical Features

CMS Subtype 1% of All CMSGene(s) 2Distinguishing Clinical FeaturesResponse to AChE Inhibitors
Post-
synaptic
CMS 		Acetylcholine receptor (AChR) deficiency50% 3 CHRNA1
CHRNB1
CHRND
CHRNE 		AChR deficiency (AR)
  • Early onset
  • Mild to severe
  • Ptosis, EOP; bulbar, arm, leg weakness
Improvement
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
Deterioration
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
Improvement
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
Improvement
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.
Synaptic
CMS 		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
Deterioration
Pre-
synaptic
CMS 		Defect in ACh synthesis4%-5% CHAT
  • Hypotonia, respiratory failure at birth
  • Episodic apnea
  • Improvement w/age
Improvement
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.
<1% PREPL
  • 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- &
post-
synaptic
CMS 		Limb-girdle-myasthenia w/glycosylation deficiency<1% ALG2
ALG14 		Overlap w/CDG syndromesSee footnote 4.
1%-2% DPAGT1
GFPT1
GMPPB
  • "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.
Improvement

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

1.

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

2.

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).

3.

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

4.

No or limited data; small number of reported individuals

5.
6.
7.

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).

3. Differential Diagnosis of Congenital Myasthenic Syndromes

Myasthenia gravis (OMIM 254200). The clinical picture of congenital myasthenic syndromes (CMS) is similar to that of myasthenia gravis (MG), in which individuals have a history of fatigable weakness involving ocular, bulbar, and limb muscles; however, the myasthenic symptoms of CMS usually start at or shortly after birth rather than in adulthood, as is usual for MG. Because seronegative autoimmune MG has been reported on occasion in children younger than age two years, MG may be difficult to differentiate from CMS, especially in later childhood or adulthood. Of note, immunosuppressive therapy does not improve clinical symptoms in CMS, whereas it does in MG.

Transient neonatal myasthenia gravis. Autoimmune MG can be passed across the placenta from mother to fetus and so can affect offspring at birth.

Childhood-onset disorders. Other genetic disorders partially resembling CMS to consider include the following:

Additional considerations include infantile botulism and brain stem anomalies.

Adulthood-onset disorders. Other genetic disorders partially resembling CMS to consider include the following:

4. Evaluation Strategies to Identify the Genetic Cause of a Congenital Myasthenic Syndrome in a Proband

Establishing a specific genetic cause of a congenital myasthenic syndrome (CMS):

  • Can aid in discussions of prognosis (which are beyond the scope of this GeneReview) and genetic counseling;
  • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.

Medical history and physical examination are directed at identifying clinical features associated with a CMS (see Table 1).

Laboratory testing is directed at identifying lab findings associated with a CMS, especially findings on EMG and response to acetylcholinesterase inhibitors.

Family history. A three-generation family history should be taken, with attention to relatives with manifestations of CMS and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.

  • A multigene panel that includes some or all of the genes listed in Table 2 is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of some of the genes associated with CMS, some panels may not include all the genes mentioned in this overview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered. Exome sequencing is most commonly used; genome sequencing is also possible.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Congenital Myasthenic Syndromes: Genes and Frequency

