NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Congenital Myasthenic Syndromes

Synonym: Congenital Myasthenia

, MD, , PhD, and , MD.

Author Information

Initial Posting: ; Last Update: July 14, 2016.

Summary

Clinical characteristics.

Congenital myasthenic syndromes (designated as CMS throughout this entry) are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. Cardiac and smooth muscle are usually not involved. 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. Major findings of the neonatal-onset subtype include: respiratory insufficiency with sudden apnea and cyanosis; feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Arthrogryposis multiplex congenita may also be present. Stridor in infancy may be an important clue to CMS. Later childhood-onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations.

Diagnosis/testing.

The diagnosis of CMS is based on clinical findings, a decremental EMG response of the compound muscle action potential (CMAP) on low-frequency (2-3 Hz) stimulation, a positive response to acetylcholinesterase (AchE) inhibitors, absence of anti-acetylcholine receptor (AChR) and anti-MuSK antibodies in the serum, and lack of improvement of clinical symptoms with immunosuppressive therapy. Pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of CMS. The most commonly associated genes include: CHAT, CHRNE, COLQ, DOK7, GFPT1, and RAPSN.

Management.

Treatment of manifestations: Most individuals with CMS benefit from AChE inhibitors and/or the potassium channel blocker 3,4-diaminopyridine (3,4-DAP); however, caution must be used in giving 3,4-DAP to young children and individuals with fast-channel CMS (FCCMS). Individuals with COLQ and DOK7 pathogenic variants usually do not respond to long-term treatment with AChE inhibitors. Some individuals with slow-channel CMS (SCCMS) are treated with quinidine, which has some major side effects and may be detrimental in individuals with AChR deficiency. Fluoxetine is reported to be beneficial for SCCMS. Ephedrine and albuterol have been beneficial in several individuals, especially as a therapeutic option for those with DOK7 or COLQ pathogenic variants.

Prevention of primary manifestations: Prophylactic anticholinesterase therapy to prevent sudden respiratory insufficiency or apneic attacks provoked by fever or infections in those with pathogenic variants in CHAT or RAPSN. Parents of infants are advised to use apnea monitors and be trained in CPR.

Agents/circumstances to avoid: Drugs known to affect neuromuscular transmission and exacerbate symptoms of myasthenia gravis (e.g., ciprofloxacin, chloroquine, procaine, lithium, phenytoin, beta-blockers, procainamide, quinidine).

Evaluation of relatives at risk: If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk asymptomatic family members, especially newborns or young children, who could benefit from early treatment to prevent sudden respiratory failure.

Genetic counseling.

Congenital myasthenic syndromes are inherited in an autosomal recessive or an autosomal dominant manner.

In autosomal recessive CMS (AR-CMS), the parents of an affected child are obligate heterozygotes and therefore carry one pathogenic variant. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has 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.

In autosomal dominant CMS (AD-CMS), some individuals have an affected parent while others have a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with AD-CMS has a 50% chance of inheriting the pathogenic variant.

Prenatal testing and preimplantation genetic diagnosis are possible if the pathogenic variant(s) have been identified in an affected family member.

Diagnosis

Suggestive Findings

Congenital myasthenic syndromes (CMS) should be suspected in individuals with the following:

  • A history of fatigable weakness involving ocular, bulbar, and limb muscles with onset at or shortly after birth or in early childhood. Post-childhood onset has been observed, but is rare [Burke et al 2003, Beeson et al 2005, Müller et al 2007a].
  • A decremental EMG response of the compound muscle action potential (CMAP) on low-frequency (2-3 Hz) stimulation (see Testing, Electrophysiologic testing)
  • A positive response to acetylcholinesterase (AchE) inhibitors(see Testing, Response to acetylcholinesterase inhibitors)
  • Absence of anti-acetylcholine receptor (anti-AChR) and anti-MuSK antibodies in the serum
    Note: (1) Absence of anti-AChR antibodies in the serum can help distinguish CMS from myasthenia gravis (MG), but does not exclude seronegative types of MG or MG with anti-MuSK antibodies [Hoch et al 2001]. (2) One case of autoimmune MG developing in an individual with CMS has been reported [Croxen et al 2002b].
  • Lack of improvement of clinical symptoms with immunosuppressive therapy
  • Absence of major pathology in a skeletal muscle biopsy specimen despite considerable muscle weakness
  • A family history consistent with either autosomal recessive or autosomal dominant inheritance

Testing

Laboratory testing

  • Serum creatine kinase (CK) concentration may be normal or slightly elevated (usually not more than tenfold the normal).
  • Anti-AChR and anti-MuSK antibody testing (serum) is negative.

Electrophysiologic testing

  • Generally, individuals should be tested for a decremental EMG response of the 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 the amplitude of the CMAP 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 so-called "double response to single nerve stimulus") in individuals with endplate AChE deficiency or slow-channel CMS (SCCMS; caused by autosomal dominant gain-of-function variants of the genes encoding the AChR subunits that prolong the time that the AChR channel is open), or in those taking high doses of AChE inhibitors.

Response to AChE inhibitors may be assessed by using intravenous injection of edrophonium (Tensilon®), a fast-acting AChE inhibitor, or by a controlled/supervised trial of oral AChE inhibitors.

Intravenous application of edrophonium chloride (known as Tensilon® test) must be performed under intensive care conditions. In adults with bodyweight higher than 30 kilograms, an initial dose of 2.0 mg is injected over 15 seconds, followed by additional doses of 3.0 mg and 5.0 mg at intervals of 60 seconds, if necessary. In newborns and infants, dosage varies [Schara et al 2012]. Maximum improvement occurs within 30 seconds of the injection and persists for minutes. An objective endpoint (e.g., improvement in ptosis, extraocular muscle weakness, tongue weakness, decremental EMG response) needs to be established prior to the injection and then carefully followed.

Alternatively, a controlled/supervised trial of oral medication with AChE inhibitor is possible. This may be helpful in patients with fatigable muscle weakness but no obvious clinical symptoms (e.g., ptosis, bulbar weakness) that can be easily monitored.

Morphologic studies. Conventional skeletal muscle biopsy and routine histochemical studies in individuals with CMS generally show no major abnormalities except for type I fiber predominance and occasionally minor myopathic changes. Note: Tubular aggregates have been described in GFPT1-associated limb-girdle CMS [Senderek et al 2011] and dystrophic changes can be found in patients with GMPPB pathogenic variants [Belaya et al 2015].

Establishing the Diagnosis

The diagnosis of CMS is established in a proband with the findings above in combination with the identification of a heterozygous or biallelic pathogenic variant(s) in one of the genes listed in Table 1a and Table 1b; these genes, encoding different proteins expressed at the neuromuscular junction, are currently known to be associated with CMS [Hantaï et al 2013, Rodríguez Cruz et al 2014, Engel et al 2015].

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing has been considered as first-tier testing if (1) mutation of a particular gene accounts for a large proportion of the disease (see Table 1a) or (2) factors including clinical findings, laboratory findings, and ancestry indicate that mutation of a particular gene is most likely.

Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.

Some clinical clues may help the clinician pinpoint the gene most likely to be involved:

  • Apneas. Perform molecular genetic testing of RAPSN, CHAT, and COLQ.
  • No response to treatment with AChE inhibitors. Consider testing for pathogenic variants in COLQ.
  • Double response to a single nerve stimulus. Consider:
  • Incremental response in CMAP amplitude following maximum voluntary contraction. Consider testing for pathogenic variant in SYT2.
  • Pes cavus and hammer toes. Consider testing for pathogenic variant in SYT2.
  • Contractures. Consider testing for pathogenic variant in RAPSN.
  • Autosomal dominant family history. Consider slow-channel CMS caused by pathogenic variants in the genes encoding AChR subunits: CHRNA1, CHRNB1, CHRND, CHRNE or SYT2-associated CMS.

Targeted analysis for pathogenic variants may be carried out first depending on the ethnic origin of the individual:

A multigene panel that includes the genes from Table 1a and Table 1b and other genes of interest (see Differential Diagnosis) may be considered as first- or second-tier option; due to the genetic heterogeneity of CMS, a multigene panel using next-generation sequencing technologies is emerging as a first-tier test. 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes the genes listed in Table 1a and Table 1b) fails to confirm a diagnosis in an individual with features of CMS. Such testing may provide an unexpected or previously unconsidered diagnosis, such as mutation in another gene that causes a similar clinical presentation.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1a.

Molecular Genetics of Congenital Myasthenic Syndromes: Most Common Genetic Causes

Gene 1, 2% of CMS Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 3 Detected by Test Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
CHAT4%-5%~100%Unknown 6
CHRNE50%~99% 7, 8, 9Unknown 6, but in single cases reported 9
COLQ10%-15%~100%Unknown 6
DOK710%-15%~100%Unknown 6
GFPT12%~100%Unknown 6
RAPSN15%-20%~85% 10Up to 15% 11

Pathogenic variants of any one of the genes included in this table account for >1% of CMS.

1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on pathogenic allelic variants detected.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

7.

The CHRNE founder pathogenic variant c.1327delG in exon 12 is present in up to 50% of individuals of European Roma and/or southeastern European origin with CMS [Abicht et al 1999, Karcagi et al 2001].

8.

The CHRNE founder pathogenic variant c.1353dupG is present in up to 20% of persons from the Maghreb (especially Algeria and Tunisia) [Beeson et al 2005].

9.
10.

Most affected individuals of European origin, especially those with respiratory failure, have the c.264C>A pathogenic variant on at least one allele; about 50% are homozygous for c.264C>A.

11.

Table 1b.

