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NEUROLOGY 2009;72:1160-1164
© 2009 American Academy of Neurology

Further evidence that mutations in FGD4/frabin cause Charcot-Marie-Tooth disease type 4H

G. M. Fabrizi, MD, PhD, F. Taioli, PhD, T. Cavallaro, MD, S. Ferrari, MD, L. Bertolasi, MD, M. Casarotto, MD, N. Rizzuto, MD, T. Deconinck, MSc, V. Timmerman, PhD and P. De Jonghe, MD, PhD

From the Section of Clinical Neurology (G.M.F., F.T., T.C., S.F., L.B., N.R.) and Neurorehabilitation Section (M.C.), Department of Neurological and Visual Sciences, University of Verona, Italy; Neurogenetics Group (T.D., P.D.J.) and Peripheral Neuropathy Group (V.T.), Molecular Genetics Department, VIB, Institute Born-Bunge and University of Antwerp; and Division of Neurology (P.D.J.), University Hospital Antwerpen, Belgium.

Address correspondence and reprint requests to Dr. Gian Maria Fabrizi, 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 gianmaria.fabrizi{at}univr.it

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.

Abbreviations: Amp = amplitude of compound motor action potential or of sensory nerve action potential; Cdc42 = cell division cycle 42; CMT-NS = Charcot-Marie-Tooth Neuropathy Score; CMT4H = Charcot-Marie-Tooth disease type 4H; DL = distal motor latency; EGR2 = early growth factor 2; FGD4/frabin = FGD1-related F-actin binding protein; GDAP1 = ganglioside-induced differentiation-associated protein 1; GEF = GDP/GTP exchange factor; MPZ = myelin protein zero; MRC = Medical Research Council; MTMR13/SBF2 = myotubularin-related protein 13/SET binding factor 2; MTMR2 = myotubularin-related protein 2; NCV = nerve conduction velocity; NDRG1 = N-myc downstream-regulated gene 1; NE = not evoked; PH = plekstrin homology; PMP22 = peripheral myelin protein 22; PRX = periaxin; SAC3 = SAC domain-containing inositol phosphatase 3; SBF2/MTMR13 = myotubularin-related protein 13/SET binding factor 2; SH3TC2/KIAA1985 = SH3 domain and tetratricopeptide repeats 2.

Supplemental data at www.neurology.org

Supported by Telethon-Italy, the Italian Ministry of University and Scientific Research, the University of Verona, the University of Antwerp, the Fund for Scientific Research (FWO-Flanders), the Medical Foundation Queen Elisabeth (GSKE), and the Interuniversity Attraction Poles P6/43 program of the Belgian Federal Science Policy Office (BELSPO).

Disclosure: The authors report no disclosures.

Received October 6, 2008. Accepted in final form December 22, 2008.






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