Research Published September 7 2016
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Congenital Myasthenic Syndromes are rare genetic diseases characterised by muscle fatiguability aggravated by effort. Researchers of the Brain and Spine Institute (Inserm/CNRS/UPMC/AP-HP), at the Pitié-Salpêtrière hospital, AP-HP, have identified mutations in the gene coding for CHT1 protein, in a particularly severe form of the disease, Congenital Myasthenic Syndromes with apneic events.

Mutations in CHT1 gene cause muscle weakness in the newborn with apneic episodes, accounting for a great respiratory distress that may result from abnormalities of both peripheral and central nervous systems. This study, published in The American Journal of Human Genetics highlights the role of CHT1 protein in the disease and opens up new leads for improving the management of patients suffering from this rare disease.

In congenital myasthenic syndromes (CMS), the neuromuscular junction functioning is disrupted. This communication area between the motor nerve controls muscle movement allowing nerve impulse transmission to the muscle.

Sophie Nicole’s team and her collaborators have led at the Institut du Cerveau – ICM, within the Pitié-Salpêtrière hospital, AP-HP, a study on patients with a severe form of prenatal hypotonia, lethal at birth and with neonatal CMS with apneic episodes with a more favourable evolution when medically supported. They have identified a number of recessive mutations (both copies of the gene must be mutated to cause the disease) of SLC5A7 gene, which encodes CHT1 protein, or choline carrier, expressed at the neuromuscular junction level. Mutations of this gene cause neuromuscular junction functional alterations. The different mutations identified are associated with a spectrum of clinical symptoms ranging from very severe lethal forms at birth to CMS with apneic episodes in newborns, who are often wrongly diagnosed as suffering from encephalopathy or even epilepsy, but whose prognosis is favourable if these episodes are medically well managed, with respiratory assistance and drug therapy (anticholinesterase).

The neuromuscular junction is a cholinergic synapse, namely, its function depends on the action of a neurotransmitter, acetylcholine. Acetylcholine released by the neuron is degraded into choline, which is recaptured by this cell via a choline carrier, CHT1 protein, to be reused, and thus maintain synapse activity.

CHT1 protein is also expressed in the central nervous system where cholinergic transmission is important for respiratory, cognitive, and behavioural functions. The broad clinical spectrum that may result from the observed mutations encourages clinicians to follow diagnosed patients to detect deficits in the central nervous system sooner. This study opens the way simultaneously to improved disease diagnosis and new therapeutic leads for the treatment of these rare forms of CMS.