Choline acetyltransferase mutations in myasthenic syndrome due to deficient acetylcholine resynthesis

Abstract

The myasthenic syndrome due to abnormal acetylcholine resynthesis is characterized by early onset, recessive inheritance, and recurrent episodes of potentially fatal apnea. Mutations in the gene encoding choline acetyltransferase (CHAT) have been found to account for this condition. We have identified five patients from three independent families with features of this disease including, in four patients, a paradoxical worsening of symptoms with cold temperatures. Electrodiagnostic studies demonstrated impaired neuromuscular transmission in all patients. In vitro microelectrode studies performed in the anconeus muscle biopsies of two patients showed moderate reduction of quantal release. Electron microscopy of the neuromuscular junction was normal in both patients. Each patient had two heterozygous CHAT mutations including L210P and P211A (family 1), V194L and V506L (family 2), and R548stop and S694C (family 3). Three of these mutations have previously been reported and suggest that, in this syndrome, some molecular defects may be more prevalent than others.

Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice

“…The generation and initial characterization of CHTknockout mice reported here demonstrates that choline transported by CHT contributes to ACh synthesis and is essential for sustaining cholinergic neurotransmission at levels required to support life. The recent report of a relatively common, nonsynonymous, single nucleotide polymorphism (SNP) in the coding region of human CHT that results in diminished choline transport (44), as well as the identification of nonsynonymous ChAT SNPs with clinical phenotypes (45,46), predicts that variations in absolute levels of cholinergic capacity might be relatively common across human populations and set risk thresholds for a variety of disorders or their onset͞severity. In addition to the well recognized deficits in cholinergic function in myasthenic syndromes, defects in the capacity for ACh synthesis in the CNS may contribute to cognitive dysfunction and dementia and may place demands on the regulatory mechanisms revealed by our studies that control CHT function.…”

Structural insights and functional implications of choline acetyltransferase

“…2 and 3) (Ohno et al, 2001). Additional mutational analysis of the ChAT encoding gene from three patients with CMS-EA from two Turkish families shows an additional mutation (Ile 336 Thr) and studies from five patients from three independent families shows three further mutations (Val 194 Leu, Arg 548 Stop, and Ser 694 Cys) (Maselli et al, 2003;Schmidt et al, 2003). Fig.…”

What Have We Learned from the Congenital Myasthenic Syndromes

“…Because each patient carried two different mutations of different biochemical pathogenicity, no clear genotype–phenotype correlation emerged except that, in the most severely affected patient, both mutations markedly reduced the expression as well as the overall catalytic efficiency of ChAT. Subsequently, eight additional CHAT mutations were detected in our laboratory, and five additional mutations (V194L, I336T, S694L, S694C, and R548X) were reported by other investigators (Maselli et al 2003; Schmidt et al 2003; Kraner et al 2003; Barisic et al 2005) but were not functionally characterized. Interestingly, no patients harboring CHAT mutations had central or autonomic nervous system findings.…”