Molecular Genetics Congenital Myasthenic Syndromes: Less Common Genetic Causes

Gene 1, 2, 3, 4% of CMS Attributed to Pathogenic Variants in This GeneComment
AGRN<1%Reported in 7 families [Huzé et al 2009, Maselli et al 2012, Karakaya et al 2014, Nicole et al 2014]
ALG2<1%Cossins et al [2013], Monies et al [2014]
ALG14<1%Cossins et al [2013]
CHRNA1<1%Several patients reported w/AD or AR variants [Croxen et al 1997, Rodríguez Cruz et al 2014]
CHRNB1<1%Quiram et al [1999]
CHRND<1%Müller et al [2006]
COL13A1<1%Logan et al [2015]
DPAGT1<1%Several patients reported [Belaya et al 2012a, Belaya et al 2012b, Basiri et al 2013, Selcen et al 2014]
GMPPB<1%Belaya et al [2015]
LAMB2<1%Reported in 1 individual w/concomitant renal failure [Maselli et al 2009]
LRP4<1%2 CMS kinships reported [Ohkawara et al 2014, Selcen et al 2015]
MUSK<1%Reported in 8 individuals from 3 families [Chevessier et al 2004, Mihaylova et al 2009, Maselli et al 2010]
MYO9A<1%Authors, personal observation
PLEC<1%Forrest et al [2010], Selcen et al [2011], Fattahi et al [2015]
PREPL<1%Régal et al [2014]
SCN4A<1%Reported in 2 unrelated individuals [Tsujino et al 2003, Habbout et al 2016]
SLC25A1<1%AR variants reported in 2 affected sibs [Chaouch et al 2014]
SLC5A7<1%Authors, personal observation
SNAP25<1%De novo AD variant in 1 patient with w/myasthenia & multiple contractures at birth, cortical hyperexcitability, cerebellar ataxia, & severe intellectual disability [Shen et al 2014]
SYT2<1%AD variants in 2 multigenerational families w/foot deformities, fatigable ocular & lower limb weakness, & response to modulators of acetylcholine release [Herrmann et al 2014, Whittaker et al 2015]

Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <1% of CMS).

1.

Genes are listed in alphabetic order.

2.
3.

Genes are not described in detail in Molecular Genetics, but may be included here (pdf).

4.

Other subtypes of CMS have been reported in the literature in a few kinships without identification of the underlying genetic defect [Engel et al 2015]. A proportion of individuals with CMS remain without molecular genetic diagnosis even after exome studies, suggesting the involvement of additional, as-yet unidentified genes in CMS.

Clinical Characteristics

Clinical Description

Onset. In the congenital myasthenic syndromes (CMS), the first myasthenic symptoms occur in general early in life, usually in the first two years. Rarely, onset is in the second to third decade of life [Milone et al 1999, Croxen et al 2002a, Burke et al 2003, Müller et al 2007a, Croxen et al 2009, Ben Ammar et al 2010, Guergueltcheva et al 2012].

Neuromuscular findings. CMS is limited to weakness of the skeletal muscles. Cardiac and smooth muscle are usually not involved. Coordination, sensation, and tendon reflexes are normal; cognitive skills are usually normal.

Neonatal presentation. Some myasthenic symptoms are present at birth.

  • Respiratory insufficiency with sudden apnea and cyanosis are common findings in neonates.
  • Neonates with CMS can have multiple joint contractures (often described as arthrogryposis multiplex congenita [AMC]) 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 [Kinali et al 2008].

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.
  • In addition, 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, with or without ptosis and ophthalmoparesis ("limb girdle myasthenia").

Dysmorphic features. In some individuals, long face, narrow jaw, and a high-arched palate have been reported [Burke et al 2004].

Cognitive skills. The vast majority of individuals with CMS have normal cognitive skills. Recently, three patients have been reported with DPAGT1-associated CMS and intellectual disability [Selcen et al 2014]. Severe intellectual disability appears to be a feature of SNAP25-associated CMS [Shen et al 2014].

Prognosis. Severity and course of disease are highly variable, ranging 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 (CMS-EA) or endplate rapsyn deficiency [Ohno et al 2001, Byring et al 2002, Ohno et al 2002].

Phenotype Correlations by Gene

Major CMS subtypes are recognized based on molecular genetic studies [Finlayson et al 2013, Engel et al 2015] (see Table 2).

Table 2.

CMS Subtypes by Gene Involved

Gene(s) Associated with DiseaseCMS SubtypeClinical Findings 1Response to AChE Inhibitors 2
CHATCMS w/episodic apnea
  • Hypotonia, respiratory failure at birth
  • Episodic apnea
  • Improvement w/age
Improvement
AChR subunit genes:
  • CHRNE
CHRNA1
  • CHRNB1
  • CHRND
Acetylcholine receptor deficiency
  • Early onset
  • Varies from mild to severe
  • Ptosis, EOP 3; bulbar, arm, leg weakness
Improvement
Slow-channel CMS
  • Selective severe neck, wrist, finger extensor weakness
  • Childhood to adult onset
  • Varies from mild to severe
  • Progressive ventilatory insufficiency; may require assisted ventilation
Often deterioration
Fast-channel CMSVaries from mild to severeImprovement
COLQEndplate AChE deficiency
  • 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 no response
DOK7DOK7-associated limb-girdle-myastheniaLimb-girdle pattern of weakness w/predominantly proximal weakness, waddling gait, & ptosis but no EOPDeterioration or no response
RAPSNEndplate rapsyn deficiencyEarly onset:
  • Hypotonia, respiratory failure at birth
  • Episodic apnea
  • Arthrogryposis multiplex congenita
  • Varies from mild to severe
Late onset:
  • Limb weakness in adolescence or adulthood resembling seronegative myasthenia gravis
Improvement
GFPT1, DPAGT1, ALG2, ALG14, GMPPB, PREPLLimb-girdle-myasthenia w/glycosylation deficiency"Limb-girdle" pattern of weakness w/predominantly proximal weakness but usually no ptosis or EOP; sometimes tubular aggregates in muscle biopsy 4Improvement

Includes only those genes for which more than a few individuals/families have been reported

1.

Because of the many private pathogenic variants and the limited number of genotype-phenotype correlations, the clinical spectrum may be broader or different from the findings listed.

2.

See Diagnosis, Testing, Response to acetylcholinesterase inhibitors.

3.

EOP = external ophthalmoplegia

4.

Genotype-Phenotype Correlations

Pathogenic variants in the genes encoding the AChR subunits (CHRNA1, CHRNB1, CHRND, CHRNE) can be inherited in an autosomal dominant or autosomal recessive manner.

Genotype-phenotype correlations are difficult to establish for those rare CMS subtypes for which pathogenic variants have been identified in only a few patients worldwide.

Penetrance

In general, reported CMS pathogenic variants have complete penetrance.

One case of reduced penetrance has been reported for slow-channel CMS (SCCMS) resulting from pathogenic variants in CHRNE [Croxen et al 2002a, Croxen et al 2009].

Nomenclature

An outdated and misleading term is familial infantile myasthenia (FIM) [Deymeer et al 1999].

Prevalence

The prevalence of CMS is estimated at one tenth that of myasthenia gravis (which has a prevalence of 25:1,000,000-125:1,000,000); however, it may be higher. At least 1000 independent kinships with identified pathogenic variants have been documented worldwide [Chaouch et al 2012b].

The population of the southeastern European Roma may be at higher risk for CMS because of an increased carrier rate (>4%) for the pathogenic variant c.1327delG in CHRNE, the gene encoding the εAChR subunit [Morar et al 2004].

Individuals from the Maghreb (especially Algeria and Tunisia) may be at higher risk for CMS because of another CHRNE founder pathogenic variant, c.1353dupG [Beeson et al 2005].

Differential Diagnosis

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. Furthermore, 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. Other disorders partially resembling CMS to consider:

Adulthood. Other disorders partially resembling CMS to consider:

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with congenital myasthenic syndromes (CMS), the following evaluations are recommended:

  • Neurologic/neuropediatric examination. Assessment of strength and motor function; in children, assessment of motor, speech, and cognitive development
  • Respiratory care. Assessment of respiratory function with baseline pulmonary function tests including forced vital capacity in sitting and supine positions and blood gas exchange. Polysomnography to identify individuals with nocturnal hypoventilation. Symptoms of hypercapnea that should be discussed: daytime headache, restless sleep, loss of concentration, snoring, recurrent respiratory infections, and weight loss. Respiratory studies may be normal between episodes in patients who experience acute crises.
  • Assessment of contractures and joint deformities by physiatrists and orthopedists; radiologic examinations if spinal deformity is observed
  • Speech therapy evaluation if dysarthria and/or hypernasal speech is present
  • For early-onset forms, assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux) and growth parameters to determine the need for feeding interventions such as gavage feeding or gastrostomy insertion
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

There are no recent published consensus guidelines for the management of CMS treatment.

Medical Treatment

The choice of medical treatment varies with the CMS subtype [Schara et al 2012, Finlayson et al 2013]. Therefore, it seems reasonable to consider a first-line genetic testing to evaluate the genetic subtype. However, there may be individual clinical situations demanding an immediate therapeutic trial. Monotherapy is the usual course of treatment for congenital myasthenia; however, a combination of drugs may be necessary to optimize the therapeutic effect and to minimize side effects.

Acetylcholineesterase (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 2) including endplate (EP) AChE deficiency, slow-channel CMS (SCCMS), and DOK7-related CMS are refractory to or deteriorate with AChE inhibitors [Schara et al 2012, Finlayson et al 2013].

3,4-diaminopyridine (3,4-DAP). Alternatively or in addition to AChE inhibitors, the potassium channel blocker 3,4-DAP may be used [Schara et al 2012, Finlayson et al 2013]. 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 treatment shows positive effects in different subtypes of CMS [Schara et al 2012, Finlayson et al 2013, Vrinten et al 2014] and may be an alternative treatment option for CMS subtypes that are refractory to AChE inhibitors, such as COLQ- and DOK7-associated CMS [Bestue-Cardiel et al 2005, Schara et al 2009, Lashley et al 2010, Witting & Vissing 2014]. It is well tolerated by most patients and improvement in strength can be profound.

