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

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Congenital Myasthenic Syndromes

Synonym: Congenital Myasthenia

, MD, , PhD, and , MD.

Author Information
, MD
Department of Neurology
Friedrich-Baur Institute
Munich, Germany
, PhD
Institute of Genetic Medicine
Newcastle University
Newcastle upon Tyne, United Kingdom
, MD
Institute of Genetic Medicine
Newcastle University
Newcastle upon Tyne, United Kingdom

Initial Posting: ; Last Revision: June 28, 2012.

Summary

Disease 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 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: feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; facial, bulbar, and generalized weakness. In addition arthrogryposis multiplex congenital may be present; respiratory insufficiency with sudden apnea and cyanosis may occur. 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, absence of anti-acetylcholine receptor (AChR) and anti-MuSK antibodies in the serum, and lack of improvement of clinical symptoms with immunosuppressive therapy. Mutations in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of CMS, including the genes encoding different subunits of the acetylcholine receptor:

  • CHRNE (εAChR subunit)
  • CHRNA1 (αAChR subunit)
  • CHRNB1 (βAChR subunit)
  • CHRND (δAChR-subunit)
  • AGRN encoding agrin
  • CHAT encoding choline O-acetyltransferase
  • COLQ encoding acetylcholinesterase collagenic tail peptide
  • DOK7 encoding protein Dok-7
  • GFPT1 encoding glucosamine--fructose-6-phosphate aminotransferase 1
  • MUSK encoding muscle, skeletal receptor tyrosine protein kinase
  • RAPSN encoding rapsyn (43-kd receptor-associated protein of the synapse)
  • SCN4A encoding the sodium channel protein type 4 subunit alpha

Management. Treatment of manifestations: Most individuals with CMS benefit from acetylcholine esterase (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 mutations 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 acetylcholine receptor (AChR) deficiency. Fluoxetine is reported to be beneficial for SCCMS. Ephedrine and albuterol have been beneficial in a few individuals, especially as a therapeutic option for those with DOK7 or COLQ mutations.

Prevention of primary manifestations: Prophylactic anticholinesterase therapy to prevent sudden respiratory insufficiency or apneic attacks provoked by fever or infections in those with mutations 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 disease-causing mutations 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, less frequently, autosomal dominant manner.

In autosomal recessive CMS (AR-CMS), the parents of an affected child are obligate heterozygotes and therefore carry one mutant allele. 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 mutation. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with AD-CMS has a 50% chance of inheriting the mutation.

Prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

Clinical Diagnosis

The clinical diagnosis of congenital myasthenic syndromes (CMS) is based on the following:

  • A history of fatigable weakness involving ocular, bulbar, and limb muscles
  • 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)
  • 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).

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 acetylcholinesterase deficiency or slow-channel CMS (SCCMS; caused by autosomal dominant gain-of-function mutations 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 acetylcholinesterase inhibitors is assessed using intravenous injection of edrophonium (Tensilon®), a fast-acting acetylcholinesterase inhibitor. 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. 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. In practice, a controlled/supervised trial of oral medication often replaces the edrophonium test.

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].

More detailed studies can be performed on an intercostal or motor point skeletal muscle biopsy including estimation of acetylcholine receptors (AChRs) per endplate, light and electron microscopic analysis of endplate morphology, and in vitro electrophysiologic studies of endplate function [Engel & Franzini-Armstrong 1994]. Such studies – usually carried out within a research setting – allow a more precise classification by pointing to a defect in an endplate-associated gene or protein.

Molecular Genetic Testing

Genes. Mutations in one of several genes encoding different proteins expressed at the neuromuscular junction are currently known to be associated with CMS [Beeson et al 2005, Engel & Sine 2005, Beeson et al 2006, Müller et al 2007b, Palace et al 2007, Engel et al 2010]. These include AGRN, CHAT, the genes encoding different subunits of the acetylcholine receptor (CHRNA1, CHRNB1, CHRND, CHRNE), COLQ, DOK7, GFPT1, MUSK, RAPSN, and SCNA4 (see also Table 1 and Table A).

Evidence for locus heterogeneity. To date, no other loci are known to be associated with CMS; however, families with CMS not linked to any of the known candidate genes have been identified. Further genetic studies may reveal new loci or candidate genes underlying CMS [Engel & Sine 2005, Müller et al 2007b].

