Congenital myasthenic syndromes (CMS) 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.
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.
Symptoms
The first myasthenic symptoms occur in general early in life, usually in the first two years.
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.
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.
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’).
In some individuals, long face, narrow jaw, and a high-arched palate have been reported.
The vast majority of individuals with CMS have normal cognitive skills. Recently, three patients have been reported with DPAGT1-associated CMS and intellectual disability. Severe intellectual disability appears to be a feature of SNAP25-associated CMS.
Causes
Congenital myasthenic syndromes are inherited in an autosomal recessive or an autosomal dominant manner. The most commonly associated genes include: CHAT, CHRNE, COLQ, DOK7, GFPT, and RAPSN.
Prevention
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.
Prophylactic anticholinesterase therapy is used 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.
Diagnosis
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.
Prognosis
Severity and course of disease are highly variable, ranging from minor symptoms (e.g., mild exercise intolerance) 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, especially in individuals with CMS with episodic apnea (CMS-EA) or endplate rapsyn deficiency.
For more information on rare genetic disorders, visit https://checkrare.com/diseases/congenital-and-genetic-conditions/
Resources
[1] https://www.ncbi.nlm.nih.gov/books/NBK1168/
[2] 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.
[3] 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.
[4] Selcen D, Shen XM, Brengman J, Li Y, Stans AA, Wieben E, Engel AG. DPAGT1 myasthenia and myopathy: genetic, phenotypic, and expression studies. Neurology. 2014;82:1822–30.
[5] Shen XM, Selcen D, Brengman J, Engel AG. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology. 2014;83:2247–55.