Presynaptic congenital myasthenic syndrome due to three novel mutations in SLC5A7 encoding the sodium-dependant high-affinity choline transporter

Abstract

SLC5A7 encodes the presynaptic sodium-dependant high-affinity choline transporter 1 (CHT), which uptakes choline to the presynaptic nerve terminal following the breakdown of acetylcholine by the acetylcholinesterase within the synaptic cleft. We report 5 patients from three consanguineous families with congenital myasthenic syndrome type 20 caused by novel mutations in SLC5A7 . The individuals from family 1 and 2 were homozygous for c.320G > A ; (p.Arg107His) and c.886G > A (p.Ala296Thr), respectively, and their phenotype was characterised by recurrent apnoeic attacks early after birth and learning and speech difficulties in childhood. Individuals from family 3 were homozygous for c.1240T > A (p.Tyr414Asn) and suffered from more severe central and peripheral manifestations with lack of spontaneous movements and respiratory drive and overall minimal response to external stimuli. All individuals tested showed neurophysiological defects compatible with impaired neuromuscular transmission. Combined treatment with cholinesterase inhibitors and β2-adrenergic agonists was beneficial in patients from family 1 and 2. Affected individuals from family 3 died from complications directly related to their underlying genetic condition. This report provides three novel pathogenic variants in SLC5A7 and highlights the variability in the clinical phenotype, severity and prognosis of this syndrome.

A new patient with congenital myasthenic syndrome type 20 due to compound heterozygous missense SLC5A7 variants suggests trends in genotype–phenotype correlation

“…Also, the severity of neuromuscular symptoms is variable among CMS20 patients (Table S1 ). Our patient fits best to the mild class of Rodríguez Cruz et al ( 2021 ) who classified CMS20 patients into three groups according to the severity of their myasthenic phenotype. In brief, Group 1 (mild) was characterized by recurrent apneic episodes with onset in the newborn period, but with improving trend later in life, with positive response to treatment and with no necessity of artificial ventilation.…”

“…In silico tools used to predict the deleteriousness of the variants are listed in File S1 . We adopted the classification of patients according to the severity of their neuromuscular picture proposed by Rodríguez Cruz et al ( 2021 ) and we grouped them into three groups: 1—mild (8 patients), 2—intermediate (8 patients) and 3—severe myasthenic phenotype (4 patients). We also grouped the patients according to their neurodevelopmental phenotype: 1—no NDD (2 patients) and 2—NDD (7 patients; from the remaining patients no data were available or the patients died in infancy).…”

“…Only 19 CMS20 patients from 14 families have been reported (Table S1 ) (Banerjee et al, 2019 ; Bauché et al, 2016 ; Pardal‐Fernández et al, 2018 ; Rodríguez Cruz et al, 2021 ; Wang et al, 2017 ), although detailed clinical information is lacking for some of them. Herein, we describe a 12‐year‐old boy with CMS20 and one novel and one known SLC5A7 variant.…”

“…The boy is the third oldest patient among the published cases, and he manifested the neuromuscular phenotype later compared to most of them. Rodríguez Cruz et al ( 2021 ) separated CMS20 patients according to the severity of their neuromuscular picture into three groups (mild, intermediate and severe myasthenic neuromuscular phenotype). We attempted to similarly classify the NDD phenotype and to correlate these features with SLC5A7 variants found in the patients.…”

Hereditary motor neuropathies

“…SLC5A7 encodes a presynaptic choline transporter (CHT), a critical determinant of synaptic acetylcholine synthesis and release at the neuromuscular junction. Recessive mutations in SLC5A7 cause congenital myasthenic syndrome disorders [25] whereas autosomal dominant mutations cause distal weakness with upper limb predominance and vocal cord paresis [26]. Noteworthy, neither fatigue was reported in cases with dHMN caused by monoallelic mutations in this gene, nor signs of neuropathy were detected in cases with myasthenic syndrome and recessive mutations.…”