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Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia.

ABSTRACT: We studied a consanguineous Palestinian Arab family segregating an autosomal recessive progressive myoclonus epilepsy (PME) with early ataxia. PME is a rare, often fatal syndrome, initially responsive to antiepileptic drugs which over time becomes refractory and can be associated with cognitive decline. Linkage analysis was performed and the disease locus narrowed to chromosome 19p13.3. Fourteen candidate genes were screened by conventional Sanger sequencing and in one, LMNB2, a novel homozygous missense mutation was identified that segregated with the PME in the family. Whole exome sequencing excluded other likely pathogenic coding variants in the linked interval. The p.His157Tyr mutation is located in an evolutionarily highly conserved region of the alpha-helical rod of the lamin B2 protein. In vitro assembly analysis of mutant lamin B2 protein revealed a distinct defect in the assembly of the highly ordered fibrous arrays typically formed by wild-type lamin B2. Our data suggests that disruption of the organisation of the nuclear lamina in neurons, perhaps through abnormal neuronal migration, causes the epilepsy and early ataxia syndrome and extends the aetiology of PMEs to include dysfunction in nuclear lamin proteins.

SUBMITTER: Damiano JA

PROVIDER: S-EPMC6281347 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia.

Damiano John A JA Afawi Zaid Z Bahlo Melanie M Mauermann Monika M Misk Adel A Arsov Todor T Oliver Karen L KL Dahl Hans-Henrik M HH Shearer A Eliot AE Smith Richard J H RJ Hall Nathan E NE Mahmood Khalid K Leventer Richard J RJ Scheffer Ingrid E IE Muona Mikko M Lehesjoki Anna-Elina AE Korczyn Amos D AD Herrmann Harald H Berkovic Samuel F SF Hildebrand Michael S MS

Human molecular genetics 20150507 16

We studied a consanguineous Palestinian Arab family segregating an autosomal recessive progressive myoclonus epilepsy (PME) with early ataxia. PME is a rare, often fatal syndrome, initially responsive to antiepileptic drugs which over time becomes refractory and can be associated with cognitive decline. Linkage analysis was performed and the disease locus narrowed to chromosome 19p13.3. Fourteen candidate genes were screened by conventional Sanger sequencing and in one, LMNB2, a novel homozygous ...[more]

PMID: 25954030

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Project description:BackgroundThe clinical demarcation of the syndrome progressive myoclonus ataxia is unclear, leading to a lack of recognition and difficult differentiation from other neurological syndromes.ObjectivesThe objective of this study was to apply a refined definition of progressive myoclonus ataxia and describe the clinical characteristics in patients with progressive myoclonus ataxia and with isolated cortical myoclonus.MethodsA retro- and prospective analysis was performed in our tertiary referral center between 1994 and 2014. Inclusion criteria for progressive myoclonus ataxia patients were the presence of myoclonus and ataxia with or without infrequent (all types, treatment responsive) epileptic seizures. Inclusion criteria for isolated cortical myoclonus was the presence of isolated cortical myoclonus. Clinical and electrophysiological characteristics data were systematically scored.ResultsA total of 14 progressive myoclonus ataxia patients (males, 7; females, 7), median age 14.5 years, and 8 isolated cortical myoclonus patients (males, 2; females, 6), median age 23.5 years, were identified. In 93% of the progressive myoclonus ataxia patients, ataxia started first (median 2 years) followed by myoclonus (4 years) and finally infrequent epilepsy (9.3 years), with a progressive course in 93%. In 64% of the progressive myoclonus ataxia patients, a genetic underlying etiology was identified, including 3 not earlier reported causative progressive myoclonus ataxia genes. In isolated cortical myoclonus patients, myoclonus started at (median) 12 years with progression over time in 63% and a single epileptic seizure in 1 patient. No genetic causes were identified.ConclusionUsing a refined definition, we could create a rather homogenous progressive myoclonus ataxia group. Patients with isolated cortical myoclonus have a different course and do not appear to evolve in progressive myoclonus ataxia. The refined progressive myoclonus ataxia definition is a successful first step toward creating a separate syndrome for both clinical practice and future genetic research. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Dataset Information

Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia.

Publications

Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia.

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