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.
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:
The CHNRG gene codes for the gamma subunit of the acetylcholine receptor (AChR). Acetylcholine receptors with the gamma subunit are receptors in embryonic form. However, no mutations in this gene are recognized to cause congenital myasthenia gravis (homozygous or compound heterozygous mutations in the CHRNG gene are recognized just to cause a lethal type of multiple pterygium syndrome). It is suggested that autoantibodies directed against the embryonic form of AChR (and not mutations in the gene) may play a predominant role in the pathogenesis of transient neonatal myasthenia gravis. Therefore CHNRG analysis is not indicated in the context of congenital mystenic syndrome testing.
According to the last updates (www.genetests.org), the mutation detection rate of the analysis of the aforementioned genes in congenital myasthenic syndrome patients is as follows:
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 kinaseRAPSN, encoding rapsyn (43-kd receptor-associated protein of the synapse)
- SCN4A, encoding the sodium channel protein type 4 subunit alpha
The CHNRG gene codes for the gamma subunit of the acetylcholine receptor (AChR). Acetylcholine receptors with the gamma subunit are receptors in embryonic form. However, no mutations in this gene are recognized to cause congenital myasthenia gravis (homozygous or compound heterozygous mutations in the CHRNG gene are recognized just to cause a lethal type of multiple pterygium syndrome). It is suggested that autoantibodies directed against the embryonic form of AChR (and not mutations in the gene) may play a predominant role in the pathogenesis of transient neonatal myasthenia gravis. Therefore CHNRG analysis is not indicated in the context of congenital mystenic syndrome testing.
According to the last updates (www.genetests.org), the mutation detection rate of the analysis of the aforementioned genes in congenital myasthenic syndrome patients is as follows:
- AGRN: rare
- CHAT: 4%-5%
- CHRNA1: <1%
- CHRNB1: <1%
- CHRND: <1%
- CHRNE: 50%
- COLQ: 10%-15%
- DOK7: 10%-15%
- GFPT1: 2%
- MUSK: rare
- RAPSN: 15%-20%
- SCN4A: rare
