Brain Advance Access published online on June 5, 2009
Brain, doi:10.1093/brain/awp115
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Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy
1 Neurogenetics Group, VIB Department of Molecular Genetics and Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium 2 Division of Neurology, University Hospital Antwerp, Antwerpen, Belgium 3 Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA 4 Northcott Neuroscience Laboratory, ANZAC Research Institute, NSW 2139, Australia 5 Molecular Medicine Laboratory, Concord Hospital, Concord, NSW 2139, Australia 6 Services of Neurology and Clinical Neurophysiology, University Hospital ‘Marqués de Valdecilla’, CIBERNED and UC, Santander, Spain 7 Peripheral Neuropathy Group, VIB Department of Molecular Genetics and Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium 8 Department of Medicine – Neuroscience, Monash University, Alfred Hospital Campus, Victoria 3084, Australia 9 Department of Neurology, Austin Health, Heidelberg, Victoria 3084, Australia 10 Department of Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands 11 Neuromuscular Centre Nijmegen, Departments of Pathology and Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands 12 Division of Haematology, University Hospital Antwerp, Antwerpen, Belgium 13 Division of Ophthalmology, University Hospital Antwerp, Antwerpen, Belgium
Correspondence to:
Peter De Jonghe, MD, PhD, Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium E-mail: peter.dejonghe{at}ua.ac.be
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.
Key Words: intermediate CMT; dynamin 2; neutropaenia; hereditary neuropathy; cataracts
Abbreviations: CMAP, compound muscle action potential; CMT, Charcot-Marie-Tooth; DI-CMTB, dominant intermediate Charcot-Marie-Tooth neuropathy type B; DNM2, dynamin 2; NCV, nerve conduction velocities; SNAP, sensory nerve action potential
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Received January 28, 2009. Revised March 10, 2009. Accepted March 27, 2009.
*Present address: Institut de Myologie, Unité de Morphologie Neuromusculaire and Centre de Référence Neuromusculaire Paris-Est, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Present address: Department of Neurology, Kennemer Gasthuis, Haarlem, The Netherlands.