Phenotypical features of a new dominant GDAP1 pathogenic variant (p.R226del) in axonal Charcot-Marie-Tooth disease

Abstract

There are few reports on axonal CMT due to dominant GDAP1 mutations. We describe two unrelated Spanish families with a dominant axonal CMT. A novel in frame GAA deletion in exon 5 of the GDAP1 gene (c.677_679del; p.R226del) was identified in both families. Disease onset varied from early childhood to adulthood. Affected family members complained of distal lower limb weakness, cramps and foot deformities with variable CMTNS score in both families. Several individuals were asymptomatic or had paraesthesia only, however neurological examination and nerve conduction studies demonstrated neuropathic signs. Transfection of HeLa cells with the p.R226del mutation led to an increased mitochondrial aggregation. We report an AD-CMT2K with large phenotypic variability due to a novel dominant GDAP1 variant. This is the second founder GDAP1 pathogenic variant reported in Spain.

Keywords: CMT2K; Charcot-Marie-Tooth; GDAP1 variants; Hereditary neuropathy; Pathogenic mutation.