Albuterol, an alternative to ephedrine, may have a role in the treatment of COLQ- and DOK7-associated CMS [Liewluck et al 2011, Burke et al 2013, Lorenzoni et al 2013, Witting & Vissing 2014].

Quinidine, fluoxetine. Some individuals with genetically defined SCCMS (caused by autosomal dominant gain-of-function variants of the genes encoding the AChR subunits that prolong the time that the AChR channel is open) have been successfully treated with quinidine, a long-lived open-channel blocker of AChR [Harper & Engel 1998]. Quinidine in turn may be detrimental in individuals with AChR deficiency.

The therapeutic benefit of fluoxetine in SCCMS has been shown [Harper et al 2003, Colomer et al 2006]; however, it may induce suicidal ideation; thus, caution is strongly suggested in its use in childhood [Engel 2007].

Overall fluoxetine appears to be the accepted first-line treatment in SCCMS, whereas quinidine is the treatment of choice in children and teenagers because of the risk of psychiatric side effects associated with fluoxetine [Chaouch et al 2012a, Chaouch et al 2012b].

Non-Medical Treatment

In addition to medical 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 each individual, their specific CMS subtype, and rate of progression.

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

  • Physical and occupational therapy
  • Speech therapy
  • Orthotics or a wheelchair
  • A percutaneous gastric 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.

Prevention of Secondary Complications

Side effects of drugs used to treat myasthenic symptoms should be carefully monitored. If necessary, individual doses should be adjusted or treatment should be stopped. For example, quinidine has some major side effects including torsades 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.

Surveillance

Routine surveillance of muscle strength and respiratory function is recommended. In some patients, 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 Medications and Myasthenia Gravis (Table 2) for a more complete.

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 in the family is known;
  • Neurologic/neuropediatric examination, electrophysiologic testing (repetitive nerve stimulation) if the pathogenic variant in the family is 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 patients with CMS [Servais et al 2013]. According to these data pregnancy was a frequent cause of clinical exacerbation but the vast majority of patients 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 patients 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 www.ClinicalTrialsRegister.eu 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Congenital myasthenic syndrome (CMS) caused by mutation of AGRN, ALG14, ALG2, CHAT, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, RAPSN, SCN4A, and SLC25A1 is always inherited in an autosomal recessive manner.

CMS caused by mutation of SYT2 and SLC5A7 is inherited in autosomal dominant manner.

SNAP25-related CMS has been described as the result of an autosomal dominant de novo pathogenic variant.

CMS associated with pathogenic variants in the genes encoding the AChR subunits (CHRNA1, CHRNB1, CHRND, and CHRNE) can be inherited in an autosomal dominant or autosomal recessive manner.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

  • The parents of a child with an autosomal recessive congenital myasthenic syndrome (AR-CMS) are obligate heterozygotes (i.e., carriers of one pathogenic variant).
  • Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has 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

  • The offspring of an individual with AR-CMS are obligate heterozygotes (carriers) for a pathogenic variant.
  • The risk that the offspring will inherit a second CMS-related pathogenic variant depends on the carrier status of the proband's reproductive partner.
  • The carrier frequency of CMS-related pathogenic variants in the general population is low.
  • 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 (see Prevalence).

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

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the CMS-related pathogenic variants in the family.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

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

  • If a parent of the proband is affected and/or has a pathogenic variant, the risk of inheriting the variant is 50%.
  • When the parents are clinically unaffected and the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to the sibs of a proband is low but greater than in the general population because of the possibility of germline mosaicism.

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

Other family members of a proband. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has a CMS-related pathogenic variant, his or her 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 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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CMS-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CMS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • Myasthenia Gravis Foundation of America, Inc. (MGFA)
    355 Lexington Avenue
    15th Floor
    New York NY 10017
    Phone: 800-541-5454 (toll-free); 212-297-2156
    Fax: 212-370-9047
    Email: mgfa@myasthenia.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Congenital Myasthenic Syndromes: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
AGRN1p36​.33AgrinAGRN homepage - Leiden Muscular Dystrophy pagesAGRNAGRN
ALG29q22​.33Alpha-1,3/1,6-mannosyltransferase ALG2ALG2 databaseALG2ALG2
ALG141p21​.3UDP-N-acetylglucosamine transferase subunit ALG14 homologALG14ALG14
CHAT10q11​.23Choline O-acetyltransferaseCHAT @ LOVD
CHAT homepage - Leiden Muscular Dystrophy pages
CHATCHAT
CHRNA12q31​.1Acetylcholine receptor subunit alphaCHRNA1 homepage - Leiden Muscular Dystrophy pages
CHRNA1 database
CHRNA1CHRNA1
CHRNB117p13​.1Acetylcholine receptor subunit betaCHRNB1 homepage - Leiden Muscular Dystrophy pages
CHRNB1 database
CHRNB1CHRNB1
CHRND2q37​.1Acetylcholine receptor subunit deltaLeiden Muscular Dystrophy pages (CHRND)CHRNDCHRND
CHRNE17p13​.2Acetylcholine receptor subunit epsilonCHRNE homepage - Leiden Muscular Dystrophy pagesCHRNECHRNE
COL13A110q22​.1Collagen alpha-1(XIII) chainCOL13A1COL13A1
COLQ3p25​.1Acetylcholinesterase collagenic tail peptideCOLQ homepage - Leiden Muscular Dystrophy pages
ESTHER www server: ESTerases and alpha/beta Hydrolase Enzymes and Relatives (COLQ)
COLQCOLQ
DOK74p16​.3Protein Dok-7DOK7 homepage - Leiden Muscular Dystrophy pagesDOK7DOK7
DPAGT111q23​.3UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferaseDPAGT1 databaseDPAGT1DPAGT1
GFPT12p13​.3Glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1GFPT1 homepage - Leiden Muscular Dystrophy pagesGFPT1GFPT1
GMPPB3p21​.31Mannose-1-phosphate guanyltransferase betaGMPPB homepageGMPPBGMPPB
LAMB23p21​.31Laminin subunit beta-2LAMB2 databaseLAMB2LAMB2
LRP411p11​.2Low-density lipoprotein receptor-related protein 4LRP4 databaseLRP4LRP4
MUSK9q31​.3Muscle, skeletal receptor tyrosine-protein kinaseMUSK homepage - Leiden Muscular Dystrophy pages
MUSK database
MUSKMUSK
MYO9A15q23Unconventional myosin-IXaMYO9AMYO9A
PLEC8q24​.3PlectinPLEC homepage - Leiden Muscular Dystrophy pagesPLECPLEC
PREPL2p21Prolyl endopeptidase-likePREPL databasePREPLPREPL
RAPSN11p11​.243 kDa receptor-associated protein of the synapseRAPSN homepage - Leiden Muscular Dystrophy pages
RAPSN database
RAPSNRAPSN
SCN4A17q23​.3Sodium channel protein type 4 subunit alpha Sodium channel, voltage-gated, type IV, alpha subunit (SCN4A) @ LOVDSCN4ASCN4A
SLC5A72q12​.3High affinity choline transporter 1SLC5A7SLC5A7
SLC25A122q11​.21Tricarboxylate transport protein, mitochondrialSLC25A1SLC25A1
SNAP2520p12​.2Synaptosomal-associated protein 25SNAP25SNAP25
SYT21q32​.1Synaptotagmin-2SYT2SYT2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Congenital Myasthenic Syndromes (View All in OMIM)

100690CHOLINERGIC RECEPTOR, NICOTINIC, ALPHA POLYPEPTIDE 1; CHRNA1
100710CHOLINERGIC RECEPTOR, NICOTINIC, BETA POLYPEPTIDE 1; CHRNB1
100720CHOLINERGIC RECEPTOR, NICOTINIC, DELTA POLYPEPTIDE; CHRND
100725CHOLINERGIC RECEPTOR, NICOTINIC, EPSILON POLYPEPTIDE; CHRNE
103320AGRIN; AGRN
118490CHOLINE ACETYLTRANSFERASE; CHAT
138292GLUTAMINE:FRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE 1; GFPT1
150325LAMININ, BETA-2; LAMB2
190315SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, CITRATE TRANSPORTER), MEMBER 1; SLC25A1
191350DOLICHYL-PHOSPHATE N-ACETYLGLUCOSAMINE PHOSPHOTRANSFERASE; DPAGT1
254210MYASTHENIC SYNDROME, CONGENITAL, 6, PRESYNAPTIC; CMS6
254300MYASTHENIC SYNDROME, CONGENITAL, 10; CMS10
601296MUSCLE, SKELETAL, RECEPTOR TYROSINE KINASE; MUSK
601462MYASTHENIC SYNDROME, CONGENITAL, 1A, SLOW-CHANNEL; CMS1A
601592RECEPTOR-ASSOCIATED PROTEIN OF THE SYNAPSE, 43-KD; RAPSN
603033COLLAGENIC TAIL OF ENDPLATE ACETYLCHOLINESTERASE; COLQ
603034MYASTHENIC SYNDROME, CONGENITAL, 5; CMS5
603967SODIUM CHANNEL, VOLTAGE-GATED, TYPE IV, ALPHA SUBUNIT; SCN4A
604270LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 4; LRP4
604875MYOSIN IXA; MYO9A
605809MYASTHENIC SYNDROME, CONGENITAL, 4A, SLOW-CHANNEL; CMS4A
607905ALG2, S. CEREVISIAE, HOMOLOG OF; ALG2
608761SOLUTE CARRIER FAMILY 5 (CHOLINE TRANSPORTER), MEMBER 7; SLC5A7
608930MYASTHENIC SYNDROME, CONGENITAL, 1B, FAST-CHANNEL; CMS1B
608931MYASTHENIC SYNDROME, CONGENITAL, 4C, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY; CMS4C
609557PROLYL ENDOPEPTIDASE-LIKE; PREPL
610285DOWNSTREAM OF TYROSINE KINASE 7; DOK7
612866ALG14, S. CEREVISIAE, HOMOLOG OF; ALG14
614198MYASTHENIC SYNDROME, CONGENITAL, 16; CMS16
614750MYASTHENIC SYNDROME, CONGENITAL, 13; CMS13
615120MYASTHENIC SYNDROME, CONGENITAL, 8; CMS8
615320GDP-MANNOSE PYROPHOSPHORYLASE B; GMPPB
616040MYASTHENIC SYNDROME, CONGENITAL, 7, PRESYNAPTIC; CMS7
616227MYASTHENIC SYNDROME, CONGENITAL, 15; CMS15
616228MYASTHENIC SYNDROME, CONGENITAL, 14; CMS14
616304MYASTHENIC SYNDROME, CONGENITAL, 17; CMS17
616313MYASTHENIC SYNDROME, CONGENITAL, 2A, SLOW-CHANNEL; CMS2A
616314MYASTHENIC SYNDROME, CONGENITAL, 2C, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY; CMS2C
616321MYASTHENIC SYNDROME, CONGENITAL, 3A, SLOW-CHANNEL; CMS3A
616322MYASTHENIC SYNDROME, CONGENITAL, 3B, FAST-CHANNEL; CMS3B
616323MYASTHENIC SYNDROME, CONGENITAL, 3C, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY; CMS3C
616324MYASTHENIC SYNDROME, CONGENITAL, 4B, FAST-CHANNEL; CMS4B
616325MYASTHENIC SYNDROME, CONGENITAL, 9, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY; CMS9
616326MYASTHENIC SYNDROME, CONGENITAL, 11, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY; CMS11
616330MYASTHENIC SYNDROME, CONGENITAL, 18; CMS18
616720MYASTHENIC SYNDROME, CONGENITAL, 19; CMS19

