title: Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy.
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.affiliation: Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Marina
authors.initials: M
authors.lastname: Kennerson
authors.forename: José
authors.initials: J
authors.lastname: Berciano
authors.forename: Antonio
authors.initials: A
authors.lastname: Garcia
authors.forename: Kristien
authors.initials: K
authors.lastname: Verhoeven
authors.forename: Elsdon
authors.initials: E
authors.lastname: Storey
authors.forename: John R
authors.initials: JR
authors.lastname: Merory
authors.forename: Henriette M E
authors.initials: HM
authors.lastname: Bienfait
authors.forename: Martin
authors.initials: M
authors.lastname: Lammens
authors.forename: Eva
authors.initials: E
authors.lastname: Nelis
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.forename: Els
authors.initials: E
authors.lastname: De Vriendt
authors.forename: Zwi N
authors.initials: ZN
authors.lastname: Berneman
authors.forename: Ilse
authors.initials: I
authors.lastname: De Veuster
authors.forename: Jefferey M
authors.initials: JM
authors.lastname: Vance
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholson
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D001772:Blood Cell Count; D002386:Cataract / Q000235:genetics; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D015331:Cohort Studies; D034285:Dynamin II / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008475:Median Nerve / Q000503:physiopathology; D008875:Middle Aged; D009154:Mutation; D009431:Neural Conduction; D010375:Pedigree; D010641:Phenotype; D013497:Sural Nerve / Q000473:pathology; D055815:Young Adult
chemical_list: D034285:Dynamin II