Gene 1% of All CMSReferences
AGRN <1% Gan et al [2020]
ALG2 <1%Cossins et al [2013], Monies et al [2014]
ALG14 <1% Cossins et al [2013]
CHAT 4%-5%Arican et al [2018], McMacken et al [2018]
CHD8 Single report Lee et al [2020]
CHRNA1 <1%Rodríguez Cruz et al [2018], Finsterer [2019]
CHRNB1 <1%
CHRND <1%
CHRNE 50%
COL13A1 1%-2% Rodríguez Cruz et al [2019]
COLQ 10%-15% Mihaylova et al [2008]
DES Single report Durmuş et al [2016]
DOK7 10%-15% Lorenzoni et al [2020]
DPAGT1 <1%Selcen et al [2014], Klein et al [2015]
GFPT1 <1%Guergueltcheva et al [2012], Bauché et al [2017]
GMPPB <1%Belaya et al [2015], Rodríguez Cruz et al [2016]
LAMA5 Single report Maselli et al [2018a]
LAMB2 Single report Maselli et al [2009]
LRP4 <1% Selcen et al [2015]
MACF1 Single report Oury et al [2019]
MUSK <1% Owen et al [2018]
MYO9A <1% O'Connor et al [2016]
PLEC <1% Mroczek et al [2020]
PREPL <1% Régal et al [2014]
RAPSN 15%-20% Della Marina et al [2020]
RPH3A Single report Maselli et al [2018b]
SCN4A <1% Finsterer [2019]
SLC5A7 <1%Bauché et al [2016], Rodríguez Cruz et al [2021]
SLC18A3 <1%O'Grady et al [2016], Hakonen et al [2019], Lamond et al [2021]
SLC25A1 <1% Balaraju et al [2020]
SNAP25 <1%Shen et al [2014], Klöckner et al [2021]
SYT2 <1%Bauché et al [2020], Maselli et al [2021]
TOR1AIP1 <1%Cossins et al [2020], Malfatti et al [2022]
UNC13A Single report Engel et al [2016]
VAMP1 <1% Polavarapu et al [2021]

CMS = congenital myasthenic syndromes

1.

Genes are listed alphabetically.

5. Management

While there are no recent published consensus guidelines for the management of congenital myasthenic syndromes (CMS), Thompson et al [2019] summarized the current knowledge about the treatments for the various subtypes of CMS as related to the underlying genetic cause.

This section provides information regarding recommendations for evaluations following initial diagnosis (Table 3), medical management in general and based (when possible) on the genetic cause (Table 4), and recommended surveillance for individuals with CMS.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a CMS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with a Congenital Myasthenic Syndrome

System/ConcernEvaluationComment
Neuromuscular Assessment of strength & motor function; in children, assessment of motor, speech, & cognitive development
Respiratory function
  • Baseline pulmonary function tests incl forced vital capacity in sitting & supine positions & blood gas exchange
  • Polysomnography to identify persons w/nocturnal hypoventilation
  • Review of history for symptoms of hypercapnia: daytime headache, restless sleep, loss of concentration, snoring, recurrent respiratory infections, weight loss
Respiratory studies may be normal between episodes in persons who experience acute crises.
Feeding ability
  • Assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux)
  • Eval of growth parameters to determine need for feeding interventions incl gavage feeding or gastrostomy insertion
Contractures /
Joint issues
  • Assessment by physiatrist &/or orthopedist
  • Radiologic exam if spinal curvature noted
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of CMS to facilitate medical & personal decision making
Family support
& resources 		Assess need for:

CMS = congenital myasthenic syndromes; MOI = mode of inheritance

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Medications Used in CMS

The choice of medication varies with the CMS subtype [Schara et al 2012, Finsterer 2019, Thompson et al 2019, Vanhaesebrouck & Beeson 2019, Huang et al 2021]; thus, genetic testing will help guide management. However, individual clinical situations may demand an immediate therapeutic trial. While monotherapy is the usual course of treatment for congenital myasthenia, a combination of drugs may be necessary to optimize the therapeutic effect and to minimize side effects [Thompson et al 2019].

Side effects of drugs used to treat myasthenic symptoms should be carefully monitored. If necessary, individual doses should be adjusted or treatment stopped.

Acetylcholinesterase (AChE) inhibitors (pyridostigmine). Although the majority of individuals with CMS benefit from AChE inhibitors (pyridostigmine), some myasthenic symptoms may remain refractory to treatment even in individuals who are otherwise responsive. Certain CMS subtypes (see Table 1), including slow-channel CMS, COLQ-related endplate AChE deficiency, and DOK7-related CMS, are refractory to or deteriorate with AChE inhibitors. See Table 5 for recommendations for treatment of those CMS subtypes.

