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Neuromuscul Disord. 2017 Dec;27(12):1087-1098. doi: 10.1016/j.nmd.2017.08.003. Epub 2017 Aug 18.

Molecular characterization of congenital myasthenic syndromes in Spain.

Author information

1
Department of Neuromuscular Diseases, Hospital Sant Joan de Déu, CIBERER U703, Barcelona, Spain. Electronic address: daninatera@hotmail.com.
2
John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
3
Department of Neurology, Hospital Universitari La Fe, Universitat de Valencia, CIBERER U763, Valencia, Spain.
4
Department of Genetics, Hospital de la Santa Creu i Sant Pau and CIBERER U705, Barcelona, Spain.
5
Department of Pediatrics, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
6
Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
7
Department of Neuromuscular Diseases, Hospital Sant Joan de Déu, CIBERER U703, Barcelona, Spain.
8
Department of Neurology, Hospital General San Jorge, Huesca, Spain.
9
Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
10
Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Medical Genetics Center, Munich, Germany.
11
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
12
Department of Pediatrics, Hospital Universitario Cruces, Bilbao, Spain.
13
Neuropathology Unit, Department of Pathology and Neuromuscular Unit, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain.
14
Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
15
Department of Pediatric Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain.
16
Department of Pediatrics, Hospital Universitario Rey Juan Carlos, Madrid, Spain.
17
Department of Neuropediatrics, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
18
Department of Neuropediatrics, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain.
19
Department of Neuropediatrics, Hospital Virgen de la Salud, Toledo, Spain.

Abstract

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations. Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124_1127dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management.

KEYWORDS:

CHRNE; COLQ; Congenital myasthenic syndrome; DOK7; GFPT1; GMPPB; Genetic mutations; RAPSN; Slow-channel syndrome

PMID:
29054425
DOI:
10.1016/j.nmd.2017.08.003
[Indexed for MEDLINE]

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