Molecular Genetic Pathogenesis

The understanding of the molecular basis of the different subtypes of CMS has been evolving since 1995. After the identification of pathogenic variants in the subunits of the nicotinic acetylcholine receptor (AChR), other genes encoding postsynaptic, presynaptic, or synaptic proteins were identified as candidate genes for CMS [Engel et al 2003, Hantaï et al 2004, Ohno & Engel 2004a, Beeson et al 2005, Engel & Sine 2005, Müller et al 2007b]. Currently, several proteins expressed at the neuromuscular junction and involved in neuromuscular transmission have been found to be involved in CMS. CMS subtypes have been classified according to the site of the underlying defect into presynaptic, synaptic, and postsynaptic CMS. This classification is still tentative because it is likely that additional subtypes of CMS will be discovered.

The neuromuscular junction (NMJ). Neuromuscular transmission depends on the calcium-dependent release of acetylcholine (ACh) from the presynaptic nerve terminal and its interaction with AChRs on the postsynaptic membrane. ACh is first synthesized in the motor nerve terminal by the action of the enzyme choline acetyltransferase (ChAT), and is transported into the synaptic vesicles via a specific uptake mechanism. Following depolarization of the motor nerve terminal by the axonal action potential, calcium influx via voltage-gated calcium channels triggers events that lead to vesicle fusion and release of acetylcholine. Binding of ACh to AChR leads to the opening of the AChR ion channel resulting in depolarization of the postsynaptic membrane. If this depolarization exceeds that required to open the voltage-gated sodium channels on the postsynaptic side, an action potential is generated and propagated throughout the muscle fiber, leading to contraction of the muscle. ACh is hydrolyzed by the enzyme acetylcholinesterase (AChE), which is localized at the basal lamina of the NMJ, and the membrane potential of the presynaptic membrane is restored when voltage-gated potassium channels open.

The majority of postsynaptic CMS subtypes involve mutation of the genes CHRNA1, CHRNB1, CHRND, and CHRNE encoding, respectively, the five homologous subunits of the adult AChR: two α subunits, and one each of β, δ, and ε. Mutation of these genes either increases or decreases the response to acetylcholine. After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to the opening of an ion-conducting channel. Each of the homologous subunits has a large N-terminal extracellular domain, four transmembrane segments (M1-M4) with the M2 domain lining the cation-selective pore. Each AChR has two acetylcholine binding pockets, one at the α/ε interface and one at the α/δ interface.

CMS with kinetic abnormalities of the acetylcholine receptor (slow-channel syndromes and fast-channel syndromes) is caused by pathogenic variants in the acetylcholine receptor subunit genes CHRNA1, CHRNB1, CHRND, and CHRNE. Two major kinetic abnormalities of AChR, resulting in slow-channel syndromes and fast-channel syndromes, have emerged. The two kinetic syndromes are physiologic and morphologic opposites and call for different therapeutic modalities.

The AChR subunits in individuals with CMS have numerous homozygous or, more frequently, compound heterozygous pathogenic variants that result in a reduced number of functional AChRs at the postsynaptic membrane. Although these low-expressor or null variants have been reported in all the genes encoding subunits of the adult AChR (i.e., CHRNA1, CHRNB1, CHRND, and CHRNE), they are concentrated in CHRNE (encoding the ε subunit), especially in its long cytoplasmic M3/M4 linker. Click here for more information on the AChR subunit genes.

CHAT

Gene structure. A presynaptic subtype of CMS has been linked to pathogenic variants in CHAT, the gene encoding choline O-acetyltransferase (ChAT) [Ohno et al 2001]. CHAT comprises 18 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Loss-of-function variants (pathogenic missense, frameshift, and stop variants) causing autosomal recessive CMS have been identified in more than 40 kinships with CMS clinically characterized as CMS-EA (episodic apnea) [Chaouch et al 2012a].

Table 3.

Selected CHAT Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.914T>Cp.Ile305ThrNM_020549​.4
NP_065574​.3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. ChAT catalyzes the reversible synthesis of acetylcholine from acetyl-coenzyme A and choline.

Abnormal gene product. Biochemical studies have established reduced catalytic efficiency and/or reduced expression of mutated gene products.

CHRNE

Gene structure. The CHRNE reference sequence NM_000080.3 comprises 12 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date, more than 50 ε subunit pathogenic variants have been reported [Ohno & Engel 2004a, Engel & Sine 2005].

  • Most such pathogenic variants are nonsense, splice site, or frameshift variants resulting in a premature termination of the translational chain.
  • Missense variants alter residues essential for assembly (e.g., glycosylation sites, the cystine loop) or in the signal peptide, also resulting in reduced gene expression. Some missense variants affecting AChR gene expression also have accompanying kinetic effects.
  • Single-nucleotide variants of a regulatory element (N-box) in the AChRε promoter region have been shown to result in reduced gene expression [Nichols et al 1999, Ohno et al 1999, Abicht et al 2002].
  • A chromosomal microdeletion of 1290 bp encompassing parts of CHRNE has been shown to result in CMS [Abicht et al 2002].

One particular single-nucleotide variant in the AChRε subunit (c.1327delG) resulting in endplate AChR deficiency has been shown to be common (~50%) in affected individuals of Romany and/or southeastern European ethnic origin [Abicht et al 1999, Karcagi et al 2001, Morar et al 2004].

Another pathogenic variant in the AChRε subunit (c.1353dupG) is frequent in the Maghreb (especially Algeria and Tunisia), likely because of an ancient founder effect [Beeson et al 2005].

Table 4.

Selected CHRNE Pathogenic Variants

GeneDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
CHRNEc.130dupGp.Glu44GlyfsTer3NM_000080​.3
NP_000071​.1
c.1327delG
(ε1267delG)
p.Glu443LysfsTer64
c.1353dupG
(ε1293insG)
p.Asn452GlufsTer4
(del1290) 2Null

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

1290-bp deletion from the promoter to exon 2 [Abicht et al 2002]

Normal gene product. CHRNE (NP_000071.1) comprises 493 amino acids.

Abnormal gene product. Morphologic studies of endplates show an increased number of endplate regions distributed over an increased span of the muscle fiber. The integrity of the junctional folds is preserved, but AChR expression on the folds is patchy and faint. The fetal type γ subunit may partially compensate for absence of the ε subunit, thereby producing a less severe phenotype.

COLQ

Gene structure. A synaptic subtype of CMS has been linked to pathogenic variants in COLQ, the gene encoding the collagenic tail ColQ. COLQ comprises 17 exons (and 2 alternate exons: 1A and 11A).

Pathogenic variants. All individuals with endplate (EP) AChE deficiency described to date have pathogenic variants in COLQ. To date, pathogenic variants (missense, frameshift, stop, and splice site variants) causing autosomal recessive CMS have been identified in more than 100 CMS kinships [Chaouch et al 2012a].

Normal gene product. The endplate species of AChE is a heteromeric asymmetric enzyme composed of one, two, or three homotetramers of globular catalytic subunits (AChET) attached to a triple-stranded collagenic tail (ColQ) anchoring the enzyme to the synaptic basal lamina. ColQ has an N-terminal proline-rich region attachment domain (PRAD), a collagenic central domain, and a C-terminal region enriched in charged residues and cysteines. Each ColQ strand can bind an AChET tetramer to its PRAD, giving rise to A4, A8, and A12 species of asymmetric AChE. Two groups of charged residues in the collagen domain (heparan sulfate proteoglycan binding domains [HSPBD]) plus other residues in the C-terminal region assure that the asymmetric enzyme is inserted into the synaptic basal lamina. The C-terminal region is also required for initiating the triple helical assembly of ColQ that proceeds from a C- to an N-terminal direction in a zipper-like manner.

Abnormal gene product. The COLQ-associated synaptic subtype of CMS is caused by the absence of acetylcholinesterase (AChE) from the synaptic cleft as a result of pathogenic variants in the triple-stranded collagenic tail (ColQ) anchoring the enzyme to the synaptic basal lamina [Donger et al 1998, Ohno et al 1998, Ohno et al 2000].

