Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy

Kristl G. Claeys, Stephan L Zuchner, Marina Kennerson, José Berciano, Antonio Garcia, Kristien Verhoeven, Elsdon Storey, John R. Merory, Henriette M E Bienfait, Martin Lammens, Eva Nelis, Jonathan Baets, Els De Vriendt, Zwi N. Berneman, Ilse De Veuster, Jeffery M Vance, Garth Nicholson, Vincent Timmerman, Peter De Jonghe

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1741-1752
Number of pages12
JournalBrain
Volume132
Issue number7
DOIs
StatePublished - Jul 1 2009

Fingerprint

Dynamin II
Tooth
Mutation
Neural Conduction
Sural Nerve
Median Nerve
Belgium
Proline
Cataract
Phenotype
Biopsy
Wheelchairs
Myelin Sheath
North America
Age of Onset
Netherlands
Spain
Axons
Reference Values

Keywords

  • Cataracts
  • Dynamin 2
  • Hereditary neuropathy
  • Intermediate CMT
  • Neutropaenia

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Claeys, K. G., Zuchner, S. L., Kennerson, M., Berciano, J., Garcia, A., Verhoeven, K., ... De Jonghe, P. (2009). Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain, 132(7), 1741-1752. https://doi.org/10.1093/brain/awp115

Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. / Claeys, Kristl G.; Zuchner, Stephan L; Kennerson, Marina; Berciano, José; Garcia, Antonio; Verhoeven, Kristien; Storey, Elsdon; Merory, John R.; Bienfait, Henriette M E; Lammens, Martin; Nelis, Eva; Baets, Jonathan; De Vriendt, Els; Berneman, Zwi N.; De Veuster, Ilse; Vance, Jeffery M; Nicholson, Garth; Timmerman, Vincent; De Jonghe, Peter.

In: Brain, Vol. 132, No. 7, 01.07.2009, p. 1741-1752.

Research output: Contribution to journalArticle

Claeys, KG, Zuchner, SL, Kennerson, M, Berciano, J, Garcia, A, Verhoeven, K, Storey, E, Merory, JR, Bienfait, HME, Lammens, M, Nelis, E, Baets, J, De Vriendt, E, Berneman, ZN, De Veuster, I, Vance, JM, Nicholson, G, Timmerman, V & De Jonghe, P 2009, 'Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy', Brain, vol. 132, no. 7, pp. 1741-1752. https://doi.org/10.1093/brain/awp115
Claeys KG, Zuchner SL, Kennerson M, Berciano J, Garcia A, Verhoeven K et al. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain. 2009 Jul 1;132(7):1741-1752. https://doi.org/10.1093/brain/awp115
Claeys, Kristl G. ; Zuchner, Stephan L ; Kennerson, Marina ; Berciano, José ; Garcia, Antonio ; Verhoeven, Kristien ; Storey, Elsdon ; Merory, John R. ; Bienfait, Henriette M E ; Lammens, Martin ; Nelis, Eva ; Baets, Jonathan ; De Vriendt, Els ; Berneman, Zwi N. ; De Veuster, Ilse ; Vance, Jeffery M ; Nicholson, Garth ; Timmerman, Vincent ; De Jonghe, Peter. / Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. In: Brain. 2009 ; Vol. 132, No. 7. pp. 1741-1752.
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AU - Kennerson, Marina

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AU - Garcia, Antonio

AU - Verhoeven, Kristien

AU - Storey, Elsdon

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AU - De Veuster, Ilse

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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.

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