CMT 2B: Phenotypic spectrum of dynamin 2 mutations

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rain. 2009 Jun 5.

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

Claeys KG, Züchner S, Kennerson M, Berciano J, A, Verhoeven K, Storey E,

Merory JR, Bienfait HM, Lammens M, Nelis E, Baets J, De Vriendt E, Berneman ZN,

De Veuster I, Vance JM, Nicholson G, Timmerman V, De Jonghe P.

1Neurogenetics Group, VIB Department of Molecular Genetics and Neurogenetics

Laboratory, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium.

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.