Biochemical studies have established three major functional consequences resulting from pathogenic variants:

  • Pathogenic variants in the PRAD-domain prevent attachment of AChET to ColQ;
  • Pathogenic variants in the collagen-domain produce a short, single-stranded ColQ that binds a single AChET tetramer and is insertion incompetent;
  • Pathogenic variants in the C-terminus hinder the triple helical assembly of the collagen domain, or produce an asymmetric species of AChE that is insertion incompetent, or both.

Neuromuscular transmission in absence of AChE is compromised by a desensitization and depolarization block of AChR at physiologic rates of stimulation, an endplate myopathy caused by cholinergic overactivity with a likely compensatory smallness of the nerve terminals and their encasement by Schwann cells. Endplate potentials and currents are prolonged in the absence of AChE, eliciting repetitive compound muscle action potentials.

DOK7

Gene structure. DOK7, encoding the postsynaptic protein Dok-7, comprises seven exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. DOK7 pathogenic variants were recently identified in individuals with congenital myasthenic syndromes affecting primarily the proximal limb muscles ("limb girdle myasthenia") [Beeson et al 2006, Müller et al 2007a, Palace et al 2007]. Since then, a large number of autosomal recessive pathogenic variants have been reported in more than 150 kinships [Chaouch et al 2012a]. Most affected individuals have the C-terminal frameshift c.1124_1127dupTGCC on at least one allele.

Table 5.

Selected DOK7 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1124_1127dupTGCCp.Ala378SerfsTer30NM_173660​.4
NP_775931​.3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Dok ("downstream of kinase") -7 is a 43-kd MuSK-interacting postsynaptic protein [Okada et al 2006] that is essential for synaptogenesis. Previously known Dok-family proteins (Dok-1 to Dok-6) play a role in signaling downstream of receptor and non-receptor phosphotyrosine kinases. Like other Dok proteins, Dok-7 has a pleckstrin-homology (PH) domain and a phosphotyrosine-binding (PTB) domain in the N-terminal moiety and multiple tyrosine residues in the C-terminal region.

Okada et al [2006] demonstrated that Dok-7 overexpression can induce the aneural activation of MuSK and subsequent clustering of AChR in cultured myotubes. Unique among adaptor proteins recruited to receptor tyrosine kinases, Dok7 is not only a substrate of MuSK, but also an activator of MuSK's kinase activity.

The crystal structure of the Dok7 PH-PTB domains in complex with a phosphopeptide representing the Dok7-binding site on MuSK revealed a dimeric arrangement of Dok7 PH-PTB that facilitates transautophosphorylation of the kinase activation loop [Bergamin et al 2010].

Abnormal gene product. Analysis of AChR clusters induced by Dok-7 harboring the pathogenic variant c.1124_1127dupTGCC showed a significant reduction in the number of branched-type AChR plaques compared to wild-type Dok-7 in fully differentiated transfected C2C12 myotubes [Beeson et al 2006]. By contrast, the ability of the c.1124_1127dupTGCC mutant to bind and induce MuSK phosphorylation was not impaired in non-differentiated myoblasts and in heterologous cells, suggesting that the C-terminal domain could play a key role in the maturation of the synaptic structure. Other pathogenic variants in the C-terminal domain of Dok-7 may have similar effects in myotubes.

GFPT1

Gene structure. GFPT1 comprises 19 exons, plus one additional alternative exon 8A, which is incorporated only into a longer isoform GFPT1L, resulting in the insertion of 18 additional amino acids. GFPT1L is mainly expressed in skeletal muscle and heart and is the predominant GFPT1 species in these tissues [Niimi et al 2001]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. GFPT1 pathogenic variants have been identified in more than 20 individuals with a subtype of CMS referred to as congenital myasthenic syndrome with tubular aggregates (CMS-TA) [Guergueltcheva et al 2012, Senderek et al 2011]. Nineteen different GFPT1 pathogenic variants comprising 13 missense pathogenic variants, four frameshifts, one nonsense variant, and one variant in the 3’-UTR were identified. No individual with CMS with two null variants in the constitutive exons resulting in a complete loss of GFPT1 expression has been identified.

Normal gene product. GFPT1 encodes an 80-kd enzyme that is part of the hexosamine biosynthesis pathway. GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway. Products of this biochemical pathway are the sugar building blocks for the glycosylation of proteins and lipids in all cells.

Abnormal gene product. Pathogenic variants in GFPT1 lead to reduced protein levels in muscle; some missense pathogenic variants also slightly reduce the enzymatic activity [Senderek et al 2011]. The precise mechanism by which GFPT1 deficiency induces a dysfunction of the neuromuscular junction is not yet understood.

RAPSN

Gene structure. RAPSN, encoding the postsynaptic protein rapsyn (43-kd receptor-associated protein of the synapse), comprises eight exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Nearly 200 pathogenic variants in RAPSN have been identified to date in the coding region (missense, frameshift, stop, and splice site variants) and the promoter region [Ohno & Engel 2004a, Engel & Sine 2005, Müller et al 2007b, Milone et al 2009, Chaouch et al 2012a].

Table 6.

Selected RAPSN Pathogenic Variants

DNA Nucleotide Change
(Alias) 1
Predicted Protein ChangeReference Sequences
c.-210A>G 2, 3
(-38A>G) 4
NANM_005055​.4
NP_005046​.2
c.-199C>G 2, 5
(-27C>G) 4
NA
c.264C>Ap.Asn88Lys

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA = not applicable

1.

Variant designation that does not conform to current naming conventions

2.

Promoter mutations. Number of nucleotides 5' of the ATG translation initiation codon

3.

An E-box pathogenic variant, c.-210A>G observed in the homozygous state, arose from a common founder in Near-Eastern Jews with marked jaw and other facial malformations [Ohno et al 2003].

4.

Alias designations are number of nucleotides 5’ of the transcription start site.

5.

One E-box pathogenic variant, c.-199C>G, was compound heterozygous with the c.264C>A pathogenic variant [Ohno et al 2003].

Normal gene product. Rapsyn, a 43-kd postsynaptic protein, plays an essential role in the clustering of AChR at the endplate. It self-associates, aggregates AChRs, and links them to the subsynaptic cytoskeleton.

Abnormal gene product. EP studies in each case have shown decreased staining for rapsyn and AChR, as well as impaired postsynaptic development. Expression studies of mutated constructs indicate that many pathogenic variants diminished co-clustering of AChR with rapsyn. For some missense variants, however, different pathogenic mechanisms that inhibited self-association of rapsyn or reduced the stability of the rapsyn protein have been discovered [Cossins et al 2006].

Less Common Genetic Causes of CMS

Click here (pdf) for more detailed information on select genes from Table 1b.

