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SYNE1-related autosomal recessive cerebellar ataxia, congenital cerebellar hypoplasia, and cognitive impairment.

ABSTRACT: The spectrin repeat-containing nuclear envelope protein 1 (SYNE1) gene encodes a family of spectrin structural proteins that are associated with anchoring the plasma membrane to the actin cytoskeleton. SYNE1-related disease is most commonly reported in autosomal recessive spinocerebellar ataxia 8, which demonstrates variable age of onset with a median of 30 years of age. However pathogenic mutations in SYNE1 are also causative of arthrogryposis multiplex congenital, a severe congenital neuromuscular condition. Here in we report monozygous twins with childhood onset ataxia, cerebellar hypoplasia, dysarthria, and cognitive impairment sharing two novel heterozygous mutations in the SYNE1 gene. Our family may expand the clinical phenotype associated with SYNE1-related disease and offers possible genotype-phenotype correlations of a rare continuum of clinical disease phenotypes from neonatal to adult onset.

SUBMITTER: Swan L

PROVIDER: S-EPMC6151335 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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SYNE1-related autosomal recessive cerebellar ataxia, congenital cerebellar hypoplasia, and cognitive impairment.

Swan Lauren L Cardinal John J Coman David D

Clinics and practice 20180701 3

The spectrin repeat-containing nuclear envelope protein 1 (SYNE1) gene encodes a family of spectrin structural proteins that are associated with anchoring the plasma membrane to the actin cytoskeleton. SYNE1-related disease is most commonly reported in autosomal recessive spinocerebellar ataxia 8, which demonstrates variable age of onset with a median of 30 years of age. However pathogenic mutations in SYNE1 are also causative of arthrogryposis multiplex congenital, a severe ...[more]

PMID: 30275942

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Project description:Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide.

Dataset Information

SYNE1-related autosomal recessive cerebellar ataxia, congenital cerebellar hypoplasia, and cognitive impairment.

Publications

<i>SYNE1</i>-related autosomal recessive cerebellar ataxia, congenital cerebellar hypoplasia, and cognitive impairment.

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