TY - JOUR

T1 - Novel Homozygous Truncating Variant Widens the Spectrum of Early-Onset Multisystemic SYNE1 Ataxia

AU - Karlsson, William Kristian

AU - Højgaard, Joan Lilja Sunnleyg

AU - Vilhelmsen, Anna

AU - Crone, Clarissa

AU - Andersen, Birgit

AU - Law, Ian

AU - Møller, Lisbeth Birk

AU - Nielsen, Troels Tolstrup

AU - Nielsen, Emilie Neerup

AU - Krag, Thomas

AU - Svenstrup, Kirsten

AU - Nielsen, Jørgen Erik

N1 - Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2022

Y1 - 2022

N2 - Pathogenic variants in the SYNE1 gene are associated with a phenotypic spectrum spanning from late-onset, slowly progressive, relatively pure ataxia to early-onset, fast progressive multisystemic disease. Since its first description in 2007 as an adult-onset ataxia in French Canadian families, subsequent identification of patients worldwide has widened the clinical spectrum and increased the number of identified pathogenic variants. We report a 20-year-old Faroese female with early-onset progressive gait problems, weakness, dysphagia, slurred speech, orthostatic dizziness, and urge incontinence. Neurological examination revealed mild cognitive deficits, dysarthria, broken slow pursuit, hypometric saccades, weakness with spasticity, hyperreflexia, absent ankle reflexes, ataxia, and wide-based, spastic gait. Magnetic resonance imaging displayed atrophy of the cerebellum, brainstem, and spinal cord. Severely prolonged central motor conduction time and lower motor neuron involvement was demonstrated electrophysiologically. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism of the cerebellum and right frontal lobe. Muscle biopsy revealed chronic neurogenic changes and near-absent immunostaining for Nesprin-1. Next-generation sequencing revealed a previously undescribed homozygous truncating, likely pathogenic variant in the SYNE1 gene. The patient’s mother and paternal grandfather were heterozygous carriers of the variant. Her father’s genotype was unobtainable. We expand the list of likely pathogenic variants in SYNE1 ataxia with a novel homozygous truncating variant with proximity to the C-terminus and relate it to a phenotype comprising early-onset cerebellar deficits, upper and lower motor neuron involvement and cognitive deficits. Also, we report novel findings of focally reduced frontal lobe FDG-PET uptake and motor evoked potential abnormalities suggestive of central demyelination.

AB - Pathogenic variants in the SYNE1 gene are associated with a phenotypic spectrum spanning from late-onset, slowly progressive, relatively pure ataxia to early-onset, fast progressive multisystemic disease. Since its first description in 2007 as an adult-onset ataxia in French Canadian families, subsequent identification of patients worldwide has widened the clinical spectrum and increased the number of identified pathogenic variants. We report a 20-year-old Faroese female with early-onset progressive gait problems, weakness, dysphagia, slurred speech, orthostatic dizziness, and urge incontinence. Neurological examination revealed mild cognitive deficits, dysarthria, broken slow pursuit, hypometric saccades, weakness with spasticity, hyperreflexia, absent ankle reflexes, ataxia, and wide-based, spastic gait. Magnetic resonance imaging displayed atrophy of the cerebellum, brainstem, and spinal cord. Severely prolonged central motor conduction time and lower motor neuron involvement was demonstrated electrophysiologically. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism of the cerebellum and right frontal lobe. Muscle biopsy revealed chronic neurogenic changes and near-absent immunostaining for Nesprin-1. Next-generation sequencing revealed a previously undescribed homozygous truncating, likely pathogenic variant in the SYNE1 gene. The patient’s mother and paternal grandfather were heterozygous carriers of the variant. Her father’s genotype was unobtainable. We expand the list of likely pathogenic variants in SYNE1 ataxia with a novel homozygous truncating variant with proximity to the C-terminus and relate it to a phenotype comprising early-onset cerebellar deficits, upper and lower motor neuron involvement and cognitive deficits. Also, we report novel findings of focally reduced frontal lobe FDG-PET uptake and motor evoked potential abnormalities suggestive of central demyelination.

KW - Ataxia

KW - Autosomal recessive

KW - Cerebellum

KW - Nesprin

KW - Spinocerebellar ataxia

KW - SYNE1

U2 - 10.1007/s12311-021-01308-w

DO - 10.1007/s12311-021-01308-w

M3 - Journal article

C2 - 34318393

AN - SCOPUS:85111569781

VL - 21

SP - 514

EP - 519

JO - Cerebellum (London, England)

JF - Cerebellum (London, England)

SN - 1473-4222

IS - 3

ER -