References

Literature Cited

  • Abicht A, Dusl M, Gallenmüller C, Guergueltcheva V, Schara U, Della Marina A, Wibbeler E, Almaras S, Mihaylova V, von der Hagen M, Huebner A, Chaouch A, Müller JS, Lochmüller H. Congenital myasthenic syndromes: achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: a study of 680 patients. Hum Mutat. 2012;33:1474–84. [PubMed: 22678886]
  • Abicht A, Stucka R, Karcagi V, Herczegfalvi A, Horvath R, Mortier W, Schara U, Ramaekers V, Jost W, Brunner J, Janssen G, Seidel U, Schlotter B, Müller-Felber W, Pongratz D, Rudel R, Lochmuller H. A common mutation (epsilon1267delG) in congenital myasthenic patients of Gypsy ethnic origin. Neurology. 1999;53:1564–9. [PubMed: 10534268]
  • Abicht A, Stucka R, Schmidt C, Briguet A, Hopfner S, Song IH, Pongratz D, Müller-Felber W, Ruegg MA, Lochmuller H. A newly identified chromosomal microdeletion and an N-box mutation of the AChR epsilon gene cause a congenital myasthenic syndrome. Brain. 2002;125:1005–13. [PubMed: 11960891]
  • Basiri K, Belaya K, Liu WW, Maxwell S, Sedghi M, Beeson D. Clinical features in a large Iranian family with a limb-girdle congenital myasthenic syndrome due to a mutation in DPAGT1. Neuromuscul Disord. 2013;23:469–72. [PMC free article: PMC3746154] [PubMed: 23591138]
  • Beeson D, Hantai D, Lochmuller H, Engel AG. 126th International Workshop: congenital myasthenic syndromes, 24-26 September 2004, Naarden, the Netherlands. Neuromuscul Disord. 2005;15:498–512. [PubMed: 15951177]
  • Beeson D, Higuchi O, Palace J, Cossins J, Spearman H, Maxwell S, Newsom-Davis J, Burke G, Fawcett P, Motomura M, Müller JS, Lochmüller H, Slater C, Vincent A, Yamanashi Y. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science. 2006;313:1975–8. [PubMed: 16917026]
  • Belaya K, Finlayson S, Cossins J, Liu WW, Maxwell S, Palace J, Beeson D. Identification of DPAGT1 as a new gene in which mutations cause a congenital myasthenic syndrome. Ann N Y Acad Sci. 2012a;1275:29–35. [PMC free article: PMC6044425] [PubMed: 23278575]
  • Belaya K, Finlayson S, Slater CR, Cossins J, Liu WW, Maxwell S, McGowan SJ, Maslau S, Twigg SR, Walls TJ. Pascual Pascual SI, Palace J, Beeson D. Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am J Hum Genet. 2012b;91:193–201. [PMC free article: PMC3397259] [PubMed: 22742743]
  • Belaya K, Rodríguez Cruz PM, Liu WW, Maxwell S, McGowan S, Farrugia ME, Petty R, Walls TJ, Sedghi M, Basiri K, Yue WW, Sarkozy A, Bertoli M, Pitt M, Kennett R, Schaefer A, Bushby K, Parton M, Lochmüller H, Palace J, Muntoni F, Beeson D. Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies. Brain. 2015;138:2493–504. [PMC free article: PMC4547052] [PubMed: 26133662]
  • Ben Ammar A, Petit F, Alexandri N, Gaudon K, Bauché S, Rouche A, Gras D, Fournier E, Koenig J, Stojkovic T, Lacour A, Petiot P, Zagnoli F, Viollet L, Pellegrini N, Orlikowski D, Lazaro L, Ferrer X, Stoltenburg G, Paturneau-Jouas M, Hentati F, Fardeau M, Sternberg D, Hantaï D, Richard P, Eymard B. Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7. J Neurol. 2010;257:754–66. [PubMed: 20012313]
  • Bergamin E, Hallock PT, Burden SJ, Hubbard SR. The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Mol Cell. 2010;39:100–9. [PMC free article: PMC2917201] [PubMed: 20603078]
  • Bestue-Cardiel M, Sáenz de Cabezón-Alvarez A, Capablo-Liesa JL, López-Pisón J, Peña-Segura JL, Martin-Martinez J, Engel AG. Congenital endplate acetylcholinesterase deficiency responsive to ephedrine. Neurology. 2005;65:144–6. [PubMed: 16009904]
  • Brownlow S, Webster R, Croxen R, Brydson M, Neville B, Lin JP, Vincent A, Newsom-Davis J, Beeson D. Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita. J Clin Invest. 2001;108:125–30. [PMC free article: PMC209343] [PubMed: 11435464]
  • Burke G, Hiscock A, Klein A, Niks EH, Main M, Manzur AY, Ng J, de Vile C, Muntoni F, Beeson D, Robb S. Salbutamol benefits children with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord. 2013;23:170–5. [PubMed: 23219351]
  • Burke G, Cossins J, Maxwell S, Owens G, Vincent A, Robb S, Nicolle M, Hilton-Jones D, Newsom-Davis J, Palace J, Beeson D. Rapsyn mutations in hereditary myasthenia: distinct early- and late-onset phenotypes. Neurology. 2003;61:826–8. [PubMed: 14504330]
  • Burke G, Cossins J, Maxwell S, Robb S, Nicolle M, Vincent A, Newsom-Davis J, Palace J, Beeson D. Distinct phenotypes of congenital acetylcholine receptor deficiency. Neuromuscul Disord. 2004;14:356–64. [PubMed: 15145336]
  • Byring RF, Pihko H, Tsujino A, Shen XM, Gustafsson B, Hackman P, Ohno K, Engel AG, Udd B. Congenital myasthenic syndrome associated with episodic apnea and sudden infant death. Neuromuscul Disord. 2002;12:548–53. [PubMed: 12117478]
  • Chaouch A, Beeson D, Hantaï D, Lochmüller H. 186th ENMC International Workshop: Congenital myasthenic syndromes 24-26 June 2011, Naarden, The Netherlands. Neuromuscul Disord. 2012a;22:566–76. [PubMed: 22230109]
  • Chaouch A, Müller JS, Guergueltcheva V, Dusl M, Schara U, Rakocević-Stojanović V, Lindberg C, Scola RH, Werneck LC, Colomer J, Nascimento A, Vilchez JJ, Muelas N, Argov Z, Abicht A, Lochmüller H. A retrospective clinical study of the treatment of slow-channel congenital myasthenic syndrome. J Neurol. 2012b;259:474–81. [PubMed: 21822932]
  • Chaouch A, Porcelli V, Cox D, Edvardson S, Scarcia P, De Grassi A, Pierri CL, Cossins J, Laval SH, Griffin H, Müller JS, Evangelista T, Töpf A, Abicht A, Huebner A, von der Hagen M, Bushby K, Straub V, Horvath R, Elpeleg O, Palace J, Senderek J, Beeson D, Palmieri L, Lochmüller H. Mutations in the mitochondrial citrate carrier SLC25A1 are associated with impaired neuromuscular transmission. J Neuromuscul Dis. 2014;1:75–90. [PMC free article: PMC4746751] [PubMed: 26870663]
  • Chevessier F, Faraut B, Ravel-Chapuis A, Richard P, Gaudon K, Bauche S, Prioleau C, Herbst R, Goillot E, Ioos C, Azulay JP, Attarian S, Leroy JP, Fournier E, Legay C, Schaeffer L, Koenig J, Fardeau M, Eymard B, Pouget J, Hantai D. MUSK, a new target for mutations causing congenital myasthenic syndrome. Hum Mol Genet. 2004;13:3229–40. [PubMed: 15496425]
  • Colomer J, Müller JS, Vernet A, Nascimento A, Pons M, Gonzalez V, Abicht A, Lochmüller H. Long-term improvement of slow-channel congenital myasthenic syndrome with fluoxetine. Neuromuscul Disord. 2006;16:329–33. [PubMed: 16621558]
  • Cossins J, Belaya K, Hicks D, Salih MA, Finlayson S, Carboni N, Liu WW, Maxwell S, Zoltowska K, Farsani GT, Laval S, Seidhamed MZ., WGS500 Consortium. Donnelly P, Bentley D, McGowan SJ, Müller J, Palace J, Lochmüller H, Beeson D. Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain. 2013;136:944–56. [PMC free article: PMC3580273] [PubMed: 23404334]
  • Cossins J, Burke G, Maxwell S, Spearman H, Man S, Kuks J, Vincent A, Palace J, Fuhrer C, Beeson D. Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations. Brain. 2006;129:2773–83. [PubMed: 16945936]
  • Croxen R, Hatton C, Shelley C, Brydson M, Chauplannaz G, Oosterhuis H, Vincent A, Newsom-Davis J, Colquhoun D, Beeson D. Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes. Neurology. 2002a;59:162–8. [PubMed: 12141316]
  • Croxen R, Hatton C, Shelley C, Brydson M, Chauplannaz G, Oosterhuis H, Vincent A, Newsom-Davis J, Colquhoun D, Beeson D. Voluntary partial retraction of: Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes. Neurology. 2009;72:294. [PubMed: 19153382]
  • Croxen R, Newland C, Beeson D, Oosterhuis H, Chauplannaz G, Vincent A, Newsom-Davis J. Mutations in different functional domains of the human muscle acetylcholine receptor alpha subunit in patients with the slow-channel congenital myasthenic syndrome. Hum Mol Genet. 1997;6:767–74. [PubMed: 9158151]
  • Croxen R, Vincent A, Newsom-Davis J, Beeson D. Myasthenia gravis in a woman with congenital AChR deficiency due to epsilon-subunit mutations. Neurology. 2002b;58:1563–5. [PubMed: 12034803]
  • Deymeer F, Serdaroglu P, Ozdemir C. Familial infantile myasthenia: confusion in terminology. Neuromuscul Disord. 1999;9:129–30. [PubMed: 10382904]
  • Donger C, Krejci E, Serradell AP, Eymard B, Bon S, Nicole S, Chateau D, Gary F, Fardeau M, Massoulie J, Guicheney P. Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic). Am J Hum Genet. 1998;63:967–75. [PMC free article: PMC1377491] [PubMed: 9758617]
  • Engel AG. The therapy of congenital myasthenic syndromes. Neurotherapeutics. 2007;4:252–7. [PMC free article: PMC1978489] [PubMed: 17395135]
  • Engel AG, Ohno K, Sine SM. Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nat Rev Neurosci. 2003;4:339–52. [PubMed: 12728262]
  • Engel AG, Shen XM, Selcen D, Sine SM. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 2015;14:461. [PubMed: 25895926]
  • Engel AG, Sine SM. Current understanding of congenital myasthenic syndromes. Curr Opin Pharmacol. 2005;5:308–21. [PubMed: 15907919]
  • Fattahi Z, Kahrizi K, Nafissi S, Fadaee M, Abedini SS, Kariminejad A, Akbari MR, Najmabadi H. Report of a patient with limb-girdle muscular dystrophy, ptosis and ophthalmoparesis caused by plectinopathy. Arch Iran Med. 2015;18:60–4. [PubMed: 25556389]
