Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome

Gina L. O'Grady, 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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1442-1448
Number of pages7
JournalNeurology
Volume87
Issue number14
DOIs
StatePublished - Oct 4 2016

Fingerprint

Congenital Myasthenic Syndromes
Vesicular Acetylcholine Transport Proteins
Pyridostigmine Bromide
Exome
Ophthalmoplegia
Isometric Contraction
Left Ventricular Dysfunction
Acetylcholine
Learning
Phenotype
Water

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

O'Grady, G. L., Verschuuren, C., Yuen, M., Webster, R., Menezes, M., Fock, J. M., ... Cooper, S. T. (2016). Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome. Neurology, 87(14), 1442-1448. https://doi.org/10.1212/WNL.0000000000003179

Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome. / O'Grady, Gina L.; Verschuuren, Corien; Yuen, Michaela; Webster, Richard; Menezes, Manoj; Fock, Johanna M.; Pride, Natalie; Best, Heather A.; Benavides Damm, Tatiana; Turner, Christian; Lek, Monkol; Engel, Andrew G; North, Kathryn N.; Clarke, Nigel F.; Macarthur, Daniel G.; Kamsteeg, Erik Jan; Cooper, Sandra T.

In: Neurology, Vol. 87, No. 14, 04.10.2016, p. 1442-1448.

Research output: Contribution to journalArticle

O'Grady, GL, Verschuuren, C, Yuen, M, Webster, R, Menezes, M, Fock, JM, Pride, N, Best, HA, Benavides Damm, T, Turner, C, Lek, M, Engel, AG, North, KN, Clarke, NF, Macarthur, DG, Kamsteeg, EJ & Cooper, ST 2016, 'Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome', Neurology, vol. 87, no. 14, pp. 1442-1448. https://doi.org/10.1212/WNL.0000000000003179
O'Grady GL, Verschuuren C, Yuen M, Webster R, Menezes M, Fock JM et al. Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome. Neurology. 2016 Oct 4;87(14):1442-1448. https://doi.org/10.1212/WNL.0000000000003179
O'Grady, Gina L. ; Verschuuren, Corien ; Yuen, Michaela ; Webster, Richard ; Menezes, Manoj ; Fock, Johanna M. ; Pride, Natalie ; Best, Heather A. ; Benavides Damm, Tatiana ; Turner, Christian ; Lek, Monkol ; Engel, Andrew G ; North, Kathryn N. ; Clarke, Nigel F. ; Macarthur, Daniel G. ; Kamsteeg, Erik Jan ; Cooper, Sandra T. / Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome. In: Neurology. 2016 ; Vol. 87, No. 14. pp. 1442-1448.
@article{e6d52256d7134542bc080a9d590b8f42,
title = "Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome",
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.",
author = "O'Grady, {Gina L.} and Corien Verschuuren and Michaela Yuen and Richard Webster and Manoj Menezes and Fock, {Johanna M.} and Natalie Pride and Best, {Heather A.} and {Benavides Damm}, Tatiana and Christian Turner and Monkol Lek and Engel, {Andrew G} and North, {Kathryn N.} and Clarke, {Nigel F.} and Macarthur, {Daniel G.} and Kamsteeg, {Erik Jan} and Cooper, {Sandra T.}",
year = "2016",
month = "10",
day = "4",
doi = "10.1212/WNL.0000000000003179",
language = "English (US)",
volume = "87",
pages = "1442--1448",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "14",

}

TY - JOUR

T1 - Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome

AU - O'Grady, Gina L.

AU - Verschuuren, Corien

AU - Yuen, Michaela

AU - Webster, Richard

AU - Menezes, Manoj

AU - Fock, Johanna M.

AU - Pride, Natalie

AU - Best, Heather A.

AU - Benavides Damm, Tatiana

AU - Turner, Christian

AU - Lek, Monkol

AU - Engel, Andrew G

AU - North, Kathryn N.

AU - Clarke, Nigel F.

AU - Macarthur, Daniel G.

AU - Kamsteeg, Erik Jan

AU - Cooper, Sandra T.

PY - 2016/10/4

Y1 - 2016/10/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84989911666&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84989911666&partnerID=8YFLogxK

U2 - 10.1212/WNL.0000000000003179

DO - 10.1212/WNL.0000000000003179

M3 - Article

VL - 87

SP - 1442

EP - 1448

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 14

ER -