CMT 4H: further evidence that mutations in FGD4/frabin cause

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Neurology. 2009 Mar 31;72(13):1160-4.

Further evidence that mutations in FGD4/frabin cause Charcot-Marie-Tooth disease

type 4H.

Fabrizi GM, Taioli F, Cavallaro T, Ferrari S, Bertolasi L, Casarotto M, Rizzuto

N, Deconinck T, Timmerman V, De Jonghe P.

Section of Clinical Neurology, Department of Neurological and Visual Sciences,

University of Verona, Ospedale Policlinico G.B. Rossi, P.le L.A. Scuro 10, 37134

Verona, Italy

BACKGROUND: Autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy

type 4H (CMT4H) manifests early onset, severe functional impairment, deforming

scoliosis, and myelin outfoldings in the nerve biopsy. Mutations in the FGD4

gene encoding the Rho-GTPase guanine-nucleotide-exchange-factor frabin were

reported in five families.

OBJECTIVE: To characterize a novel mutation in FGD4 and describe the related

phenotype.

METHODS: A 20-year-old woman born of healthy consanguineous parents and affected

with early-onset peroneal muscular atrophy underwent standard clinical,

electrophysiologic, and pathologic (sural nerve biopsy) investigations.

Mutational analysis of FGD4 was performed by direct sequencing of genomic DNA.

Transcriptional analysis was done by reverse transcriptase PCR on leukocyte RNA.

RESULTS: The proband disclosed a moderately severe, scarcely progressive CMT,

markedly slowed nerve conduction velocities, and a demyelinating neuropathy

characterized by prominent myelin outfoldings. Mutational analysis disclosed a

c.1762-2a>g transition in the splice-acceptor site of intron 14, which was

predicted to cause a truncated frabin (p.Tyr587fsX14).

CONCLUSIONS: The report confirms genetic heterogeneity of FGD4, demonstrates

that CMT4H has variable functional impairment, and suggests that frabin plays a

crucial role during myelin formation.