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J Neuromuscul Dis. 2019 Jul 22. doi: 10.3233/JND-190404. [Epub ahead of print]

A Novel Mutation in MARS in a Patient with Charcot-Marie-Tooth Disease, Axonal, Type 2U with Congenital Onset.

Author information

1
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
2
Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
3
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
4
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
5
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.

Abstract

Charcot-Marie-Tooth disease is a phenotypically and genetically heterogeneous group of disorders affecting both motor and sensory neurons. Exome sequencing has driven discovery of genes responsible for Charcot-Marie-Tooth with more than 70 genes now associated with this neuromuscular disease. The MARS gene was recently reported as the cause of Charcot-Marie-Tooth 2U, an axonal sensorimotor polyneuropathy with adult-onset, slowly progressive disease reported in six patients. We report here a patient with a progressive, early childhood-onset, motor-predominant form of Charcot-Marie-Tooth disease. Exome sequencing identified a novel MARS variant (c.1189G>A; p.Ala397Thr) that was not present in her unaffected mother; her unaffected father was unavailable. Further studies using structural modeling and a yeast humanization assay support pathogenicity of the variant. Our study expands the phenotype of Charcot-Marie-Tooth 2U, while highlighting the utility of functional assays to evaluate variant pathogenicity.

KEYWORDS:

CMT2U; Charcot-Marie-Tooth disease type 2U; MARS; early-onset neuropathy; exome sequencing

PMID:
31356216
DOI:
10.3233/JND-190404

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