Table 1. Summary of Molecular Genetic Testing Used in Congenital Myasthenic Syndromes

Gene 1Proportion of CMS Attributed to Mutations in this Gene 2Test MethodMutations Detected 3
AGRNRare 4Sequence analysis 5Sequence variants
Deletion/duplication analysis 6None reported 7
CHAT4%-5%Sequence analysis 5Sequence variants
Targeted mutation analysis c.914T>C
Deletion /duplication analysis 6None reported 7
CHRNA1<1%Sequence analysis 5Sequence variants
Deletion/duplication analysis 6None reported 7
CHRNB1<1%Sequence analysis 5Sequence variants
Deletion/duplication analysis 6Exonic or whole-gene deletions 8
CHRND<1%Sequence analysis 5Sequence variants
Deletion/duplication analysis 6None reported 9
CHRNE50%Sequence analysis 5Sequence variants
Targeted mutation analysisc.1327delG 10
c.1353dup 11
Deletion/duplication analysis 6Exonic or whole-gene deletions 12
COLQ10%-15%Sequence analysis 5Sequence variants
Deletion/duplication analysis 6None reported 7
DOK710%-15%Sequence analysis 5Sequence variants
Targeted mutation analysisc.1124_1127dupTGCC 13
Deletion/duplication analysis 6Exonic or whole-gene deletions 14
GFPT12%Sequence analysis 5Sequence variants
MUSKRare 15Sequence analysis 5Sequence variants
Deletion/duplication analysis 6None reported 5
RAPSN15%-20%Sequence analysis 5Sequence variants 16
Targeted mutation analysis c.264C>A 17
Deletion/duplication analysis 6Exonic or whole-gene deletions 18
SCN4ARare 19Sequence analysis 5Sequence variants

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. Estimated percentage based on individuals with CMS investigated at the authors' laboratory and on published data [Beeson et al 2005, Engel & Sine 2005, Chaouch et al 2012b]

3. See Molecular Genetics for information on allelic variants.

4. Mutations in AGRN have been reported in one family [Huze et al 2009].

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Utility of deletion/duplication analysis for this gene is unknown.

8. Quiram et al [1999]

9. Müller et al [2006]

10. The CHRNE founder mutation 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].

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

12. Abicht et al [2002]

13. Most affected individuals have the European founder mutation c.1124_1127dupTGCC in DOK7 on at least one allele.

14. Selcen et al [2008]

15. Mutations in MUSK have been reported in eight individuals from three families [Chevessier et al 2004, Mihaylova et al 2009, Maselli et al 2010].

16. RAPSN mutations are dispersed throughout the translated region. Mutations have been identified in the E-box element of the promoter (See Molecular Genetics).

17. Most affected individuals of European origin, especially those with respiratory failure, have the c.264C>A mutation on at least one allele; about 50% are homozygous for c.264C>A. When only one c.264C>A mutation is identified in an individual, it is appropriate to sequence the entire gene including the promoter to detect a second heteroallelic mutation.

18. Müller et al [2004a], Gaudon et al [2010].

19. Mutations in SCN4A have been reported in one individual [Tsujino et al 2003].

Testing Strategy

To confirm/establish the diagnosis in a proband. Targeted mutation analysis may be carried out depending on the ethnic origin of the patient:

  • German or central / western European origin. RAPSN mutation c.264C>A and DOK7 mutation c.1124_1127dupTGCC
  • Southeastern European or Roma origin. CHRNE mutation c.1327delG
  • From the Maghreb (especially Algeria and Tunisia). CHRNE mutation c.1353dup

In case of heterozygosity for one of the mutations mentioned above, the entire gene including the promoter should be sequenced to detect a second heteroallelic mutation.

Sequential molecular genetic testing should be based on the proportion of CMS attributed to a mutation in each of the genes included in Table 1.

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 mutation in COLQ or RAPSN.
  • Limb-girdle phenotype. Consider testing for mutation in DOK7, COLQ, and GFPT1.
  • Double response to a single nerve stimulus. Consider:
    • A mutation in COLQ;
      OR
    • A slow-channel CMS with a mutation in one of the genes encoding the AChR subunits (CHRNA1, CHRNB1, CHRND, CHRNE).
  • Contractures. Consider testing for mutation in RAPSN.
  • Autosomal dominant family history. Consider slow-channel CMS caused by mutations of the genes encoding AChR subunits: CHRNA1, CHRNB1, CHRND, CHRNE. (All other CMS subtypes are inherited in an autosomal recessive manner.)

Carrier testing for at-risk relatives when the mode of inheritance is autosomal recessive requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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, Ben Ammar et al 2010, Guergueltcheva et al 2011].

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].

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. AMC seems to be particularly common in infants with truncating RAPSN mutations [Brownlow et al 2001, Burke et al 2003, Beeson et al 2005]. (See also Genetically Related Disorders, Fetal akinesia deformation sequence).

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, particularly in those with DOK7 mutations [Kinali et al 2008].

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.

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’ [LGM]).

In some individuals, a high-arched palate and distinctive facial features have been reported.

CMS is limited to weakness of the skeletal muscles. Cardiac and smooth muscle are not involved. Cognitive skills, coordination, sensation, and tendon reflexes are normal.

