Dominant GDAP1 mutations cause predominantly mild CMT phenotypes

M. Zimoń, J. Baets, G. M. Fabrizi, E. Jaakkola, D. Kabzińska, J. Pilch, A. B. Schindler, David Cornblath, K. H. Fischbeck, M. Auer-Grumbach, C. Guelly, N. Huber, E. De Vriendt, V. Timmerman, U. Suter, I. Hausmanowa-Petrusewicz, A. Niemann, A. Kochański, P. De Jonghe, A. Jordanova

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)540-548
Number of pages9
JournalNeurology
Volume77
Issue number6
DOIs
StatePublished - Aug 9 2011

Fingerprint

Charcot-Marie-Tooth Disease
Phenotype
Mutation
Tooth
Penetrance
GDAP protein
Protein
Causes
Teeth
Introns
Virulence
Disease Progression
Counseling
Exons
Alleles

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Zimoń, M., Baets, J., Fabrizi, G. M., Jaakkola, E., Kabzińska, D., Pilch, J., ... Jordanova, A. (2011). Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology, 77(6), 540-548. https://doi.org/10.1212/WNL.0b013e318228fc70

Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. / Zimoń, M.; Baets, J.; Fabrizi, G. M.; Jaakkola, E.; Kabzińska, D.; Pilch, J.; Schindler, A. B.; Cornblath, David; Fischbeck, K. H.; Auer-Grumbach, M.; Guelly, C.; Huber, N.; De Vriendt, E.; Timmerman, V.; Suter, U.; Hausmanowa-Petrusewicz, I.; Niemann, A.; Kochański, A.; De Jonghe, P.; Jordanova, A.

In: Neurology, Vol. 77, No. 6, 09.08.2011, p. 540-548.

Research output: Contribution to journalArticle

Zimoń, M, Baets, J, Fabrizi, GM, Jaakkola, E, Kabzińska, D, Pilch, J, Schindler, AB, Cornblath, D, Fischbeck, KH, Auer-Grumbach, M, Guelly, C, Huber, N, De Vriendt, E, Timmerman, V, Suter, U, Hausmanowa-Petrusewicz, I, Niemann, A, Kochański, A, De Jonghe, P & Jordanova, A 2011, 'Dominant GDAP1 mutations cause predominantly mild CMT phenotypes', Neurology, vol. 77, no. 6, pp. 540-548. https://doi.org/10.1212/WNL.0b013e318228fc70
Zimoń M, Baets J, Fabrizi GM, Jaakkola E, Kabzińska D, Pilch J et al. Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology. 2011 Aug 9;77(6):540-548. https://doi.org/10.1212/WNL.0b013e318228fc70
Zimoń, M. ; Baets, J. ; Fabrizi, G. M. ; Jaakkola, E. ; Kabzińska, D. ; Pilch, J. ; Schindler, A. B. ; Cornblath, David ; Fischbeck, K. H. ; Auer-Grumbach, M. ; Guelly, C. ; Huber, N. ; De Vriendt, E. ; Timmerman, V. ; Suter, U. ; Hausmanowa-Petrusewicz, I. ; Niemann, A. ; Kochański, A. ; De Jonghe, P. ; Jordanova, A. / Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. In: Neurology. 2011 ; Vol. 77, No. 6. pp. 540-548.
@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. Zimoń and J. Baets and Fabrizi, {G. M.} and E. Jaakkola and D. Kabzińska and J. Pilch and Schindler, {A. B.} and David Cornblath 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. Kochański and {De Jonghe}, P. and A. Jordanova",
year = "2011",
month = "8",
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",

}

TY - JOUR

T1 - Dominant GDAP1 mutations cause predominantly mild CMT phenotypes

AU - Zimoń, M.

AU - Baets, J.

AU - Fabrizi, G. M.

AU - Jaakkola, E.

AU - Kabzińska, D.

AU - Pilch, J.

AU - Schindler, A. B.

AU - Cornblath, David

AU - Fischbeck, K. H.

AU - Auer-Grumbach, M.

AU - Guelly, C.

AU - Huber, N.

AU - De Vriendt, E.

AU - Timmerman, V.

AU - Suter, U.

AU - Hausmanowa-Petrusewicz, I.

AU - Niemann, A.

AU - Kochański, A.

AU - De Jonghe, P.

AU - Jordanova, A.

PY - 2011/8/9

Y1 - 2011/8/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80052917055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052917055&partnerID=8YFLogxK

U2 - 10.1212/WNL.0b013e318228fc70

DO - 10.1212/WNL.0b013e318228fc70

M3 - Article

C2 - 21753178

AN - SCOPUS:80052917055

VL - 77

SP - 540

EP - 548

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 6

ER -