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Neurological Sciences

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01-03-2019 | Original Article

Clinical and genetic characterization of an Italian family with slow-channel syndrome

Authors: Corrado Angelini, Ludovico Lispi, Cecilia Salvoro, Maria Luisa Mostacciuolo, Giovanni Vazza

Published in: Neurological Sciences | Issue 3/2019

Abstract

Introduction

The slow-channel congenital myasthenic syndrome (SCCMS) is a postsynaptic form of congenital myasthenic syndromes (CMSs), a clinically heterogeneous group of disorders caused by genetic defects leading to an abnormal signal transmission at the endplate.

Methods

We report clinical and molecular data of a multigenerational family in which the presentation of a progressive proximal-distal weakness with ocular involvement led to a number of different clinical diagnoses.

Results

A comprehensive genetic study which included whole-genome linkage analysis and whole-exome sequencing identified a heterozygous missense substitution (c.721C>T, p.L241F) in the ε subunit of the acetylcholine receptor (CHRNE) that was consistent with clinical weakness in all patients.

Discussion

SCCMS is characterized by a broad and heterogeneous clinical phenotype in which disease onset, symptoms, severity, and progression can be highly variable even between family members. The identification of a CHRNE mutation allowed to make the definitive diagnosis of CMS in this family and contributed to define the clinical spectrum of this disease.

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Beeson D (2016) Congenital myasthenic syndromes: recent advances. Curr Opin Neurol 29:565–571. https://doi.org/10.1097/WCO.0000000000000370 CrossRefPubMed

Abicht A, Dusl M, Gallenmüller C, Guergueltcheva V, Schara U, Della Marina A, Wibbeler E, Almaras S, Mihaylova V, von der Hagen M, Huebner A, Chaouch A, Müller JS, Lochmüller H (2012) Congenital myasthenic syndromes: achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: a study of 680 patients. Hum Mutat 33:1474–1484. https://doi.org/10.1002/humu.22130 CrossRefPubMed

Engel AG, Lambert EH, Mulder DM, Torres CF, Sahashi K, Bertorini TE, Whitaker JN (1982) A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine-induced ion channel. Ann Neurol 11:553–569. https://doi.org/10.1002/ana.410110603 CrossRefPubMed

Croxen R, Hatton C, Shelley C, Brydson M, Chauplannaz G, Oosterhuis H, Vincent A, Newsom-Davis J, Colquhoun D, Beeson D (2002) Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes. Neurology 59:162–168. https://doi.org/10.1212/WNL.59.2.162 CrossRefPubMed

Ghim J, Chelakkot C, Bae Y-S, Ryu SH (2016) Accumulating insights into the role of phospholipase D2 in human diseases. Adv Biol Regul 61:42–46. https://doi.org/10.1016/J.JBIOR.2015.11.010 CrossRefPubMed

Hackman P, Sarparanta J, Lehtinen S, Vihola A, Evilä A, Jonson PH, Luque H, Kere J, Screen M, Chinnery PF, Åhlberg G, Edström L, Udd B (2013) Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1. Ann Neurol 73:500–509. https://doi.org/10.1002/ana.23831 CrossRefPubMed

Pegoraro E, Gavassini BF, Borsato C, Melacini P, Vianello A, Stramare R, Cenacchi G, Angelini C (2007) MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy. Neuromuscul Disord 17:321–329. https://doi.org/10.1016/j.nmd.2007.01.010 CrossRefPubMed

Nonaka I, Sunohara N, Ishiura S, Satoyoshi E (1981) Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 51:141–155. https://doi.org/10.1016/0022-510X(81)90067-8 CrossRefPubMed

Oosterhuis HJ, Newsom-Davis J, Wokke JH et al (1987) The slow channel syndrome. Two new cases. Brain 110(Pt 4):1061–1079CrossRefPubMed

10.

Colomer J, Müller JS, Vernet A, Nascimento A, Pons M, Gonzalez V, Abicht A, Lochmüller H (2006) Long-term improvement of slow-channel congenital myasthenic syndrome with fluoxetine. Neuromuscul Disord 16:329–333. https://doi.org/10.1016/j.nmd.2006.02.009 CrossRefPubMed

11.

Zhu H, Pytel P, Gomez CM (2014) Selective inhibition of caspases in skeletal muscle reverses the apoptotic synaptic degeneration in slow-channel myasthenic syndrome. Hum Mol Genet 23:69–77. https://doi.org/10.1093/hmg/ddt397 CrossRefPubMed

12.

Engel AG, Ohno K, Milone M, Wang HL, Nakano S, Bouzat C, Pruitt JN 2nd, Hutchinson DO, Brengman JM, Bren N, Sieb JP, Sine SM (1996) New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum Mol Genet 5:1217–1227

13.

Hatton CJ, Shelley C, Brydson M, Beeson D, Colquhoun D (2003) Properties of the human muscle nicotinic receptor, and of the slow-channel myasthenic syndrome mutant epsilonL221F, inferred from maximum likelihood fits. J Physiol 547:729–760. https://doi.org/10.1113/jphysiol.2002.034173 CrossRefPubMedPubMedCentral

14.

Engel AG, Shen X-M, Selcen D, Sine SM (2010) What have we learned from the congenital myasthenic syndromes. J Mol Neurosci 40:143–153. https://doi.org/10.1007/s12031-009-9229-0 CrossRefPubMed

15.

Chevessier F, Peter C, Mersdorf U, Girard E, Krejci E, McArdle JJ, Witzemann V (2012) A new mouse model for the slow-channel congenital myasthenic syndrome induced by the AChR εL221F mutation. Neurobiol Dis 45:851–861. https://doi.org/10.1016/j.nbd.2011.10.024 CrossRefPubMed

16.

Harper CM, Fukodome T, Engel AG (2003) Treatment of slow-channel congenital myasthenic syndrome with fluoxetine. Neurology 60:1710–1713CrossRefPubMed

Title: Clinical and genetic characterization of an Italian family with slow-channel syndrome
Authors: Corrado Angelini
Ludovico Lispi
Cecilia Salvoro
Maria Luisa Mostacciuolo
Giovanni Vazza
Publication date: 01-03-2019
Publisher: Springer International Publishing
Published in: Neurological Sciences / Issue 3/2019
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI: https://doi.org/10.1007/s10072-018-3645-2

At a glance: The STEP trials

Springer Medicine

Clinical and genetic characterization of an Italian family with slow-channel syndrome

Abstract

Introduction

Methods

Results

Discussion

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Methods

Results

Discussion

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