Major CMS subtypes are recognized based on molecular genetic studies in research laboratories (see Table 2).

Table 2. CMS Subtypes by Gene Involved

Gene in which Mutation is CausativeCMS SubtypeClinical Findings 1Response to AChE Inhibitors 2
CHATCMS with episodic apnea (CMS-EA)
  • Hypotonia, respiratory failure at birth
  • Episodic apnea
  • Improvement with age
Improvement
AChR
subunit
genes:
  • CHRNE
  • CHRNA1
  • CHRNB1
  • CHRND
Acetylcholine receptor (AChR) deficiency
  • Early onset
  • Varies from mild to severe
  • Ptosis, EOP 3; bulbar, arm, leg weakness
Improvement
Slow-channel CMS (SCCMS)
  • Selective severe neck, wrist, finger extensor weakness
  • Onset from childhood to adult
  • Varies from mild to severe
  • Progressive ventilatory insufficiency; may require assisted ventilation
Often deterioration
Fast-channel CMS (FCCMS)Varies from mild to severe Improvement
COLQ Endplate acetylcholinesterase (EP AChE) deficiency
  • Often severe
  • In some with C-terminal missense mutations: later presentation, milder clinical course
  • Ophthalmoparesis
  • 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 with predominantly proximal weakness, waddling gait, and ptosis but no ophthalmoparesisDeterioration or no response
RAPSNEndplate (EP) rapsyn deficiency
  • Rapsyn-EO (early onset)
  • Hypotonia, respiratory failure at birth
  • Episodic apnea
  • Arthrogryposis multiplex congenital
  • Varies from mild to severe
  • Rapsyn-LO (late onset)
  • Limb weakness in adolescence or adulthood resembling seronegative myasthenia gravis
  • Other 4
Improvement
GFPT1GFPT1-associated limb-girdle-myasthenia (CMS-TA)“Limb-girdle” pattern of weakness with predominantly proximal weakness but usually no ptosis or ophthalmoparesis; sometimes tubular aggregates (TA) in muscle biopsy 5Improvement

Includes only those genes in which more than a few individuals/families have been reported. Does not include AGRN, MUSK, and SCN4A, as only single individuals or a few families have been described with mutations in these genes. Does not include either PLEC (as mutations are primarily associated with epidermolysis bullosa simplex [Selcen et al 2011]) or LAMB2 (as mutations are primarily associated with kidney problems (nephrosis) [Maselli et al 2009]).

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

2. See Testing, Response to acetylcholinesterase inhibitors)

3. EOP = external ophthalmoplegia

4. A recessive E-box mutation in the RAPSN promotor region results in benign CMS with distinct facial malformation [Ohno et al 2003].

5. Senderek et al [2011], Guergueltcheva et al [2011]

Other subtypes of CMS have been reported in the literature in a few kinships without identification of the underlying genetic defect [Walls et al 1993, Banwell et al 1999, Rodolico et al 2002, Beeson et al 2005, Milone et al 2006]. Some have been thoroughly characterized by morphologic and in vitro electrophysiologic studies pointing toward a presumed lesion, but others are not yet completely classified.

Genotype-Phenotype Correlations

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

Some clinical clues point to specific genetic defects [Engel 2001, Ohno et al 2001, Byring et al 2002, Engel & Ohno 2002, Ohno et al 2002, Burke et al 2004, Beeson et al 2005, Cossins et al 2006, Müller et al 2007a, Palace et al 2007]. See Table 2 and Testing Strategy.

Genotype-phenotype correlations are difficult to establish for rare CMS subtypes with identified mutations in only a few patients worldwide (AGRN, MUSK, SCN4A).

Penetrance

In general, reported CMS mutations have complete penetrance.

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

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 mutations have been documented worldwide [Chaouch et al 2012b].

Founder mutations have been identified in several populations:

Differential Diagnosis

Myasthenia gravis. 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 include:

Adulthood. Other disorders partially resembling CMS to consider include:

A few individuals with myasthenic findings and major findings as a part of other systemic disorders have been reported.

  • Biallelic mutation of LAMB2 causes Pierson syndrome (OMIM 609049), an autosomal recessive disorder characterized by severe congenital nephrotic syndrome and extremely small nonreactive pupils (microcoria) resulting from aplasia or atrophy of the dilatator pupillae muscle. One individual with biallelic LAMB2 mutations and Pierson syndrome with end stage renal disease (microcystic nephrosis) requiring kidney transplantation had the onset of myasthenic findings in early infancy [Maselli et al 2009].
  • Biallelic mutation of PLEC1 causes epidermolysis bullosa simplex with muscular dystrophy of later onset (EBS-MD) (OMIM 226670). In three individuals from three families, biallelic PLEC mutations resulted in EBS-MD with variable skin findings and late-onset myasthenic symptoms associated with a neuromuscular transmission defect [Forrest et al 2010, Selcen et al 2011]. In addition, mutations in PLEC affecting the 1f isoform of plectin, which has a suggested specific role in skeletal muscle, cause limb-girdle muscular dystrophy type 2Q in Turkish families, characterized by early childhood onset of proximal muscle weakness and atrophy without skin involvement [Gundesli et al 2010].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with congenital myasthenic syndromes (CMS), evaluation of respiratory function in children is recommended.

