Dominant GDAP1 mutations cause predominantly mild CMT phenotypes

Abstract

Objective Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are commonly associated with autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy; however, in rare instances, they also lead to autosomal dominant Charcot-Marie-Tooth (ADCMT). We aimed to investigate the frequency of disease-causing heterozygous GDAP1 mutations in ADCMT and their associated phenotype. Methods We performed mutation analysis in a large cohort of ADCMT patients by means of bidirectional sequencing of coding regions and exon-intron boundaries of GDAP1. Intragenic GDAP1 deletions were excluded using an allele quantification assay. We confirmed the pathogenic character of one sequence variant by in vitro experiments assaying mitochondrial morphology and function. Results In 8 Charcot-Marie-Tooth disease (CMT) families we identified 4 pathogenic heterozygous GDAP1 mutations, 3 of which are novel. Three of the mutations displayed reduced disease penetrance. Disease onset in the affected individuals was variable, ranging from early childhood to adulthood. Disease progression was slow in most patients and overall severity milder than typically seen in autosomal recessive GDAP1 mutations. Electrophysiologic changes are heterogeneous but compatible with axonal neuropathy in the majority of patients. Conclusions With this study, we broaden the phenotypic and genetic spectrum of autosomal dominant GDAP1-associated neuropathies. We show that patients with dominant GDAP1 mutations may display clear axonal CMT, but may also have only minimal clinical and electrophysiologic abnormalities. We demonstrate that cell-based functional assays can be reliably used to test the pathogenicity of unknown variants. We discuss the implications of phenotypic variability and the reduced penetrance of autosomal dominant GDAP1 mutations for CMT diagnostic testing and counseling.

Emery-Dreifuss muscular dystrophy type 2 associated (?) with mild peripheral polyneuropathy

“…To elucidate the genetic background of the disease in our patient we analysed five genes: PMP22, GDAP1, GJB1, MPZ, and MFN2, causative for CMT disease. Heterozygous mutations in GDAP1 segregate with a mild form of axonal neuropathy with slow progression, resembling the clinical course observed in our patient [11]. Analysis of the GDAP1 gene in our patient did not reveal mutations.…”

Mitochondrial Dysfunction in a Patient with 8q21.11 Deletion and Charcot-Marie-Tooth Disease Type 2K due to <b><i>GDAP1</i></b> Haploinsufficiency

“…The GDAP1 gene deletion (as a part of the large 8q21.11 deletion) could have contributed to her regression, since it encodes the GDAP1 protein (ganglioside-induced differentiation-associated protein 1). The latter has been shown to be involved in mitochondrial function and a signal transduction pathway in neuronal development [Knott et al, 2008;Cassereaua et al, 2011;Palmomeres et al, 2011;Zimoń et al, 2011]. Mutations in this gene have been associated with both autosomal recessive and dominant CMT2K, which is a progressive disorder that affects the peripheral nerves [Bird, 1998].…”

Autosomal dominant neuropathy of the axonal Charcot–Marie–Tooth type 2

“…Definition, genetics, and pathogenesis CMT2K designates severe AR as well as rare and mild AD axonal neuropathies [70][71][72] caused by mutations of the GDAP1 (ganglioside-induced differentiation-associated protein 1) gene. CMT2K is allelic with severe AR demyelinating CMT4A (Chapter 11).…”