  • Finlayson S, Beeson D, Palace J. Congenital myasthenic syndromes: an update. Pract Neurol. 2013;13:80–91. [PubMed: 23468559]
  • Forrest K, Mellerio JE, Robb S, Dopping-Hepenstal PJ, McGrath JA, Liu L, Buk SJ, Al-Sarraj S, Wraige E, Jungbluth H. Congenital muscular dystrophy, myasthenic symptoms and epidermolysis bullosa simplex (EBS) associated with mutations in the PLEC1 gene encoding plectin. Neuromuscul Disord. 2010;20:709–11. [PubMed: 20624679]
  • Ganetzky R, Izumi K, Edmondson A, Muraresku CC, Zackai E, Deardorff M, Ganesh J. Fetal akinesia deformation sequence due to a congenital disorder of glycosylation. Am J Med Genet A. 2015;167A:2411–7. [PubMed: 26033833]
  • Gaudon K, Pénisson-Besnier I, Chabrol B, Bouhour F, Demay L, Ben Ammar A, Bauché S, Vial C, Nicolas G, Eymard B, Hantaï D, Richard P. Multiexon deletions account for 15% of congenital myasthenic syndromes with RAPSN mutations after negative DNA sequencing. J Med Genet. 2010;47:795–6. [PubMed: 20930056]
  • Guergueltcheva V, Müller JS, Dusl M, Senderek J, Oldfors A, Lindbergh C, Maxwell S, Colomer J, Mallebrera CJ, Nascimento A, Vilchez JJ, Muelas N, Kirschner J, Nafissi S, Kariminejad A, Nilipour Y, Bozorgmehr B, Najmabadi H, Rodolico C, Sieb JP, Schlotter B, Schoser B, Herrmann R, Voit T, Steinlein OK, Najafi A, Urtizberea A, Soler DM, Muntoni F, Hanna MG, Chaouch A, Straub V, Bushby K, Palace J, Beeson D, Abicht A, Lochmüller H. Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations. J Neurol. 2012;259:838–50. [PubMed: 21975507]
  • Habbout K, Poulin H, Rivier F, Giuliano S, Sternberg D, Fontaine B, Eymard B, Morales RJ, Echenne B, King L, Hanna MG, Männikkö R, Chahine M, Nicole S, Bendahhou S. A recessive Nav1.4 mutation underlies congenital myasthenic syndrome with periodic paralysis. Neurology. 2016;86:161–9. [PMC free article: PMC4731685] [PubMed: 26659129]
  • Hantaï D, Nicole S, Eymard B. Congenital myasthenic syndromes: an update. Curr Opin Neurol. 2013;26:561–8. [PubMed: 23995276]
  • Hantaï D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Curr Opin Neurol. 2004;17:539–51. [PubMed: 15367858]
  • Harper CM, Engel AG. Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol. 1998;43:480–4. [PubMed: 9546329]
  • Harper CM, Fukodome T, Engel AG. Treatment of slow-channel congenital myasthenic syndrome with fluoxetine. Neurology. 2003;60:1710–3. [PubMed: 12771277]
  • Herrmann DN, Horvath R, Sowden JE, Gonzalez M, Sanchez-Mejias A, Guan Z, Whittaker RG, Almodovar JL, Lane M, Bansagi B, Pyle A, Boczonadi V, Lochmüller H, Griffin H, Chinnery PF, Lloyd TE, Littleton JT, Zuchner S. Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy. Am J Hum Genet. 2014;95:332–9. [PMC free article: PMC4157148] [PubMed: 25192047]
  • Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med. 2001;7:365–8. [PubMed: 11231638]
  • Huzé C, Bauché S, Richard P, Chevessier F, Goillot E, Gaudon K, Ben Ammar A, Chaboud A, Grosjean I, Lecuyer HA, Bernard V, Rouche A, Alexandri N, Kuntzer T, Fardeau M, Fournier E, Brancaccio A, Rüegg MA, Koenig J, Eymard B, Schaeffer L, Hantaï D. Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. Am J Hum Genet. 2009;85:155–67. [PMC free article: PMC2725239] [PubMed: 19631309]
  • Jurkat-Rott K, Holzherr B, Fauler M, Lehmann-Horn F. Sodium channelopathies of skeletal muscle result from gain or loss of function. Pflugers Arch. 2010;460:239–48. [PMC free article: PMC2883924] [PubMed: 20237798]
  • Karakaya M, Ceyhan-Birsoy O, Beggs AH, Topaloglu H. A novel missense mutation in the AGRN gene causing congenital myasthenic syndrome mimicking neck myopathy. Berlin, Germany: 19th International Congress of the World-Muscle-Society. 2014.
  • Karcagi V, Tournev I, Schmidt C, Herczegfalvi A, Guergueltcheva V, Litvinenko I, Song IH, Abicht A, Lochmuller H. Congenital myasthenic syndrome in southeastern European Roma (Gypsies). Acta Myologica. 2001;20:231–8.
  • Kinali M, Beeson D, Pitt MC, Jungbluth H, Simonds AK, Aloysius A, Cockerill H, Davis T, Palace J, Manzur AY, Jimenez-Mallebrera C, Sewry C, Muntoni F, Robb SA. Congenital myasthenic syndromes in childhood: diagnostic and management challenges. J Neuroimmunol. 2008;201-202:6–12. [PubMed: 18707767]
  • Lashley D, Palace J, Jayawant S, Robb S, Beeson D. Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7. Neurology. 2010;74:1517–23. [PMC free article: PMC2875925] [PubMed: 20458068]
  • Liewluck T, Selcen D, Engel AG. Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and Dok-7 myasthenia. Muscle Nerve. 2011;44:789–94. [PMC free article: PMC3196786] [PubMed: 21952943]
  • Logan CV, Cossins J, Rodríguez Cruz PM, Parry DA, Maxwell S, Martínez-Martínez P, Riepsaame J, Abdelhamed ZA, Lake AV, Moran M, Robb S, Chow G, Sewry C, Hopkins PM, Sheridan E, Jayawant S, Palace J, Johnson CA, Beeson D. Congenital myasthenic syndrome type 19 is caused by mutations in COL13A1, encoding the atypical non-fibrillar collagen type XIII α1 chain. Am J Hum Genet. 2015;97:878–85. [PMC free article: PMC4678414] [PubMed: 26626625]
  • Lorenzoni PJ, Scola RH, Kay CS, Filla L, Miranda AP, Pinheiro JM, Chaouch A, Lochmüller H, Werneck LC. Salbutamol therapy in congenital myasthenic syndrome due to DOK7 mutation. J Neurol Sci. 2013;331:155–7. [PubMed: 23790237]
  • Maselli RA, Arredondo J, Cagney O, Ng JJ, Anderson JA, Williams C, Gerke BJ, Soliven B, Wollmann RL. Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. Hum Mol Genet. 2010;19:2370–9. [PMC free article: PMC2876883] [PubMed: 20371544]
  • Maselli RA, Fernandez JM, Arredondo J, Navarro C, Ngo M, Beeson D, Cagney O, Williams DC, Wollmann RL, Yarov-Yarovoy V, Ferns MJ. LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. Hum Genet. 2012;131:1123–35. [PMC free article: PMC4795461] [PubMed: 22205389]
  • Maselli RA, Ng JJ, Anderson JA, Cagney O, Arredondo J, Williams C, Wessel HB, Abdel-Hamid H, Wollmann RL. Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. J Med Genet. 2009;46:203–8. [PMC free article: PMC2643050] [PubMed: 19251977]
  • Mihaylova V, Salih MA, Mukhtar MM, Abuzeid HA, El-Sadig SM, von der Hagen M, Huebner A, Nürnberg G, Abicht A, Müller JS, Lochmüller H, Guergueltcheva V. Refinement of the clinical phenotype in musk-related congenital myasthenic syndromes. Neurology. 2009;73:1926–8. [PubMed: 19949040]
  • Milone M, Shen XM, Ohno K, Harper MC, Fukudome T, Stilling G, Brengman JM, Engel AG. Unusual congenital myasthenic syndrome (CMS) with endplate AChR deficiency caused by alpha- subunit mutations and a remitting-relapsing clinical course. Neurology. 1999;52:A188.
  • Milone M, Shen XM, Selcen D, Ohno K, Brengman J, Iannaccone ST, Harper CM, Engel AG. Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients. Neurology. 2009;73:228–35. [PMC free article: PMC2715575] [PubMed: 19620612]
  • Monies DM, Al-Hindi HN, Al-Muhaizea MA, Jaroudi DJ, Al-Younes B, Naim EA, Wakil SM, Meyer BF, Bohlega S. Clinical and pathological heterogeneity of a congenital disorder of glycosylation manifesting as a myasthenic/myopathic syndrome. Neuromuscul Disord. 2014;24:353–9. [PubMed: 24461433]
  • Morar B, Gresham D, Angelicheva D, Tournev I, Gooding R, Guergueltcheva V, Schmidt C, Abicht A, Lochmuller H, Tordai A, Kalmar L, Nagy M, Karcagi V, Jeanpierre M, Herczegfalvi A, Beeson D, Venkataraman V, Warwick Carter K, Reeve J, de Pablo R, Kucinskas V, Kalaydjieva L. Mutation history of the roma/gypsies. Am J Hum Genet. 2004;75:596–609. [PMC free article: PMC1182047] [PubMed: 15322984]
  • Müller JS, Abicht A, Burke G, Cossins J, Richard P, Baumeister SK, Stucka R, Eymard B, Hantai D, Beeson D, Lochmuller H. The Congenital Myasthenic Syndrome mutation RAPSN N88K derives from an ancient Indo-European founder. J Med Genet. 2004a;41:e104. [PMC free article: PMC1735862] [PubMed: 15286164]
  • Müller JS, Abicht A, Christen HJ, Stucka R, Schara U, Mortier W, Huebner A, Lochmuller H. A newly identified chromosomal microdeletion of the rapsyn gene causes a congenital myasthenic syndrome. Neuromuscul Disord. 2004b;14:744–9. [PubMed: 15482960]
  • Müller JS, Baumeister SK, Schara U, Cossins J, Krause S, von der Hagen M, Huebner A, Webster R, Beeson D, Lochmüller H, Abicht A. CHRND mutation causes a congenital myasthenic syndrome by impairing co-clustering of the acetylcholine receptor with rapsyn. Brain. 2006;129:2784–93. [PubMed: 16916845]
  • Müller JS, Herczegfalvi A, Vilchez JJ, Colomer J, Bachinski LL, Mihaylova V, Santos M, Schara U, Deschauer M, Shevell M, Poulin C, Dias A, Soudo A, Hietala M, Aärimaa T, Krahe R, Karcagi V, Huebner A, Beeson D, Abicht A, Lochmüller H. Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Brain. 2007a;130:1497–506. [PubMed: 17439981]
  • Müller JS, Mihaylova V, Abicht A, Lochmüller H. Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission. Expert Rev Mol Med. 2007b;9:1–20. [PubMed: 17686188]