Treatment of Manifestations

AChE inhibitors (pyridostigmine). Although the majority of individuals with CMS benefit from acetylcholine esterase (AChE) inhibitors (pyridostigmine), some myasthenic symptoms may remain refractory to treatment even in individuals who are otherwise responsive. Certain CMS subtypes (see Table 2) such as endplate acetylcholinesterase deficiency (EP AChE deficiency), slow-channel CMS (SCCMS), or DOK7-related CMS are refractory to or deteriorate with AChE inhibitors [Engel 2007, Palace et al 2007, Kinali et al 2008, Schara & Lochmüller 2008].

3,4-diaminopyridine (3,4 DAP). Alternatively or in addition to AChE inhibitors, the potassium channel blocker 3,4-DAP may be used [Palace et al 1991, Anlar et al 1996, Banwell et al 2004, Beeson et al 2005, Engel 2007]. 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 mutations of the genes encoding the 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, 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]. 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].

Quinidine, fluoxetine. Some individuals with genetically defined slow-channel CMS (SCCMS; caused by autosomal dominant gain-of-function mutations 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.

Recently, 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].

Prevention of Primary Manifestations

Sudden respiratory insufficiency or apneic attacks provoked by fever or infections are common in individuals with underlying mutations 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, such as 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 underlying COLQ and DOK7 mutations, 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. A more complete list can be obtained online.

Evaluation of Relatives at Risk

If the disease-causing mutations 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.

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

Pregnancy Management

Limited data on pregnancy management in CMS are available [Terblanche et al 2008, Chaouch et al 2012b].

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Other

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

Apart from the autosomal dominant slow-channel CMS (SCCMS), all other CMS are inherited in an autosomal recessive manner.

Mutations in AGRN, CHAT, COLQ, DOK7, GFPT1, MUSK, RAPSN, and SCN4A are always associated with autosomal recessive CMS.

Mutations of 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 and therefore carry one mutant allele.
  • Heterozygotes (carriers) are clinically asymptomatic.

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.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are clinically asymptomatic.

Offspring of a proband

  • The offspring of an individual with an AR-CMS are obligate heterozygotes (carriers) for a disease-causing mutation.
  • The risk that the offspring will inherit a second disease-causing CMS-causing allele depends on the carrier status of the proband's reproductive partner.
  • The carrier frequency of CMS-related mutations 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.

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

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations have been identified in the proband.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

Sibs of a proband

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

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-causing mutation, 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, clarification of carrier status, 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, or are carriers or at risk of being carriers.

Considerations in families with an apparent de novo mutation. 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 mutation. 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

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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)
    3300 East Sunrise Drive
    Tucson AZ 85718
    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

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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
254210MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH EPISODIC APNEA
254300MYASTHENIA, LIMB-GIRDLE, FAMILIAL
601296MUSCLE, SKELETAL, RECEPTOR TYROSINE KINASE; MUSK
601462MYASTHENIC SYNDROME, CONGENITAL, SLOW-CHANNEL; SCCMS
601592RECEPTOR-ASSOCIATED PROTEIN OF THE SYNAPSE, 43-KD; RAPSN
603033COLLAGENIC TAIL OF ENDPLATE ACETYLCHOLINESTERASE; COLQ
603967SODIUM CHANNEL, VOLTAGE-GATED, TYPE IV, ALPHA SUBUNIT; SCN4A
608931MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY
610285DOWNSTREAM OF TYROSINE KINASE 7; DOK7
615120MYASTHENIC SYNDROME, CONGENITAL, WITH PRE- AND POSTSYNAPTIC DEFECTS; CMSPPD

Molecular Genetic Pathogenesis

The understanding of the molecular basis of the different subtypes of CMS has been evolving since 1995. After the identification of mutations 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, Hantai 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.

Mutations in acetylcholine receptor subunit genes. The majority of postsynaptic CMS subtypes identified to date are caused by mutations in AChR subunit genes that either increase or decrease 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. The adult muscle AChR is composed of five homologous subunits: two α subunits, and one each of β, δ, and ε. Each subunit 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.

For a detailed summary of gene and protein information, see Table A, Gene Symbol.

