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Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy.
Brain. 2009 Jul; 132(Pt 7):1741-52.B

Abstract

Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain); Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2, which are all located in the pleckstrin homology domain, they were situated in the middle domain and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the patients were wheelchair-bound. The mean age at onset was 16 years with a large variability ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-Marie-Tooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less pronounced reduction of motor median NCV (41-46 m/s) with normal amplitudes in two families. Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal myelin thickenings--findings very similar to those previously reported in the Australian family. We conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-Marie-Tooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is associated with neutropaenia or cataracts.

Authors+Show Affiliations

Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19502294

Citation

Claeys, Kristl G., et al. "Phenotypic Spectrum of Dynamin 2 Mutations in Charcot-Marie-Tooth Neuropathy." Brain : a Journal of Neurology, vol. 132, no. Pt 7, 2009, pp. 1741-52.
Claeys KG, Züchner S, Kennerson M, et al. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain. 2009;132(Pt 7):1741-52.
Claeys, K. G., Züchner, S., Kennerson, M., Berciano, J., Garcia, A., Verhoeven, K., Storey, E., Merory, J. R., Bienfait, H. M., Lammens, M., Nelis, E., Baets, J., De Vriendt, E., Berneman, Z. N., De Veuster, I., Vance, J. M., Nicholson, G., Timmerman, V., & De Jonghe, P. (2009). Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain : a Journal of Neurology, 132(Pt 7), 1741-52. https://doi.org/10.1093/brain/awp115
Claeys KG, et al. Phenotypic Spectrum of Dynamin 2 Mutations in Charcot-Marie-Tooth Neuropathy. Brain. 2009;132(Pt 7):1741-52. PubMed PMID: 19502294.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. AU - Claeys,Kristl G, AU - Züchner,Stephan, AU - Kennerson,Marina, AU - Berciano,José, AU - Garcia,Antonio, AU - Verhoeven,Kristien, AU - Storey,Elsdon, AU - Merory,John R, AU - Bienfait,Henriette M E, AU - Lammens,Martin, AU - Nelis,Eva, AU - Baets,Jonathan, AU - De Vriendt,Els, AU - Berneman,Zwi N, AU - De Veuster,Ilse, AU - Vance,Jefferey M, AU - Nicholson,Garth, AU - Timmerman,Vincent, AU - De Jonghe,Peter, Y1 - 2009/06/05/ PY - 2009/6/9/entrez PY - 2009/6/9/pubmed PY - 2009/9/10/medline SP - 1741 EP - 52 JF - Brain : a journal of neurology JO - Brain VL - 132 IS - Pt 7 N2 - Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain); Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2, which are all located in the pleckstrin homology domain, they were situated in the middle domain and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the patients were wheelchair-bound. The mean age at onset was 16 years with a large variability ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-Marie-Tooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less pronounced reduction of motor median NCV (41-46 m/s) with normal amplitudes in two families. Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal myelin thickenings--findings very similar to those previously reported in the Australian family. We conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-Marie-Tooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is associated with neutropaenia or cataracts. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/19502294/Phenotypic_spectrum_of_dynamin_2_mutations_in_Charcot_Marie_Tooth_neuropathy_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awp115 DB - PRIME DP - Unbound Medicine ER -