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

Human Genetics volume 137, pages 911–919 (2018)Cite this article

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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Affiliations

  1. Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children’s Hospital, University Hospital, LMU Munich, Lindwurmstraße 4, 80337, Munich, Germany

    Katharina Vill, Wolfgang Müller-Felber, Astrid Blaschek, Moritz Tacke & Lucia Gerstl

  2. genetikum, Center for Human Genetics, Neu-Ulm, Germany

    Dieter Gläser & Marius Kuhn

  3. University Clinic and Policlinic of Radiology, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany

    Veronika Teusch

  4. Department of Radiology, Klinikum Schwabing, Städtisches Klinikum München, Munich, Germany

    Veronika Teusch

  5. Neurological Practice & Neuropoint Patient Academy, Ulm, Germany

    Herbert Schreiber

  6. Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany

    Joachim Weis

  7. Department of Pediatrics and Neuropediatrcs, Klinikum Aschaffenburg-Alzenau, Aschaffenburg, Germany

    Jörg Klepper

  8. Institute for Sleep Medicine and Neuromuscular Disorders, Muenster University Hospital, Münster, Germany

    Anja Schirmacher, Bianca Dräger & Peter Young

  9. Friedrich Baur Institute at the Department of Neurology, University Hospital, LMU Munich, Munich, Germany

    Manuela Wiessner & Jan Senderek

  10. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany

    Tim M. Strom

  11. Department of Neurology, Neurophysiology, Early Rehabilitation and Sleep Medicine, Klinikum Christophsbad, Göppingen, Germany

    Kristina Hofmeister-Kiltz

  12. Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK

    Rita Horvath

Authors
  1. Katharina Vill
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  2. Wolfgang Müller-Felber
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  3. Dieter Gläser
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  4. Marius Kuhn
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  5. Veronika Teusch
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  6. Herbert Schreiber
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  7. Joachim Weis
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  8. Jörg Klepper
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  9. Anja Schirmacher
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  10. Astrid Blaschek
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  11. Manuela Wiessner
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  12. Tim M. Strom
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  13. Bianca Dräger
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  14. Kristina Hofmeister-Kiltz
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  15. Moritz Tacke
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  16. Lucia Gerstl
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  17. Peter Young
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  18. Rita Horvath
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  19. Jan Senderek
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Corresponding author

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)

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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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  • DOI: https://doi.org/10.1007/s00439-018-1952-6