Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy.
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.
Claeys
Kristl G
KG
Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
Züchner
Stephan
S
Kennerson
Marina
M
Berciano
José
J
Garcia
Antonio
A
Verhoeven
Kristien
K
Storey
Elsdon
E
Merory
John R
JR
Bienfait
Henriette M E
HM
Lammens
Martin
M
Nelis
Eva
E
Baets
Jonathan
J
De Vriendt
Els
E
Berneman
Zwi N
ZN
De Veuster
Ilse
I
Vance
Jefferey M
JM
Nicholson
Garth
G
Timmerman
Vincent
V
De Jonghe
Peter
P
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
D034285:Dynamin II