CHAT

Gene structure. A presynaptic subtype of CMS has been linked to mutations in CHAT, the gene encoding choline O-acetyltransferase (ChAT) [Ohno et al 2001]. CHAT comprises 18 exons.

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

Table 3. Selected CHAT Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid 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 (www​.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.

COLQ

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

Pathogenic allelic variants. All individuals with endplate (EP) AChE deficiency described to date have pathogenic mutations in COLQ. To date, mutations (missense, frameshift, stop, and splice site mutations) 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 consequence of mutations 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 mutations:

  • Mutations in the PRAD-domain prevent attachment of AChET to ColQ;
  • Mutations in the collagen-domain produce a short, single-stranded ColQ that binds a single AChET tetramer and is insertion incompetent;
  • Mutations 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.

AGRN

Gene structure. The complete cDNA of AGRN comprises 36 exons. Agrin mRNA undergoes cell-specific alternative splicing at several sites. An amino acid insert of the isoform secreted by motor neurons is required for MuSK activation and for formation of the neuromuscular junction.

Pathogenic allelic variants. A single homozygous mutation (c.5125G>C) was identified in two affected siblings from a consanguineous family by Huze et al 2009.

Table 4. Selected AGRN Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.5125G>Cp.Gly1709ArgNM_198576​.3
NP_940978​.2

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. The protein (NP_940978.2) has 2045 amino acids. Agrin is a heparan sulfate proteoglycan that has been shown to bind to laminins via its amino-terminal domain 14 and to interact via its carboxy-terminal part with LRP4 and a-dystroglycan. Agrin is a neuronal aggregating factor that induces the aggregation of acetylcholine receptors and other postsynaptic proteins on muscle fibers and is crucial for the formation of the neuromuscular junction. Agrin activates the MuSK by binding and activating the postsynaptic LRP4-MuSK-DOK7 complex to recruit downstream signaling components which triggers the local aggregation and synthesis of postsynaptic acetylcholine receptors (AChRs) and other postsynaptic proteins, such as the cytoskeletal protein rapsyn.

Abnormal gene product. The homozygous mutation c.5125G>C causes a p.Gly1709Arg substitution. The resulting mutant agrin is expressed and localized correctly in patient muscle, but the overall organization of the neuromuscular junction is disturbed, affecting both the pre- and postsynaptic regions. Experimental findings in rat muscle injected with mutant agrin indicate that the mutation does not interfere with the ability of agrin to induce postsynaptic structures but that it dramatically disturbs the maintenance of the neuromuscular junction.

AChR Subunit Genes: CHRNA1, CHRNB1, CHRND, CHRNE

CMS with kinetic abnormalities of the acetylcholine receptor (slow-channel syndromes and fast-channel syndromes) is caused by mutations 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.

Gene structure. The CHRNA1 reference sequence NM_000079.3 comprises ten exons. The CHRNB1 reference sequence NM_000747.2 comprises 11 exons. The CHRND reference sequence NM_000751.1 comprises 12 exons. The CHRNE reference sequence NM_000080.3 comprises 12 exons.

Pathogenic allelic variants

  • Slow-channel syndrome. Slow-channel syndromes are caused by dominant gain-of-function mutations. To date, several autosomal dominant missense mutations have been described [Ohno & Engel 2004a, Engel & Sine 2005, Navedo et al 2006, Shen et al 2006]. Mutations have been identified in different AChR subunits and in different functional domains of the subunits. Several mutations are located in the transmembrane domains (M2 domains of α, β, δ, and ε subunits, and in the M1 domain of the α, β, and ε subunit) or in the extracellular domain of the α and ε subunit (see OMIM 601462).
  • Fast-channel syndrome. The fast-channel CMSs are caused by recessive loss-of-function mutations. A number of fast-channel mutations have been identified [Ohno & Engel 2004a, Engel & Sine 2005, Palace et al 2012]. The mutations are located in different functional domains of the AChR α, β, and δ subunit. Usually, the mutated allele causing the kinetic abnormality is accompanied by a null mutation in the second allele. In all cases, the kinetic mutation dominates the clinical phenotype.

Normal gene product. The five homologous subunits of the adult AChR (two α subunits, and one each of β, δ, and ε) each have a large N terminal extracellular domain and four transmembrane segments (M1-M4); the M2 domain lines the cation-selective pore.

