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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.

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


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.


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


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