FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Varón syndrome.

24. Mai, 2020

Zimmermann M1, Schuster S2, Boesch S3, Korenke GC4, Mohr J5, Reichbauer J6, Kernstock C7, Kotzot D8, Spahlinger V6, Schüle-Freyer R2, Schöls L2.

Abstract

Background:
Charcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varón syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death.

Objectives:
To analyse the phenotypic spectrum of FIG4-related disease and explore effects of residual FIG4 protein.

Methods:
Phenotyping of five new patients with FIG4-related disease. Western Blot analyses of FIG4 from patient fibroblasts.

Results:
Next generation sequencing revealed compound heterozygous variants in FIG4 in five patients. All five patients presented with peripheral neuropathy, various degree of dysmorphism and a central nervous system involvement comprising Parkinsonism in 3/5 patients, cerebellar ataxia (1/5), spasticity of lower limbs (1/5), epilepsy (1/5) and/or cognitive deficits (2/5). Onset varied between the first and the seventh decade. There was no residual FIG4 protein detectable in fibroblasts of the four analysed patients.

Conclusion:
This study extends the phenotypic spectrum of FIG4-related disease to Parkinsonism as a feature and demonstrates new phenotypes on a continuum between CMT4J and Yunis Varón syndrome.

  1. Department of Neurology and Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany. Electronic address: milan.zimmermann@med.uni-tuebingen.de..
  2. Department of Neurology and Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany.
  3. Department of Neurology, Medical University, Christoph-Probst-Platz 52, 6020, Innsbruck, Austria.
  4. Department of Neuropediatrics, University of Oldenburg, Rahel-Straus-Straße 10, 26133, Oldenburg, Germany.
  5. Center for Genomics and Transcriptomics (CeGaT) GmbH and Practice for Human Genetics, Paul-Ehrlich-Straße 23, 72076, Tübingen, Germany.
  6. Department of Neurology and Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
  7. University Eye Hospital, Center for Ophthalmology, Elfriede-Aulhorn-Str. 7, 72076, Tübingen, Germany.
  8. Institute of Human Genetics, Medical University Innsbruck, Christoph-Probst-Platz 52, 6020, Innsbruck, Austria; Division of Clinical Genetics, Department of Pediatrics, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria.