@article{1d41c7502f104ebf9319a3cb88c3a12a,
title = "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.",
author = "M. Zimo{\'n} and J. Baets and Fabrizi, {G. M.} and E. Jaakkola and D. Kabzi{\'n}ska and J. Pilch and Schindler, {A. B.} and Cornblath, {D. R.} and Fischbeck, {K. H.} and M. Auer-Grumbach and C. Guelly and N. Huber and {De Vriendt}, E. and V. Timmerman and U. Suter and I. Hausmanowa-Petrusewicz and A. Niemann and A. Kocha{\'n}ski and {De Jonghe}, P. and A. Jordanova",
note = "Funding Information: Study funding: This study was supported by the University of Antwerp, the Fund for Scientific Research (FWO-Flanders, grant G017209N ), the “Association Belge contre les Maladies Neuromusculaires” (ABMM), the Medical Foundation Queen Elisabeth (GSKE), the Interuniversity Attraction Poles P6/43 program of the Belgian Federal Science Policy Office (BELSPO), the “Methusalem excellence grant” of the Flemish Government, and the Austrian Science Fond (FWF, P19455-B05 ). M.Z. and J.B. are supported by PhD fellowships of the FWO-Flanders. This study was also supported by the Polish Ministry of Science and Higher Education (grant No. NN 402 27 63 36 ) to A.K. Work in the laboratory of U.S. is supported by the Swiss National Science Foundation and the NCCR Neural Plasticity and Repair. Funding Information: M. Zimo{\'n}, Dr. Baets, Dr. Fabrizi, Dr. Jaakkola, Dr. Kabzinska, Dr. Pilch, and A.B. Schindler report no disclosures. Dr. Cornblath serves/has served on scientific advisory boards for Ardea Biosciences, Inc., Avigen, Inc., Pfizer Inc, Johnson & Johnson, GlaxoSmithKline, Abbott, Acorda Therapeutics Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Baxter International Inc., Bionevia Pharmaceuticals Inc., Bristol-Myers Squibb, Cebix, CSL Behring, Eisai Inc., Exelixis Inc., FoldRx, Genzyme Corporation, Keryx Biopharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation, Octapharma AG, Sangamo BioSciences, Inc., sanofi-aventis, and Talecris Biotherapeutics; holds and has received license fee payments for patents re: Total neuropathy score (nurse, clinical), Methods to assess neuropathy. Dr. Fischbeck receives intramural research support from the NIH/NINDS. Dr. Auer-Grumbach, Dr. Guelly, N. Huber, E. De Vriendt, and Dr. Timmerman report no disclosures. Dr. Suter receives research support from the Swiss National Science Foundation and the NCCR Neural Plasticity and Repair. Dr. Hausmanowa-Petrusewicz, Dr. Niemann, Dr. Kochanski, Dr. De Jonghe, and Dr. Jordanova report no disclosures. ",
year = "2011",
month = aug,
day = "9",
doi = "10.1212/WNL.0b013e318228fc70",
language = "English (US)",
volume = "77",
pages = "540--548",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "6",
}