The proteins encoded by these genes:

Abnormal gene product

  • Slow-channel syndrome. Patch-clamp studies of mutant AChR channels reveal prolonged activation episodes of the AChR in the presence of ACh. This results in prolonged endplate currents and potentials, exceeding the refractory period of the muscle fiber action potential. Therefore, a single nerve stimulus elicits one or more repetitive CMAPs as described in Harper & Engel [1998]. During physiologic activity, the prolonged endplate potentials may undergo staircase summation, producing a depolarization block. Moreover, these factors cause cationic overloading of the junctional sarcoplasm resulting in myopathic changes with loss of AChR from degenerating junctional folds and altered endplate geometry with widening of the synaptic space and subsynaptic alterations.
  • Fast-channel syndrome. In this subtype of CMS with kinetic abnormalities of the AChR, the channel-opening events are abnormally brief and there are usually fewer activation episodes. Fast-channel mutations affect one or more of the following functions of AChR: affinity for ACh, efficiency of gating, and stabilization of channel kinetics. Endplate studies reveal normal or reduced AChR numbers. The structural integrity of the postsynaptic membrane is preserved. The common electrophysiologic features are rapidly decaying endplate currents, abnormally brief channel activation periods, and a reduced quantal response owing to the reduced probability of channel opening.

Acetylcholine receptor deficiency with or without minor kinetic abnormality: caused by mutations in the acetylcholine receptor subunit genes CHRNA1; CHRNB1; CHRND; CHRNE

Pathogenic allelic variants. The AChR subunits in individuals with CMS have numerous homozygous or, more frequently, heteroallelic recessive mutations that result in a reduced number of functional AChRs at the postsynaptic membrane. These low-expressor or null mutations have been reported in all subunits of the adult AChR. However, they are concentrated in the ε subunit and especially in its long cytoplasmic M3/M4 linker.

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

  • Most such mutations are nonsense, splice site, or frameshift mutations resulting in a premature termination of the translational chain.
  • Missense mutations 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 mutations affecting AChR gene expression also have accompanying kinetic effects.
  • Point mutations 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 point mutation of 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 mutation of the AChRε subunit (c.1353dup) may be frequent in the Maghreb (especially Algeria and Tunisia) because of an ancient founder effect [Beeson et al 2005].

Normal gene product. The five homologous subunits of the adult AChR (two α-subunits, and one each of β, δ, and ε) each have a large N-terminal extracellular domain and four transmembrane segments (M1-M4); the M2 domain lines the cation-selective pore.

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.

Table 5. Selected CHRNE Pathogenic Allelic Variants

Gene SymbolDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
CHRNEc.1327delG
(ε1267delG)
p.Glu443LysfsTer64NM_000080​.3
NP_000071​.1
c.1353dup
(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 (www​.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]

DOK7

Gene structure. DOK7, encoding the postsynaptic protein Dok-7, comprises seven exons.

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

Table 6. Selected DOK7 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid 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 (www​.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 PHPTB 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 mutation 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 mutations of the C-terminal domain of Dok-7 may have similar effects in myotubes.

RAPSN

Gene structure. RAPSN, encoding the postsynaptic protein rapsyn (43-kd receptor-associated protein of the synapse), comprises eight exons.

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

Table 7. Selected RAPSN Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias) 1
Protein Amino Acid Change Reference Sequences
c.-209A>G 2, 3
(-38A>G) 4
NANM_005055​.4
NP_005046​.2
c.-198C>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 (www​.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 mutation, c.-209A>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 mutation, c.-198C>G, was compound heterozygous with the p.Asn88Lys mutation [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 mutant constructs indicate that many mutations diminished co-clustering of AChR with rapsyn. However, different pathogenic mechanisms for some missense mutations that inhibited self-association of rapsyn or reduced the stability of the rapsyn protein have been uncovered [Cossins et al 2006].

MUSK

Gene structure. MUSK comprises 14 exons.

Pathogenic allelic variants. Chevessier et al [2004] identified two heteroallelic mutations (frameshift and missense) in an individual with CMS. Muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression [Chevessier et al 2004]. To date, MUSK mutations have been reported in eight individuals with CMS from three families [Chevessier et al 2004, Mihaylova et al 2009, Maselli et al 2010].

Normal gene product. MUSK encodes the postsynaptic muscle-specific receptor tyrosine kinase (MuSK; muscle, skeletal receptor tyronsine-protein kinase). MuSK plays an essential role in the agrin-MuSK-rapsyn pathway in organizing the postsynaptic scaffold and in inducing the high concentration of AChR and tyrosine kinases of the ErB family in the postsynaptic membrane.

Abnormal gene product. Expression studies of mutant constructs have indicated that the frameshift mutation prevents MuSK expression; that the missense mutation diminishes the expression and stability of MuSK but not its kinase activity; and that overexpression of the missense mutant in mouse muscle results in decreased EP AChR and aberrant axonal outgrowth [Chevessier et al 2004].

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].

