Rare slow channel congenital myasthenic syndromes without repetitive compound muscle action potential and dramatic respo
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ORIGINAL ARTICLE
Rare slow channel congenital myasthenic syndromes without repetitive compound muscle action potential and dramatic response to low dose fluoxetine Hacer Durmus1 · Heinrich Sticht2 · Serdar Ceylaner3 · Said Hashemolhosseini2 · Feza Deymeer1 Received: 7 August 2020 / Accepted: 15 September 2020 © Belgian Neurological Society 2020
Abstract Congenital myasthenic syndromes are rare hereditary disorders caused by mutations associated with proteins of the neuromuscular junction. Abnormal ‘‘gain of function’’ mutations result in prolonged nicotinic acetylcholine receptor channel open state causing a rare subtype of CMS, slow-channel CMS (SCCMS). Mutations in the delta subunit encoding the gene, CHRND, resulting in SCCMS are extremely rare. An important clue to the diagnosis of SCCMS is repetitive CMAP’s. Fluoxetine, usually at high doses, is used to treat SCCMS. The mutation, recently described in one patient, was identified by whole exome sequencing and validated, and its segregation with the disease was ascertained by Sanger sequencing. Here, we describe clinical and genetic findings of an early onset SCCMS patient carrying a very rare missense mutation c.880C > T in CHRND causing a highly conserved leucine to phenylalanine substitution in the M2 domain of CHRND. The patient had no repetitive CMAP. He had a dramatic response to fluoxetine at low–moderate doses (40 mg/day), increasing over months: Being wheelchair bound, he could walk independently after treatment. Rare cases may offer insight into the pathological gating mechanism leading to CMS. SCCMS should be suspected even without a repetitive CMAP. Fluoxetine at relatively low doses can be a very effective treatment. Keywords Congenital myasthenic syndromes · CHRND · AChR delta subunit · Slow channel · Fluoxetine
Introduction Congenital myasthenic syndromes (CMS) are rare hereditary disorders caused by mutations in proteins which assemble either in the pre- or postsynaptic apparatus or are part of the extracellular matrix of the neuromuscular junction (NMJ). Most postsynaptic CMS are caused by mutations in different subunits of skeletal muscle nicotinic acetylcholine receptor (AChR), resulting in endplate AChR deficiency or impairing the kinetic properties of the channel (slow- or fast-channels), or both [1–3]. Slow-channel CMS (SCCMS) may be caused by abnormal ‘‘gain of function’’ mutations resulting in * Hacer Durmus [email protected] 1
Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34390, Capa, Istanbul, Turkey
2
Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
3
Intergen Genetic Center, Ankara, Turkey
either prolonged channel opening and decreased closing, or increased affinity of AChRs for the neurotransmitter acetylcholine (ACh) [4–6]. Up to the present, at least 26 autosomal dominant mutations have been identified in the α, β, and ε subunits of the AChR causing SCCMS [7–9], but only two mutations (δS268F and δS268Y) were reported in the δ subu
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