  • Nichols P, Croxen R, Vincent A, Rutter R, Hutchinson M, Newsom-Davis J, Beeson D. Mutation of the acetylcholine receptor epsilon-subunit promoter in congenital myasthenic syndrome. Ann Neurol. 1999;45:439–43. [PubMed: 10211467]
  • Nicole S, Chaouch A, Torbergsen T, Bauché S, de Bruyckere E, Fontenille MJ, Horn MA, van Ghelue M, Løseth S, Issop Y, Cox D, Müller JS, Evangelista T, Stålberg E, Ioos C, Barois A, Brochier G, Sternberg D, Fournier E, Hantaï D, Abicht A, Dusl M, Laval SH, Griffin H, Eymard B, Lochmüller H. Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy. Brain. 2014;137:2429–43. [PubMed: 24951643]
  • Niimi M, Ogawara T, Yamashita T, Yamamoto Y, Ueyama A, Kambe T, Okamoto T, Ban T, Tamanoi H, Ozaki K, Fujiwara T, Fukui H, Takahashi EI, Kyushiki H, Tanigami A. Identification of GFAT1-L, a novel splice variant of human glutamine: fructose-6-phosphate amidotransferase (GFAT1) that is expressed abundantly in skeletal muscle. J Hum Genet. 2001;46:566–71. [PubMed: 11587069]
  • Ohkawara B, Cabrera-Serrano M, Nakata T, Milone M, Asai N, Ito K, Ito M, Masuda A, Ito Y, Engel AG, Ohno K. LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner. Hum Mol Genet. 2014;23:1856–68. [PMC free article: PMC3943522] [PubMed: 24234652]
  • Ohno K, Anlar B, Engel AG. Congenital myasthenic syndrome caused by a mutation in the Ets-binding site of the promoter region of the acetylcholine receptor epsilon subunit gene. Neuromuscul Disord. 1999;9:131–5. [PubMed: 10382905]
  • Ohno K, Brengman J, Tsujino A, Engel AG. Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme. Proc Natl Acad Sci U S A. 1998;95:9654–9. [PMC free article: PMC21394] [PubMed: 9689136]
  • Ohno K, Engel AG. Congenital myasthenic syndromes: gene mutations. Neuromuscul Disord. 2004a;14:117–22. [PubMed: 14702950]
  • Ohno K, Engel AG. Lack of founder haplotype for the rapsyn mutation; N88K is an ancient founder mutation or arises from multiple founders. J Med Genet. 2004b;41:e8. [PMC free article: PMC1757267] [PubMed: 14729848]
  • Ohno K, Engel AG, Brengman JM, Shen XM, Heidenreich F, Vincent A, Milone M, Tan E, Demirci M, Walsh P, Nakano S, Akiguchi I. The spectrum of mutations causing end-plate acetylcholinesterase deficiency. Ann Neurol. 2000;47:162–70. [PubMed: 10665486]
  • Ohno K, Engel AG, Shen XM, Selcen D, Brengman J, Harper CM, Tsujino A, Milone M. Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome. Am J Hum Genet. 2002;70:875–85. [PMC free article: PMC379116] [PubMed: 11791205]
  • Ohno K, Sadeh M, Blatt I, Brengman JM, Engel AG. E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Hum Mol Genet. 2003;12:739–48. [PubMed: 12651869]
  • Ohno K, Tsujino A, Brengman JM, Harper CM, Bajzer Z, Udd B, Beyring R, Robb S, Kirkham FJ, Engel AG. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc Natl Acad Sci U S A. 2001;98:2017–22. [PMC free article: PMC29374] [PubMed: 11172068]
  • Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006;312:1802–5. [PubMed: 16794080]
  • Palace J, Lashley D, Newsom-Davis J, Cossins J, Maxwell S, Kennett R, Jayawant S, Yamanashi Y, Beeson D. Clinical features of the DOK7 neuromuscular junction synaptopathy. Brain. 2007;130:1507–15. [PubMed: 17452375]
  • Quiram PA, Ohno K, Milone M, Patterson MC, Pruitt NJ, Brengman JM, Sine SM, Engel AG. Mutation causing congenital myasthenia reveals acetylcholine receptor beta/delta subunit interaction essential for assembly. J Clin Invest. 1999;104:1403–10. [PMC free article: PMC409847] [PubMed: 10562302]
  • Ravenscroft G, Sollis E, Charles AK, North KN, Baynam G, Laing NG. Fetal akinesia: review of the genetics of the neuromuscular causes. J Med Genet. 2011;48:793–801. [PubMed: 21984750]
  • Régal L, Shen XM, Selcen D, Verhille C, Meulemans S, Creemers JW, Engel AG. PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome. Neurology. 2014;82:1254–60. [PMC free article: PMC4001208] [PubMed: 24610330]
  • Richard P, Gaudon K, Andreux F, Yasaki E, Prioleau C, Bauche S, Barois A, Ioos C, Mayer M, Routon MC, Mokhtari M, Leroy JP, Fournier E, Hainque B, Koenig J, Fardeau M, Eymard B, Hantai D. Possible founder effect of rapsyn N88K mutation and identification of novel rapsyn mutations in congenital myasthenic syndromes. J Med Genet. 2003;40:e81. [PMC free article: PMC1735489] [PubMed: 12807980]
  • Rodríguez Cruz PM, Palace J, Beeson D. Inherited disorders of the neuromuscular junction: an update. J Neurol. 2014;261:2234–43. [PubMed: 25305004]
  • Schara U, Barisic N, Deschauer M, Lindberg C, Straub V, Strigl-Pill N, Wendt M, Abicht A, Müller JS, Lochmüller H. Ephedrine therapy in eight patients with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord. 2009;19:828–32. [PubMed: 19837590]
  • Schara U, Della Marina A, Abicht A. Congenital myasthenic syndromes: current diagnostic and therapeutic approaches. Neuropediatrics. 2012;43:184–93. [PubMed: 22911480]
  • Selcen D, Shen XM, Brengman J, Li Y, Stans AA, Wieben E, Engel AG. DPAGT1 myasthenia and myopathy: genetic, phenotypic, and expression studies. Neurology. 2014;82:1822–30. [PMC free article: PMC4035711] [PubMed: 24759841]
  • Selcen D, Juel VC, Hobson-Webb LD, Smith EC, Stickler DE, Bite AV, Ohno K, Engel AG. Myasthenic syndrome caused by plectinopathy. Neurology. 2011;76:327–36. [PMC free article: PMC3034415] [PubMed: 21263134]
  • Selcen D, Ohkawara B, Shen XM, McEvoy K, Ohno K, Engel AG. Impaired synaptic development, maintenance, and neuromuscular transmission in LRP4-related myasthenia. JAMA Neurol. 2015;72:889–96. [PMC free article: PMC4532561] [PubMed: 26052878]
  • Senderek J, Müller JS, Dusl M, Strom TM, Guergueltcheva V, Diepolder I, Laval SH, Maxwell S, Cossins J, Krause S, Muelas N, Vilchez JJ, Colomer J, Mallebrera CJ, Nascimento A, Nafissi S, Kariminejad A, Nilipour Y, Bozorgmehr B, Najmabadi H, Rodolico C, Sieb JP, Steinlein OK, Schlotter B, Schoser B, Kirschner J, Herrmann R, Voit T, Oldfors A, Lindbergh C, Urtizberea A, von der Hagen M, Hübner A, Palace J, Bushby K, Straub V, Beeson D, Abicht A, Lochmüller H. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet. 2011;88:162–72. [PMC free article: PMC3035713] [PubMed: 21310273]
  • Servais L, Baudoin H, Zehrouni K, Richard P, Sternberg D, Fournier E, Eymard B, Stojkovic T. Pregnancy in congenital myasthenic syndrome. J Neurol. 2013;260:815–9. [PubMed: 23108489]
  • Shen XM, Selcen D, Brengman J, Engel AG. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology. 2014;83:2247–55. [PMC free article: PMC4277673] [PubMed: 25381298]
  • Tan-Sindhunata MB, Mathijssen IB, Smit M, Baas F, de Vries JI, van der Voorn JP, Kluijt I, Hagen MA, Blom EW, Sistermans E, Meijers-Heijboer H, Waisfisz Q, Weiss MM, Groffen AJ. Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence. Eur J Hum Genet. 2015;23:1151–7. [PMC free article: PMC4538208] [PubMed: 25537362]
  • Tsujino A, Maertens C, Ohno K, Shen XM, Fukuda T, Harper CM, Cannon SC, Engel AG. Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci U S A. 2003;100:7377–82. [PMC free article: PMC165883] [PubMed: 12766226]
  • Vogt J, Harrison BJ, Spearman H, Cossins J, Vermeer S, ten Cate LN, Morgan NV, Beeson D, Maher ER. Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Am J Hum Genet. 2008;82:222–7. [PMC free article: PMC2253973] [PubMed: 18179903]
  • Vrinten C, van der Zwaag AM, Weinreich SS, Scholten RJ, Verschuuren JJ. Ephedrine for myasthenia gravis, neonatal myasthenia and the congenital myasthenic syndromes. Cochrane Database Syst Rev. 2014;(12):CD010028. [PubMed: 25515947]
  • Whittaker RG, Herrmann DN, Bansagi B, Hasan BA, Lofra RM, Logigian EL, Sowden JE, Almodovar JL, Littleton JT, Zuchner S, Horvath R, Lochmüller H. Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome. Neurology. 2015;85:1964–71. [PMC free article: PMC4664120] [PubMed: 26519543]
  • Witting N, Vissing J. Pharmacologic treatment of downstream of tyrosine kinase 7 congenital myasthenic syndrome. JAMA Neurol. 2014;71:350–4. [PubMed: 24425145]

Suggested Reading

Chapter Notes

Revision History

  • 14 July 2016 (ha) Comprehensive update posted live
  • 28 June 2012 (cd) Revision: targeted mutation analysis of CHRNA1 no longer listed in the GeneTests™ Laboratory Directory as being available clinically
  • 22 March 2012 (me) Comprehensive update posted live
  • 26 September 2006 (aa) Revision: clinical testing available for: mutation scanning of RAPSN, CHAT, COLQ, CHRNB1, and CHRND; sequence analysis of CHRNE and CHRNA1; targeted mutation analysis of RAPSN mutation p.N88K, CHAT mutation p.I305T, and CHRNA1 mutation p.G153S; prenatal diagnosis for CHAT, CHRNA1, CHRNB1, CHRND, CHRNE, COLQ, and RAPSN
  • 20 September 2005 (aa) Revision: sequence analysis for RAPSN clinically available
  • 8 August 2005 (me) Comprehensive update posted live
  • 9 May 2003 (me) Review posted live
  • 30 January 2003 (aa) Original submission
Copyright © 1993-2018, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2018 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1168PMID: 20301347

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...