Abstract
Congenital myasthenic syndrome (CMS) is a neuromuscular transmission disorder caused by mutations in genes encoding neuromuscular junction proteins. CMS due to choline acetyltransferase (CHAT) gene mutation is characterized by episodic apnoea. To date, 52 cases of CMS caused by CHAT gene mutations have been reported. Here, we report a neonate with the third hemizygous mutation [a 4.9 Mb deletion [10q11.22–10q11.23 (chr10: 46123781–51028772)] containing the whole CHAT gene and c.1976A>T (p.Gln659Leu in the CHAT gene)]. The c.1976A>T (p.Gln659Leu) variant had not been reported in the ExAC or gnomAD databases and was predicted to be pathogenic. The alignment of amino acid sequences revealed that glutamine at codon 659 is highly conserved in different species and causes structural changes in the substrate-binding site. Our female patient with neonate-onset CMS presented with apnoea, dyspnoea, feeding difficulties, weak crying, and seizure-like episodes, and her respiration was ventilator dependent. The prostigmine test was positive. This case may help to further elucidate clinical features and treatment methods in neonate-onset CMS caused by CHAT gene mutations.
Highlights
Congenital myasthenic syndromes (CMSs) are rare genetically heterogeneous diseases caused by abnormal signal transduction due to mutations in genes coding for proteins expressed at the neuromuscular junction (NMJ)
Mutations located near the active-site tunnel, impairing substrate binding, result in more severe phenotypic effects in patients with choline acetyltransferase (CHAT)-related CMS [12,13,14]
Our patient presented with dyspnoea, ventilator dependence, and apnoea
Summary
Congenital myasthenic syndromes (CMSs) are rare genetically heterogeneous diseases caused by abnormal signal transduction due to mutations in genes coding for proteins expressed at the neuromuscular junction (NMJ). They account for approximately 5% of CMS probands [1]. Mutations located near the active-site tunnel, impairing substrate binding, result in more severe phenotypic effects in patients with CHAT-related CMS [12,13,14]. Schwartz et al reported the second hemizygous CHAT mutation in a patient with CMS in 2018 [16]. A neonate with CMS carried a 4.9 Mb deletion and a c.1976A>T (p.Gln659Leu) mutation in the CHAT gene. Whole exome sequencing showed a hemizygous mutation in CHAT (c.1976A>T, p.Gln659Leu), which likely accounts for the patient’s phenotype. The wholeexome sequencing validated by Sanger sequencing indicated that the patient carries a hemizygous mutation in exon of CHAT (c.1976A>T, p.Gln659Leu), which is inherited from her father (Figure 1E)
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