title: Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease.
abstract: Mutations in the ganglioside-induced-differentiation-associated protein 1 gene (GDAP1) can cause Charcot-Marie-Tooth (CMT) disease with demyelinating (CMT4A) or axonal forms (CMT2K and ARCMT2K). Most of these mutations present a recessive inheritance, but few autosomal dominant GDAP1 mutations have also been reported. We performed a GDAP1 gene screening in a clinically well-characterized series of 81 index cases with axonal CMT neuropathy, identifying 17 patients belonging to 4 unrelated families in whom the heterozygous p.R120W was found to be the only disease-causing mutation. The main objective was to fully characterize the neuropathy caused by this mutation. The clinical picture included a mild-moderate phenotype with onset around adolescence, but great variability. Consistently, ankle dorsiflexion and plantar flexion were impaired to a similar degree. Nerve conduction studies revealed an axonal neuropathy. Muscle magnetic resonance imaging studies demonstrated selective involvement of intrinsic foot muscles in all patients and a uniform pattern of fatty infiltration in the calf, with distal and superficial posterior predominance. Pathological abnormalities included depletion of myelinated fibers, regenerative clusters and features of axonal degeneration with mitochondrial aggregates. Our findings highlight the relevance of dominantly transmitted p.R120W GDAP1 gene mutations which can cause an axonal CMT with a wide clinical profile.
authors.affiliation: Department of Neurology, University Hospital Universitari La Fe, Valencia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Sivera
authors.forename: Carmen
authors.initials: C
authors.lastname: Espinós
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Vílchez
authors.forename: Fernando
authors.initials: F
authors.lastname: Mas
authors.forename: Dolores
authors.initials: D
authors.lastname: Martínez-Rubio
authors.forename: María José
authors.initials: MJ
authors.lastname: Chumillas
authors.forename: Fernando
authors.initials: F
authors.lastname: Mayordomo
authors.forename: Nuria
authors.initials: N
authors.lastname: Muelas
authors.forename: Luis
authors.initials: L
authors.lastname: Bataller
authors.forename: Francesc
authors.initials: F
authors.lastname: Palau
authors.forename: Teresa
authors.initials: T
authors.lastname: Sevilla
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000235:genetics; D001369:Axons / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D014364:Tryptophan / Q000235:genetics; D055815:Young Adult
chemical_list: C118663:GDAP protein; D009419:Nerve Tissue Proteins; D014364:Tryptophan; D001120:Arginine