Further evidence that mutations in FGD4/frabin cause Charcot-Marie-Tooth disease type 4H.
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.
Fabrizi
G M
GM
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@univr.it
Taioli
F
F
Cavallaro
T
T
Ferrari
S
S
Bertolasi
L
L
Casarotto
M
M
Rizzuto
N
N
Deconinck
T
T
Timmerman
V
V
De Jonghe
P
P