Pathogenic allelic variants. GFPT1 mutations have been identified in 24 individuals from 14 families with a subtype of CMS named congenital myasthenic syndrome with tubular aggregates (CMS-TA) [Senderek et al 2011, Guergueltcheva et al 2011]. Nineteen different GFPT1 mutations consisting of 13 missense mutations, four frameshift mutations, one nonsense mutation, and one variant in the 3’-UTR were identified. No individual with CMS with two null mutations 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 glucosamine-6-phosphate (GlcN-6-P) 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. Mutations in GFPT1 lead to reduced protein levels in muscle; some missense mutations 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.

SCN4A

Gene structure. SCN4A (NM_000334.4) comprises 24 exons.

Pathogenic allelic variants. Only one individual with CMS and two heteroallelic SCN4A mutations (c.4325T>A [p.Val1442Glu] and c.737C>T [p.Ser246Leu]) has been identified to date [Tsujino et al 2003]. Several other gain-of-function mutations of SCN4A have been identified in a variety of disorders of muscle membrane excitability: potassium-aggravated myotonia, paramyotonia congenita, and hyperkalemic periodic paralysis (for review, see Cannon [2000]).

Table 8. Selected SCN4A Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.737C>Tp.Ser246LeuNM_000334​.4
NP_000325​.4
c.4325T>Ap.Val1442Glu

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The reference sequence NP_000325.4 has 1836 amino acids. SCN4A encodes the sodium channel protein type 4 subunit alpha (Nav1.4), which mediates the voltage-dependent sodium ion permeability of the postsynaptic membrane to generate and propagate an action potential.

Abnormal gene product. Expression studies on the observed mutations in HEK cells revealed that the Na channel with the p.Val1442Glu substitution showed marked enhancement of fast inactivation close to the resting potential and enhanced use-dependent inactivation on high frequency stimulation; that with the p.Ser246Leu substitution showed only minor kinetic abnormalities, suggesting that it is a benign variant. Nav1.4 expression at the endplates and over the sarcolemma was normal by immunocytochemical criteria [Tsujino et al 2003].

