SACS variants are a relevant cause of autosomal recessive hereditary motor and sensory neuropathy

Abstract

Mutations in the SACS gene have been initially reported in a rare autosomal recessive cerebellar ataxia syndrome featuring prominent cerebellar atrophy, spasticity and peripheral neuropathy as well as retinal abnormalities in some cases (autosomal recessive spastic ataxia of Charlevoix–Saguenay, ARSACS). In the past few years, the phenotypic spectrum has broadened, mainly owing to the availability and application of high-throughput genetic testing methods. We identified nine patients (three sib pairs, three singleton cases) with isolated, non-syndromic hereditary motor and sensory neuropathy (HMSN) who carried pathogenic SACS mutations, either in the homozygous or compound heterozygous state. None of the patients displayed spasticity or pyramidal signs. Ataxia, which was noted in only three patients, was consistent with a sensory ataxia. Nerve conduction and nerve biopsy studies showed mixed demyelinating and axonal neuropathy. Brain MRI scans were either normal or revealed isolated upper vermis atrophy of the cerebellum. Our findings confirm the broad clinical spectrum associated with SACS mutations, including pure polyneuropathy without characteristic clinical and brain imaging manifestations of ARSACS.

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Funding

This work was supported by the German Federal Ministry of Education and Research (BMBF) through the German Network for Charcot-Marie-Tooth Neuropathies (CMT-Net) (01GM1511B, 01GM1511D, 01GM1511E; to Katharina Vill, Joachim Weis, Peter Young, Wolfgang Müller-Felber and Jan Senderek) and the Fritz-Thyssen-Stiftung (Az10.15.1.021MN; to Jan Senderek).

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Correspondence to Katharina Vill.

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Supplementary material 3: Supplemental Video File: Patient A-II:2, showing pes cavus (A), foot drop and impaired heel walking (B), difficulty walking on a line (C) and reduced ability to hop on one foot (D). (WMV 9038 KB)

Supplementary material 3: Supplemental Video File: Patient A-II:2, showing pes cavus (A), foot drop and impaired heel walking (B), difficulty walking on a line (C) and reduced ability to hop on one foot (D). (WMV 9038 KB)

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Vill, K., Müller-Felber, W., Gläser, D. et al. SACS variants are a relevant cause of autosomal recessive hereditary motor and sensory neuropathy. Hum Genet 137, 911–919 (2018). https://doi.org/10.1007/s00439-018-1952-6

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