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Mutation in RNF170 causes sensory ataxic neuropathy with vestibular areflexia: a CANVAS mimic
  1. Andrea Cortese1,2,
  2. Ilaria Callegari1,3,
  3. Riccardo Currò1,3,
  4. Elisa Vegezzi1,3,
  5. Silvia Colnaghi3,
  6. Maurizio Versino4,
  7. Enrico Alfonsi3,
  8. Giuseppe Cosentino1,3,
  9. Enzamaria Valente1,3,
  10. Simone Gana3,
  11. Cristina Tassorelli1,3,
  12. Anna Pichiecchio1,3,
  13. Alexander M Rossor2,
  14. Enrico Bugiardini2,
  15. Antonio Biroli5,
  16. Daniela Di Capua6,
  17. Henry Houlden2,
  18. Mary M Reilly2
  1. 1 Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
  2. 2 Department for Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK
  3. 3 IRCCS Mondino Foundation, Pavia, Italy
  4. 4 Neurology Unit, ASST Settelaghi-Insubria University-DMC, Varese, Italy
  5. 5 Neurosurgery Unit, ASST Spedali Civili of Brescia, Brescia, Italy
  6. 6 Neurologia, Hospital de Especialidades Eugenio Espejo, Quito, Ecuador
  1. Correspondence to Dr Andrea Cortese, Department of Neuromuscular Disease University College London Institute of Neurology, University College London Institute of Neurology, London WC1N 3BG, UK; andrea.cortese{at}ucl.ac.uk

https://doi.org/10.1136/jnnp-2020-323719

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    Introduction

    Sensory neuronopathy or ganglionopathy is a type of peripheral neuropathy characterised by primary and selective destruction of the dorsal root ganglia leading to degeneration of both central and peripheral neurites of sensory neurons.1

    There is a narrow differential diagnosis for a sensory ganglionopathy which includes paraneoplastic (anti-Hu antibodies), autoimmune (Sjogren syndrome,), toxic (cisplatin, pyridoxine) and genetic (Friedreich’s ataxia and mitochondrial disease due to POLG1 mutations) causes.2 More recently biallelic AAGGG expansion in replication factor complex subunit 1 have been identified as a major cause of sensory ataxia neuropathy, often with cerebellar and vestibular involvement (CANVAS).3 4 However, a significant fraction of patients with a sensory ganglionopathy remain genetically undiagnosed.

    In 2004 Valdamanis et al identified a heterozygous p.Arg199Cys mutation in ring finger protein 170 (RNF170) responsible for a rare form of sensory ataxia in two families from eastern Canada sharing a founder haplotype.5–7 Affected cases showed progressive sensory loss and ataxia due to degeneration of the posterior columns, but normal sensory nerve conduction.

    By exome-sequencing we have identified the same p.Arg199Cys RNF170 mutation in an Ecuadorian family affected by an autosomal dominant late-onset progressive sensory ganglionopathy. Unlike the previously reported cases from Eastern Canada, affected members showed evidence of ganglionic/postganglionic involvement of the sensory peripheral nerves. Also, bilateral vestibular areflexia was identified in the index case, mimicking CANVAS.

    Case presentation

    The index case (III-3, figure 1A) is a 57-year-old woman with onset of poor balance at the age of 47 years, followed by dysaesthesia and sensory loss in her feet and hands. At the age of 57 years she was referred for neurological evaluation, by which time she required a walking aid. Her past medical history was notable for rheumatic fever and gastro-oesophageal reflux. A sister had similar symptoms and her father and paternal grandmother both reported progressive …

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    Footnotes

    • Contributors AC: study concept and design, analysis and interpretation of data, draft of the manuscript. AC, IC, RC, EV, SC, MV, CT, AB, DDC, EA, GC, AP: acquisition of the data. AC, EB, AMR, SG, EV, HH, MMR: analysis and interpretation of the genetic data. All authors revised the manuscript.

    • Funding AC thanks Medical Research Council, (MR/T001712/1), Wellcome Trust (204841/Z/16/Z), Fondazione CARIPLO (2019–1836), Italian Ministry of Health Ricerca Corrente 2018–2019 and the Inherited Neuropathy Consortium (INC) for grant support. MMR is grateful to the Medical Research Council (MRC), MRC Centre grant (G0601943), and to the National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712) for their support. The INC (U54NS065712) is a part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and the NINDS. This research was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

    • Competing interests None declared.

    • Patient consent for publication Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.