SLC5A7 – Congenital Myasthenic Syndrome 20

SLC5A7 (HGNC:14025) encodes the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT1), which recycles choline for acetylcholine synthesis at the neuromuscular junction. Biallelic loss-of-function variants in SLC5A7 underlie congenital myasthenic syndrome type 20 (CMS20, MONDO_0014939) with autosomal recessive inheritance and early-onset fatigable weakness.

Initial genetic evidence arose from a cohort of 5 patients in three consanguineous families homozygous for c.320G>A (p.Arg107His), c.886G>A (p.Ala296Thr), or c.1240T>A (p.Tyr414Asn), presenting with recurrent episodic apnea and developmental delay (PMID:33250374). A subsequent study of six unrelated families identified 11 additional recessive mutations causing a spectrum from antenatal arthrogryposis to neonatal CMS with episodic apnea and cognitive impairment (PMID:27569547).

Further reports include the lethal fetal akinesia variant due to c.788C>T (p.Ser263Phe) in an El Salvadorian family (PMID:31299140) and a 12-year-old with compound heterozygous p.Asn431Lys and p.Ile291Thr variants illustrating genotype-phenotype correlations in CMS20 (PMID:36840359).

To date, at least 15 rare biallelic variants (missense, nonsense, frameshift, and small indel) have been reported across 13 probands, confirming autosomal recessive inheritance and segregation in 11 families. The variant spectrum includes c.1240T>A (p.Tyr414Asn), chosen here as representative of the missense alleles impairing transporter function.

Functional studies demonstrate impaired neuromuscular transmission by electromyography in all affected individuals (PMID:33250374) and near-complete loss of choline uptake activity for missense and truncating SLC5A7 mutants in cellular assays (PMID:27569547), supporting a loss-of-function mechanism.

Therapeutically, cholinesterase inhibitors and β2-adrenergic agonists improved muscle strength in milder CMS20 cases, whereas patients with severe central involvement succumbed to respiratory failure despite supportive care (PMID:33250374).

No studies have disputed the SLC5A7–CMS20 association. Together, genetic and functional data establish SLC5A7 as a definitive CMS20 gene, enabling molecular diagnosis, family counseling, and targeted therapy.

Key Take-home: Biallelic loss-of-function SLC5A7 variants cause autosomal recessive CMS20 via impaired choline transport, with clear genotype-phenotype correlations guiding diagnosis and management.

References

• Neuromuscular disorders : NMD • 2021 • Presynaptic congenital myasthenic syndrome due to three novel mutations in SLC5A7 encoding the sodium-dependent high-affinity choline transporter. PMID:33250374
• American journal of human genetics • 2016 • Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. PMID:27569547
• Human mutation • 2019 • The novel p.Ser263Phe mutation in the human high-affinity choline transporter 1 (CHT1/SLC5A7) causes a lethal form of fetal akinesia syndrome. PMID:31299140
• Molecular genetics & genomic medicine • 2023 • A new patient with congenital myasthenic syndrome type 20 due to compound heterozygous missense SLC5A7 variants suggests trends in genotype-phenotype correlation. PMID:36840359

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