Congenital Myasthenic Syndromes

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 testing are possible if the pathogenic variant(s) have been identified in an affected family member.

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

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:
  • A pathogenic variant in COLQ;
    OR
  • A slow-channel CMS with a pathogenic variant in one of the genes encoding the AChR subunits (CHRNA1, CHRNB1, CHRND, CHRNE).
• 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:

• German or central/western European origin. RAPSN pathogenic variant c.264C>A and DOK7 pathogenic variant c.1124_1127dupTGCC
• Southeastern European or Roma origin. CHRNE pathogenic variant c.1327delG
• From the Maghreb (especially Algeria and Tunisia). CHRNE pathogenic variant c.1353dupG
• From Spain or Portugal. CHRNE pathogenic variant c.130dupG

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.

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).

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.

• Gain-of-function variants in CHRNA1, CHRNB1, CHRND, or CHRNE that alter the kinetic properties of the AChR result in the autosomal dominant slow-channel CMS (SCCMS) [Engel et al 2003].
• Loss-of-function variants in the AChR subunit genes (CHRNA1, CHRNB1, CHRND, CHRNE) are associated with autosomal recessive CMS [Hantaï et al 2004, Ohno & Engel 2004a, Engel & Sine 2005].
• Some clinical clues point to specific genetic defects [Abicht et al 2012, Finlayson et al 2013, Engel et al 2015]. For example, arthrogryposis multiplex congenita [AMC]) appears to be particularly common in infants with truncating RAPSN pathogenic variants [Brownlow et al 2001, Burke et al 2003, Beeson et al 2005]. Stridor in infancy may occur in CMS, particularly in those with DOK7 pathogenic variants [Kinali et al 2008]. See Table 2 and Establishing the Diagnosis.

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