molecular genetic tests for cms: congenital

like myasthenia gravis, congenital myasthenic syndrome (cms) produces weakness and fatigue caused by problems at the neuromuscular junction but while mg is autoimmune, cms is an inherited disease caused by defective genes. genes defective in cms are required for making the ach receptor or other components of the neuromuscular junction. cmss are inherited in an ar, or, less frequently, ad manner. as its name implies, cms usually has a congenital onset, but it can manifest in children and even in adults. later-onset cases tend to be less severe.there are many types of cms, grouped into three main categories named for the part of the neuromuscular junction thats affected: 1) presynaptic: insufficient release of ach, symptom commonly manifests as cms with episodic apnea (cms-ea), which has its onset in infancy and causes oculobulbar weakness and episodes of apnea. 2) postsynaptic (fast-channel cms: ach receptors are missing or don stay open long enough, decresed activity at the nmj) symptoms vary from mild to severe. in infants, may cause severe weakness, feeding and respiratory problems, and delayed motor milestones. childhood and adult-onset cases often cause ptosis and fatigue, but usually don interfere with daily living. 3) synaptic (slow-channel cms): ach receptors stay open too long, increased activity at the nmj. infant-onset cases cause severe weakness, often leading to loss of mobility and respiratory problems in adolescence. adult-onset cases may not be disabling. 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, negative tests for anti-acetylcholine receptor (achr) and anti-musk antibodies in the serum, and lack of improvement of clinical symptoms with immunosuppressive therapy. specific diagnosis of a cms is important as some medications that benefit one type of cms can be detrimental in another type. strategies for therapy are based on whether a given cms decreases or increases the synaptic response to acetylcholine (ach). several genes encoding different proteins expressed at the neuromuscular junction are currently known to be associated with cms. these include the following: the genes encoding different subunits of the acetylcholine receptor: chrne: achr-subunit, chrna1: achr-subunit, chrnb1: achr-subunit, chrnd: achr-subunit. the gene encoding the collagenic tail subunit of the acetylcholinesterase: colq, the gene of the choline acetyltransferase: chat, the gene encoding rapsyn: rapsn, the gene encoding the voltage-gated sodium channel of skeletal muscle (nav1.4): scn4a, the gene encoding the muscle-specific receptor tyrosine kinase: musk. in most slow-channel patients, the opening events of the achr channel are greatly prolonged these syndromes are caused by dominantly inherited gain-of-function mutations in different achr subunits. some slow-channel syndromes with less prolonged opening events of the achr channel are determined by recessive inheritance. all other cmss identified to date are caused by recessive loss-of-function mutations in various endplate-specific proteins. many patients with cms were mistakenly given a diagnosis of mg, and subjected to decades of pointless immunosuppressive therapy before finally getting an accurate diagnosis.up to now we’ve seen four patients that had been diagnosed as mg and candidated for thymectomy but finally they were diagnosed as cms. recently molecular genetic test for the genes,chrna1, chrnb1, chrne , chrnd & rapsn are available in our lab besides the single fiber emg as a clinical tool to the specific diagnoses of the cmss is available in iran too. neonates with arthrogryposis multiplex congenita resulting from a lack of fetal movement in utero have been reported to have cms. arthrogryposis seems to be particularly common in individuals with neonatal onset of symptoms and truncating mutations of the rapsyn gene. we highly recommend the paper “the therapy of congenital myasthenic syndromes” by andrew g. engel in nih public accsss. we recommend a genetic testing algorithm (the address is below) to help the clinician pinpoint the most likely causative gene in individuals with cms based mainly on family size, ethnic origin, inheritance pattern, and phenotypic findings. (http://www.genetests.org/servlet/access?id=8888890&key;=tksbsalp6r7tj&gry;=insertgry&fcn;=y&fw;=jb4k&filename;=/glossary/profiles/cms/figure1.html)