3,4-diaminopyridine (3,4-DAP). Alternatively or in addition to AChE inhibitors, the potassium channel blocker 3,4-DAP may be used. This drug increases the release of ACh and prolongs the presynaptic action potential. Of note, two children with fast-channel CMS (FCCMS; caused by autosomal recessive loss-of-function variants of the genes encoding the acetylcholine receptor [AChR] subunits that shorten the time that the AChR channel is open) died when started on 3,4-DAP [Beeson et al 2005]. Although a relation to 3,4-DAP has not been proven, clinicians must be cautious when using 3,4-DAP in young children and in individuals with FCCMS.

Ephedrine (adrenergic agonist) treatment shows positive effects in different subtypes of CMS [Schara et al 2012, Rodríguez Cruz et al 2015] (see Table 5). It is well tolerated by most individuals and improvement in strength can be profound.

Albuterol, a beta-2-agonist, is effective in several CMS subtypes, in particular in endplate AChE deficiency, and in patients with DOK7 pathogenic variants. Moreover, in patients with CMS responsive to AChE inhibitors, it may mitigate the detrimental effects on the endplate fine structure caused by long-term anticholinesterase treatment [Vanhaesebrouck et al 2019].

Table 5.

Congenital Myasthenic Syndromes: Medication Recommendations for Certain Genetic Causes and Subtypes

Gene(s) /
Subtype(s) 1		TreatmentCommentsReferences
AChR subunit genes 2 /
Slow-channel CMS		Adults: fluoxetine 3
Children & teenagers: quinidine 4		In those w/pathogenic variants in 1 of the AChR subunit genes but w/the AChR deficiency subtype, quinidine may be detrimental.Chaouch et al [2012], Thompson et al [2019]
COLQ / Endplate AChE deficiency
DOK7 / Defect in AChR clustering pathway		 One of the following:
EphedrineWell tolerated by most persons; improvement in strength can be profound.Wargon et al [2012], Thompson et al [2019]
AlbuterolFirst-line treatment or alternative to ephedrine in AChE deficiencyWargon et al [2012], Witting & Vissing [2014], Thompson et al [2019]
1.

For a detailed summary of treatment options in rare CMS subtypes see Thompson et al [2019].

2.

CHRNA1, CHRNB1, CHRND, CHRNE

3.

Fluoxetine may induce suicidal ideation; thus, caution is strongly suggested in its use in childhood.

4.

Quinidine has some major side effects including torsade de pointes (a potentially life-threatening arrhythmia), hypotension, cinchonism (or quininism), and hypersensitivity reactions. In individuals with CMS, adverse effects including exacerbation of weakness and development of respiratory failure may occur.

Non-Pharmaceutical Treatment

In addition to medication therapy, a multidisciplinary approach to the clinical management of the affected individual greatly improves quality of life and can influence survival. Management should be tailored to the individual, the specific CMS subtype, and the rate of progression.

Depending on the individual clinical situation, clinical management may include the following:

  • Physical and occupational therapy
  • Speech therapy
  • Orthotics or a wheelchair
  • A percutaneous gastrostomy tube
  • Ventilatory support

Prevention of Primary Manifestations

Sudden respiratory insufficiency or apneic attacks provoked by fever or infections are common in individuals with pathogenic variants in CHAT or RAPSN, even if the myasthenic symptoms are mild between crises. These individuals should receive prophylactic anticholinesterase therapy.

Note: Less frequently, acute respiratory events may also occur in other CMS subtypes. Parents of infants are advised to use apnea monitors and be trained in CPR.

Surveillance

Regular surveillance of muscle strength and respiratory function is recommended, usually at least every six months in children and every 12 months in adults. In some individuals, especially those with COLQ and DOK7 pathogenic variants, slowly progressive respiratory impairment is seen with increasing age. Symptoms of nighttime hypoventilation should be considered.

