Variants in SLC18A3, Vesicular Acetylcholine Transporter, Cause Congenital Myasthenic Syndrome

Overview

Journal Neurology

Specialty Neurology

Date 2016 Sep 4

PMID 27590285

Citations 31

Authors

Gina L OGrady

Corien Verschuuren

Michaela Yuen

Richard Webster

Manoj Menezes

Johanna M Fock

Natalie Pride

Heather A Best

Tatiana Benavides Damm

Christian Turner

Monkol Lek

Andrew G Engel

Kathryn N North

Nigel F Clarke

Daniel G MacArthur

Erik-Jan Kamsteeg

Sandra T Cooper

Affiliations

Soon will be listed here.

Abstract

Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3.

Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing.

Results: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures.

Conclusions: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans.

Citing Articles

Binding mechanism and antagonism of the vesicular acetylcholine transporter VAChT.

Ma Q, Ma K, Dong Y, Meng Y, Zhao J, Li R Nat Struct Mol Biol. 2025; .

PMID: 39806024 DOI: 10.1038/s41594-024-01462-9.

Cis-regulatory elements driving motor neuron-selective viral payload expression within the mammalian spinal cord.

Nagy M, Price S, Wang K, Gill S, Ren E, Jayne L Proc Natl Acad Sci U S A. 2024; 121(49):e2418024121.

PMID: 39602276 PMC: 11626145. DOI: 10.1073/pnas.2418024121.

Congenital myasthenic syndrome secondary to pathogenic variants in the SLC5A7 gene: report of two cases.

Muntadas J, Hyland M, Martinez M, Young J, Chong J, Bamshad M BMC Med Genomics. 2024; 17(1):207.

PMID: 39135055 PMC: 11318227. DOI: 10.1186/s12920-024-01977-6.

Streamlined Full-Length Total RNA Sequencing of Paraformaldehyde-Fixed Brain Tissues.

Ji B, Chen J, Gong H, Li X Int J Mol Sci. 2024; 25(12).

PMID: 38928210 PMC: 11204141. DOI: 10.3390/ijms25126504.

Structural insights into VAChT neurotransmitter recognition and inhibition.

Zhang Y, Dai F, Chen N, Zhou D, Lee C, Song C Cell Res. 2024; 34(9):665-668.

PMID: 38862671 PMC: 11369146. DOI: 10.1038/s41422-024-00986-5.

References

Engel A, Shen X, Selcen D, Sine S . Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 2015; 14(4):420-34. PMC: 4520251. DOI: 10.1016/S1474-4422(14)70201-7. View

Stankiewicz P, Kulkarni S, Dharmadhikari A, Sampath S, Bhatt S, Shaikh T . Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats. Hum Mutat. 2011; 33(1):165-79. PMC: 3655525. DOI: 10.1002/humu.21614. View

Abicht A, Dusl M, Gallenmuller C, Guergueltcheva V, Schara U, Della Marina A . Congenital myasthenic syndromes: achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: a study of 680 patients. Hum Mutat. 2012; 33(10):1474-84. DOI: 10.1002/humu.22130. View

de Castro B, De Jaeger X, Martins-Silva C, Lima R, Amaral E, Menezes C . The vesicular acetylcholine transporter is required for neuromuscular development and function. Mol Cell Biol. 2009; 29(19):5238-50. PMC: 2747982. DOI: 10.1128/MCB.00245-09. View

Eymard B, Hantai D, Estournet B . Congenital myasthenic syndromes. Handb Clin Neurol. 2013; 113:1469-80. DOI: 10.1016/B978-0-444-59565-2.00016-2. View

Lawal H, Krantz D . SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med. 2013; 34(2-3):360-72. PMC: 3727660. DOI: 10.1016/j.mam.2012.07.005. View

Ohno K, Tsujino A, Brengman J, Harper C, Bajzer Z, Udd B . Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc Natl Acad Sci U S A. 2001; 98(4):2017-22. PMC: 29374. DOI: 10.1073/pnas.98.4.2017. View

Juel V . Evaluation of neuromuscular junction disorders in the electromyography laboratory. Neurol Clin. 2012; 30(2):621-39. DOI: 10.1016/j.ncl.2011.12.012. View

Menezes M, Waddell L, Lenk G, Kaur S, MacArthur D, Meisler M . Whole exome sequencing identifies three recessive FIG4 mutations in an apparently dominant pedigree with Charcot-Marie-Tooth disease. Neuromuscul Disord. 2014; 24(8):666-70. PMC: 4096049. DOI: 10.1016/j.nmd.2014.04.010. View

10.

Eiden L, Schafer M, Weihe E, Schutz B . The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine. Pflugers Arch. 2003; 447(5):636-40. DOI: 10.1007/s00424-003-1100-5. View

11.

Herrmann D, Horvath R, Sowden J, Gonzalez M, Gonzales M, Sanchez-Mejias A . Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy. Am J Hum Genet. 2014; 95(3):332-9. PMC: 4157148. DOI: 10.1016/j.ajhg.2014.08.007. View

12.

Maselli R, Arredondo J, Ferns M, Wollmann R . Synaptic basal lamina-associated congenital myasthenic syndromes. Ann N Y Acad Sci. 2013; 1275:36-48. DOI: 10.1111/j.1749-6632.2012.06807.x. View

13.

Rodrigues H, Fonseca M, Camargo W, Lima P, Martinelli P, Naves L . Reduced expression of the vesicular acetylcholine transporter and neurotransmitter content affects synaptic vesicle distribution and shape in mouse neuromuscular junction. PLoS One. 2013; 8(11):e78342. PMC: 3832638. DOI: 10.1371/journal.pone.0078342. View

14.

Shen X, Selcen D, Brengman J, Engel A . Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology. 2014; 83(24):2247-55. PMC: 4277673. DOI: 10.1212/WNL.0000000000001079. View

15.

Schara U, Christen H, Durmus H, Hietala M, Krabetz K, Rodolico C . Long-term follow-up in patients with congenital myasthenic syndrome due to CHAT mutations. Eur J Paediatr Neurol. 2009; 14(4):326-33. DOI: 10.1016/j.ejpn.2009.09.009. View

16.

Prado V, Martins-Silva C, de Castro B, Lima R, Barros D, Amaral E . Mice deficient for the vesicular acetylcholine transporter are myasthenic and have deficits in object and social recognition. Neuron. 2006; 51(5):601-12. DOI: 10.1016/j.neuron.2006.08.005. View

17.

Nogajski J, Kiernan M, Ouvrier R, Andrews P . Congenital myasthenic syndromes. J Clin Neurosci. 2008; 16(1):1-11. DOI: 10.1016/j.jocn.2008.05.001. View

18.

Pitt M . Update in electromyography. Curr Opin Pediatr. 2013; 25(6):676-81. DOI: 10.1097/MOP.0000000000000023. View

19.

Lara A, Damasceno D, Pires R, Gros R, Gomes E, Gavioli M . Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure. Mol Cell Biol. 2010; 30(7):1746-56. PMC: 2838086. DOI: 10.1128/MCB.00996-09. View

20.

Brandon E, Mellott T, Pizzo D, Coufal N, DAmour K, Gobeske K . Choline transporter 1 maintains cholinergic function in choline acetyltransferase haploinsufficiency. J Neurosci. 2004; 24(24):5459-66. PMC: 6729318. DOI: 10.1523/JNEUROSCI.1106-04.2004. View