A novel phenotype of AChR-deficiency syndrome with predominant facial and distal weakness resulting from the inclusion of an evolutionary alternatively-spliced exon in CHRNA1

被引：2

作者：

Cruz, Pedro M. Rodriguez ^{[1
]}

Ravenscroft, Gianina ^{[2
,3
]}

Natera, Daniel ^{[4
]}

Carr, Aisling ^{[5
]}

Manzur, Adnan ^{[6
,7
]}

Liu, Wei Wei ^{[8
]}

Vella, Norbert R. ^{[9
]}

Jerico, Ivonne ^{[10
]}

Gonzalez-Quereda, Lidia ^{[11
,12
]}

Gallano, Pia ^{[11
,12
]}

Montalto, Simon Attard ^{[13
]}

Davis, Mark R. ^{[14
]}

Lamont, Phillipa J. ^{[15
]}

Laing, Nigel G. ^{[2
,3
,14
]}

Bourque, Pierre ^{[16
]}

Nascimento, Andres ^{[4
]}

Muntoni, Francesco ^{[6
,7
]}

Polavarapu, Kiran ^{[16
]}

Lochmueller, Hanns ^{[1
,16
,17
,18
,19
]}

Palace, Jacqueline ^{[20
]}

Beeson, David ^{[8
,20
]}

机构：

[1] Barcelona Inst Sci & Technol, Ctr Genom Regulat, Ctr Nacl Anal Genom, CNAG CRG, Barcelona, Spain

[2] Harry Perkins Inst Med Res, Nedlands, WA, Australia

[3] Univ Western Australia, Ctr Med Res, Nedlands, WA, Australia

[4] Hosp St Joan Deu, Neuromuscular Unit, Barcelona, Spain

[5] UCL Queen Sq Inst Neurol, Natl Hosp Neurol & Neurosurg, Ctr Neuromuscular Dis, Queen Sq, London, England

[6] UCL Great Ormond St Inst Child Hlth, Dubowitz Neuromuscular Ctr, NIHR Biomed Res Ctr, London, England

[7] Great Ormond St Hosp Children NHS Fdn Trust, London, England

[8] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Neurosci Grp, Oxford, England

[9] Mater Dei Hosp, Dept Neurosci, Msida, Malta

[10] Hosp Univ Navarra, IdisNa Inst Invest Sanitaria Navarra, Dept Neurol, Pamplona, Spain

[11] ISCIII, Ctr Biomed Res Rare Dis CIBERER, Madrid, Spain

[12] Hosp Santa Creu & Sant Pau, IIB St Pau, Dept Genet, Barcelona, Spain

[13] Mater Dei Hosp, Dept Paediat, Msida, Malta

[14] Western Australian Dept Hlth, Dept Diagnost Genom, Neurogenet Unit, PathWest Lab Med, Nedlands, WA, Australia

[15] Royal Perth Hosp, Dept Neurol, Nedlands, WA, Australia

[16] Univ Ottawa, Childrens Hosp Eastern Ontario Res Inst, Ottawa, ON, Canada

[17] Ottawa Hosp, Dept Med, Div Neurol, Ottawa, ON, Canada

[18] Univ Ottawa, Brain & Mind Res Inst, Ottawa, ON, Canada

[19] Univ Freiburg, Fac Med, Med Ctr, Dept Neuropediat & Muscle Disorders, Freiburg, Germany

[20] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England

来源：

NEUROMUSCULAR DISORDERS | 2023年 / 33卷 / 02期

关键词：

Congenital myasthenic syndrome; AChR-deficiency; Slow channel syndrome; CHRNE; CHRNA1; P3A exon; alternative splicing; non-functional exon; distal weakness; CONGENITAL MYASTHENIC SYNDROME; RECEPTOR ALPHA-SUBUNIT; 2; ISOFORMS; MUSCLE; MUTATION; EXPRESSION;

D O I：

10.1016/j.nmd.2022.12.011

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Primary acetylcholine receptor deficiency is the most common subtype of congenital myasthenic syndrome, resulting in reduced amount of acetylcholine receptors expressed at the muscle endplate and impaired neuromuscular transmission. AChR deficiency is caused mainly by pathogenic variants in the & epsilon;- subunit of the acetylcholine receptor encoded by CHRNE, although pathogenic variants in other subunits are also seen. We report the clinical and molecular features of 13 patients from nine unrelated kinships with acetylcholine receptor deficiency harbouring the CHRNA1 variant NM_001039523.3:c.257G > A (p.Arg86His) in homozygosity or compound heterozygosity. This variant results in the inclusion of an alternatively-spliced evolutionary exon (P3A) that causes expression of a non-functional acetylcholine receptor & alpha;-subunit. We compare the clinical findings of this group to the other cases of acetylcholine receptor deficiency within our cohort. We report differences in phenotype, highlighting a predominant pattern of facial and distal weakness in adulthood, predominantly in the upper limbs, which is unusual for acetylcholine receptor deficiency syndromes, and more in keeping with slow-channel syndrome or distal myopathy. Finally, we stress the importance of including alternative exons in variant analysis to increase the probability of achieving a molecular diagnosis.& COPY; 2022 Elsevier B.V. All rights reserved.

引用

页码：161 / 168

页数：8