Mutations in riboflavin transporter present with severe sensory loss and deafness in childhood

Authors

  • Myriam Srour MD,,

    1. Laboratory of Neurogenetics of Motion, Montreal Neurological Institute, McGill University, Montréal, Canada
    2. Division of Pediatric Neurology, Montreal Children's Hospital-McGill University Health Center, Montréal, Canada
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  • Maria Lisa Putorti MSc,,

    1. Laboratory of Neurogenetics of Motion, Montreal Neurological Institute, McGill University, Montréal, Canada
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  • Jeremy Schwartzentruber MSc,,

    1. McGill University and Genome Quebec Innovation Centre, Montréal, Canada
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  • Véronique Bolduc PhD,,

    1. Laboratory of Neurogenetics of Motion, Montreal Neurological Institute, McGill University, Montréal, Canada
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  • Michael Israel Shevell MD,,

    1. Division of Pediatric Neurology, Montreal Children's Hospital-McGill University Health Center, Montréal, Canada
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  • FORGE Canada Consortium,

  • Chantal Poulin MD,,

    1. Division of Pediatric Neurology, Montreal Children's Hospital-McGill University Health Center, Montréal, Canada
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  • Erin O'ferrall MD,,

    1. Department of Neurology & Neurosurgery and Department of Pathology, Montreal Neurological Institute, McGill University, Montréal, Canada
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  • Daniela Buhas MD,,

    1. Department of Medical Genetics, Montreal Children's Hospital-McGill University Health Centre, Montréal, Canada
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  • Jacek Majewski PhD,,

    1. McGill University and Genome Quebec Innovation Centre, Montréal, Canada
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  • Bernard Brais MD, PhD

    Corresponding author
    1. Laboratory of Neurogenetics of Motion, Montreal Neurological Institute, McGill University, Montréal, Canada
    • Correspondence to: B. Brais, Departments of Neurology, Neurosurgery, and Human Genetics, Faculty of Medicine, McGill University, Montreal Neurological Institute, 3801, University Street, Room 658, Montreal, Quebec, H3A 2B4, Canada; e-mail: bernard.brais@mcgill.ca

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  • This study was supported by the Association de la neuropathie sensitive and was selected for study by the FORGE Canada Steering Committee, consisting of K. Boycott (U. Ottawa), J. Friedman (U. British Columbia), J. Michaud (U. Montreal), F. Bernier (U. Calgary), M. Brudno (U. Toronto), B. Fernandez (Memorial U.), B. Knoppers (McGill U.), M. Samuels (U. de Montreal), and S. Scherer (U. Toronto). M.S. holds a CIHR Clinician-Scientist training award. Bernard Brais certifies that all co-authors have seen and agree with the content of the manuscript. The authors have no competing financial interest.

ABSTRACT

Introduction: We have identified a large consanguineous Lebanese family with 5 individuals with severe childhood-onset recessive sensory loss associated with deafness and variable optic atrophy. Methods: Autozygosity mapping was performed in all affected individuals, followed by whole-exome sequencing (WES) in 2 individuals. Results: WES identified a homozygous missense mutation (c.916G>A, p.G306R) in the cerebral riboflavin transporter SLC52A2, recently shown to cause Brown-Vialetto-Van-Laere syndrome (BVVLS), which is considered primarily a motor neuronopathy. Our patients have a phenotype distinct from BVVLS, characterized by severe progressive sensory loss mainly affecting vibration and proprioception that evolves to include sensorineural hearing loss in childhood, variable degrees of optic atrophy, and marked upper extremity weakness and atrophy. Treatment of 3 patients with 400 mg/day riboflavin over 3 months produced definite clinical improvement. Conclusions: Mutations in SLC52A2 result in a recognizable phenotype distinct from BVVLS. Early recognition of this disorder is critical, given its potential treatability. Muscle Nerve 50: 775–779, 2014

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