Agents/Circumstances to Avoid

A number of drugs are known to affect neuromuscular transmission and therefore exacerbate symptoms of myasthenia gravis (e.g., ciprofloxacin, chloroquine, procaine, lithium, phenytoin, beta-blockers, procainamide, and quinidine). These drugs are not absolutely contraindicated and may be used with caution in CMS. See Myasthenia Gravis: Cautionary Drugs for a more complete list.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic at-risk relatives of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures ‒ especially newborns or young children, who could benefit from early treatment to prevent sudden respiratory failure. Evaluations can include:

  • Molecular genetic testing if the pathogenic variant(s) in the family are known;
  • Neurologic/neuropediatric examination and electrophysiologic testing (repetitive nerve stimulation) if the pathogenic variant(s) in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Data on pregnancies in CMS are limited. Seventeen pregnancies were reported in eight French individuals with CMS [Servais et al 2013]. According to these data pregnancy was a frequent cause of clinical exacerbation but the vast majority of individuals recovered their pre-pregnancy clinical status six months after delivery. The children's outcome was excellent, except for one newborn who developed a severe neonatal (autosomal dominant) slow-channel CMS. Pregnant individuals should be closely followed by neurologists during the course of pregnancy. Careful respiratory and cardiac surveillance should be initiated in consultation with obstetric specialists.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

6. Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Congenital myasthenic syndromes (CMS) are typically inherited in an autosomal recessive manner. Less commonly, CMS is inherited in an autosomal dominant manner (Table 3).

Table 3.

Congenital Myasthenic Syndromes: Mode of Inheritance

MOICMS-Related Genes
AR AGRN
ALG2
ALG14
CHAT 		COL13A1
COLQ
DES
DOK7 		DPAGT1
GFPT1
GMPPB
LAMA5 		LAMB2
LRP4
MACF1
MUSK 		MYO9A
PLEC
PREPL
RAPSN 		RPH3A
SCN4A
SLC5A7
SLC18A3 		SLC25A1
TOR1AIP1
UNC13A
VAMP1
AD CHD8 SNAP25
AD or AR CHRNA1 1CHRNB1 1CHRND 1CHRNE 1SYT2 2

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance

1.

Heterozygous gain-of-function variants result in autosomal dominant slow-channel CMS. Biallelic loss-of-function variants result in autosomal recessive CMS.

2.

Heterozygous missense variants result in autosomal dominant CMS. Biallelic loss-of-function variants result in autosomal recessive CMS.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

  • The parents of a child with autosomal recessive congenital myasthenic syndrome (ARCMS) are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
  • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CMS-causing pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants, additional possibilities to consider include:
    • A large deletion (i.e., a copy number variation) in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
    • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [Shchagina et al 2020].
  • Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an ARCMS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • Unless an affected individual's reproductive partner also has ARCMS or is a carrier, offspring will be obligate heterozygotes (carriers) for an ARCMS-causing pathogenic variant.
  • In populations with a high carrier rate and/or a high rate of consanguineous marriages, the risk to the offspring of an affected individual of being affected is increased.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ARCMS-causing pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the ARCMS-causing pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with autosomal dominant congenital myasthenic syndrome (ADCMS) have an affected parent.
  • A proband with ADCMS may have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with ADCMS caused by a de novo pathogenic variant is unknown.
  • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
    • The proband has a de novo pathogenic variant.
    • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
  • The family history of some individuals diagnosed with ADCMS may appear to be negative because of failure to recognize the disorder in affected family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Reduced penetrance is unlikely to be a factor in ADCMS with severe clinical presentation at birth but may be taken into account when considering the family history of a proband with a milder late-onset form.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
  • If the proband has a known ADCMS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with ADCMS has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has an ADCMS-causing pathogenic variant, the parent's family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the CMS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Chapter Notes

Author Notes

Dr Hanns Lochmüller's lab website: lochmullerlab.org

Revision History

  • 23 December 2021 (ha) Comprehensive update posted live; scope changed to overview
  • 14 July 2016 (ha) Comprehensive update posted live
  • 22 March 2012 (me) Comprehensive update posted live
  • 8 August 2005 (me) Comprehensive update posted live
  • 9 May 2003 (me) Review posted live
  • 30 January 2003 (aa) Original submission

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Tests in GTR by Gene

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