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

• Published in: Neuromuscular disorders : NMD 2021-01, Vol.31 (1), p.21-28
• Main Authors: Rodríguez Cruz, Pedro M., Hughes, Imelda, Manzur, Adnan, Munot, Pinki, Ramdas, Sithara, Wright, Ronnie, Breen, Catherine, Pitt, Mathew, Pagnamenta, Alistair T., Taylor, Jenny C., Palace, Jacqueline, Beeson, David
• Format: Article
• Language: English
• Subjects: Congenital myasthenic syndromes; High-affinity choline transporter; Neuromuscular junction; SLC5A7; ß2-adrenergic agonists
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2020.10.006

•This report provides three novel pathogenic variants in SLC5A7 causing CMS type 20.•CMS type 20 is remarkably variable in clinical phenotype, severity and prognosis.•Additional treatment with β2-adrenergic agonists may be useful in some patients. 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.