References

Literature Cited

  1. 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]
  2. 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]
  3. Anlar B, Varli K, Ozdirim E, Ertan M. 3,4-diaminopyridine in childhood myasthenia: double-blind, placebo-controlled trial. J Child Neurol. 1996;11:458–61. [PubMed: 9120223]
  4. Banwell BL, Ohno K, Sieb JP, Engel AG. Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine. Neuromuscul Disord. 2004;14:202–7. [PubMed: 15036330]
  5. Banwell BL, Russel J, Fukudome T, Shen XM, Stilling G, Engel AG. Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. J Neuropathol Exp Neurol. 1999;58:832–46. [PubMed: 10446808]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. Cannon SC. Spectrum of sodium channel disturbances in the nondystrophic myotonias and periodic paralyses. Kidney Int. 2000;57:772–9. [PubMed: 10720928]
  16. 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]
  17. 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]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. Deymeer F, Serdaroglu P, Ozdemir C. Familial infantile myasthenia: confusion in terminology. Neuromuscul Disord. 1999;9:129–30. [PubMed: 10382904]
  24. 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]
  25. Engel AG. ENMC International Workshop: congenital myasthenic syndromes. 22-23 October, 1999, Naarden, the Netherlands. Neuromuscul Disord. 2001;11:315–21. [PubMed: 11297949]
  26. Engel AG, Franzini-Armstrong C, eds. Myology: Basic and Clinical. New York, NY: McGraw-Hill; 1994.
  27. Engel AG, Ohno K. Congenital myasthenic syndromes. Adv Neurol. 2002;88:203–15. [PubMed: 11908226]
  28. 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]
  29. Engel AG, Sine SM. Current understanding of congenital myasthenic syndromes. Curr Opin Pharmacol. 2005;5:308–21. [PubMed: 15907919]
  30. Engel AG. The therapy of congenital myasthenic syndromes. Neurotherapeutics. 2007;4:252–7. [PMC free article: PMC1978489] [PubMed: 17395135]
  31. Engel AG, Shen XM, Selcen D, Sine SM. What have we learned from the congenital myasthenic syndromes. J Mol Neurosci. 2010;40:143–53. [PMC free article: PMC3050586] [PubMed: 19688192]
  32. 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]
  33. 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]
  34. 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. 2011 [PubMed: 21975507]
  35. Gundesli H, Talim B, Korkusuz P, Balci-Hayta B, Cirak S, Akarsu NA, Topaloglu H, Dincer P. Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb-girdle muscular dystrophy. Am J Hum Genet. 2010;87:834–41. [PMC free article: PMC2997373] [PubMed: 21109228]
  36. Hantai D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Curr Opin Neurol. 2004;17:539–51. [PubMed: 15367858]
  37. Harper CM, Engel AG. Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol. 1998;43:480–4. [PubMed: 9546329]
  38. Harper CM, Fukodome T, Engel AG. Treatment of slow-channel congenital myasthenic syndrome with fluoxetine. Neurology. 2003;60:1710–3. [PubMed: 12771277]
  39. 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]
  40. 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]
  41. 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]
  42. 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.
  43. 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]
  44. 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]
  45. 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]
  46. 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]
  47. 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]
  48. 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]
  49. Milone M, Fukuda T, Shen XM, Tsujino A, Brengman J, Engel AG. Novel congenital myasthenic syndromes associated with defects in quantal release. Neurology. 2006;66:1223–9. [PubMed: 16525123]
  50. 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.
  51. 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]
  52. 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]
  53. 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]
  54. 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]
  55. 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]
  56. 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]
  57. 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]
  58. Müller JS, Mildner G, Muller-Felber W, Schara U, Krampfl K, Petersen B, Petrova S, Stucka R, Mortier W, Bufler J, Kurlemann G, Huebner A, Merlini L, Lochmuller H, Abicht A. Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients. Neurology. 2003;60:1805–10. [PubMed: 12796535]
  59. Navedo MF, Lasalde-Dominicci JA, Báez-Pagán CA, Díaz-Pérez L, Rojas LV, Maselli RA, Staub J, Schott K, Zayas R, Gomez CM. Novel beta subunit mutation causes a slow-channel syndrome by enhancing activation and decreasing the rate of agonist dissociation. Mol Cell Neurosci. 2006;32:82–90. [PubMed: 16624571]
  60. 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]
  61. 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]
  62. Ohno K, Engel AG. Congenital myasthenic syndromes: gene mutations. Neuromuscul Disord. 2004a;14:117–22. [PubMed: 14702950]
  63. 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]
  64. 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]
  65. 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]
  66. 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]
  67. 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]
  68. 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]
  69. 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]
  70. 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]
  71. Palace J, Lashley D, Bailey S, Jayawant S, Carr A, McConville J, Robb S, Beeson D. Clinical features in a series of fast channel congenital myasthenia syndrome. Neuromuscul Disord. 2012;22:112–7. [PubMed: 21940170]
  72. 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]
  73. Palace J, Wiles CM, Newsom-Davis J. 3,4-Diaminopyridine in the treatment of congenital (hereditary) myasthenia. J Neurol Neurosurg Psychiatry. 1991;54:1069–72. [PMC free article: PMC1014681] [PubMed: 1783919]
  74. 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]
  75. 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]
  76. 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]
  77. Rodolico C, Toscano A, Autunno M, Messina S, Nicolosi C, Aguennouz M, Laura M, Girlanda P, Messina C, Vita G. Limb-girdle myasthenia: clinical, electrophysiological and morphological features in familial and autoimmune cases. Neuromuscul Disord. 2002;12:964–9. [PubMed: 12467753]
  78. 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]
  79. Schara U, Lochmüller H. Therapeutic strategies in congenital myasthenic syndromes. Neurotherapeutics. 2008;5:542–7. [PubMed: 19019305]
  80. 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]
  81. Selcen D, Milone M, Shen XM, Harper CM, Stans AA, Wieben ED, Engel AG. Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Ann Neurol. 2008;64:71–87. [PMC free article: PMC2570015] [PubMed: 18626973]
  82. 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]
  83. Shen XM, Deymeer F, Sine SM, Engel AG. Slow-channel mutation in acetylcholine receptor alphaM4 domain and its efficient knockdown. Ann Neurol. 2006;60:128–36. [PubMed: 16685696]
  84. Srour M, Bolduc V, Guergueltcheva V, Lochmüller H, Gendron D, Shevell MI, Poulin C, Mathieu J, Bouchard JP, Brais B. DOK7 mutations presenting as a proximal myopathy in French Canadians. Neuromuscul Disord. 2010;20:453–7. [PubMed: 20610155]
  85. Terblanche N, Maxwell C, Keunen J, Carvalho JC. Obstetric and anesthetic management of severe congenital myasthenia syndrome. Anesth Analg. 2008;107:1313–5. [PubMed: 18806046]
  86. 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]
  87. Walls TJ, Engel AG, Nagel AS, Harper CM, Trastek VF. Congenital myasthenic syndrome associated with paucity of synaptic vesicles and reduced quantal release. Ann N Y Acad Sci. 1993;681:461–8. [PubMed: 8395161]

Suggested Reading

  1. Engel AG. Congenital myasthenic syndromes in 2012. Curr Neurol Neurosci Rep. 2012;12:92–101. [PubMed: 21997714]

Chapter Notes

Revision History

  • 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 to live Web site
  • 9 May 2003 (me) Review posted to live Web site
  • 30 January 2003 (aa) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

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

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1168PMID: 20301347
PubReader format: click here to try

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
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...