Charcot-Marie-Tooth disease: genetic and clinical spectrum in a Spanish clinical series.
OBJECTIVE
To determine the genetic distribution and the phenotypic correlation of an extensive series of patients with Charcot-Marie-Tooth disease in a geographically well-defined Mediterranean area.


METHODS
A thorough genetic screening, including most of the known genes involved in this disease, was performed and analyzed in this longitudinal descriptive study. Clinical data were analyzed and compared among the genetic subgroups.


RESULTS
Molecular diagnosis was accomplished in 365 of 438 patients (83.3%), with a higher success rate in demyelinating forms of the disease. The CMT1A duplication (PMP22 gene) was the most frequent genetic diagnosis (50.4%), followed by mutations in the GJB1 gene (15.3%), and in the GDAP1 gene (11.5%). Mutations in 13 other genes were identified, but were much less frequent. Sixteen novel mutations were detected and characterized phenotypically.


CONCLUSIONS
The relatively high frequency of GDAP1 mutations, coupled with the scarceness of MFN2 mutations (1.1%) and the high proportion of recessive inheritance (11.6%) in this series exemplify the particularity of the genetic distribution of Charcot-Marie-Tooth disease in this region.
From the Departments of Neurology (R.S., T.S., J.J.V., J.F.V., N.M., L.B.), Clinical Neurophysiology (M.J.C.), and Genetics (J.M.M.), Hospital Univesitari i Politècnic La Fe, Valencia; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (T.S., J.J.V., M.J.C., N.M., L.B.), Valencia; Departments of Medicine (T.S., J.J.V.) and Genetics (C.E.), University of Valencia; Program in Rare and Genetic Diseases (D.M.-R., F.P., C.E.), Centro de Investigación Príncipe Felipe (CIPF), Valencia; Centro de Investigación Biomédica en Red de Enfermedades Raras (D.M.-R., J.M.M., F.P., C.E.), Valencia; IBV-CSIC Associated Unit at CIPF (D.M.-R., F.P., C.E.), Valencia; and School of Medicine (F.P.), University of Castilla-La Mancha, Ciudad Real, Spain.
Rafael
R
Sivera
Teresa
T
Sevilla
Juan Jesús
JJ
Vílchez
Dolores
D
Martínez-Rubio
María José
MJ
Chumillas
Juan Francisco
JF
Vázquez
Nuria
N
Muelas
Luis
L
Bataller
José María
JM
Millán
Fancesc
F
Palau
Carmen
C
Espinós
D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005530:Foot Deformities / Q000209:etiology; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D053580:Muscle Strength / Q000502:physiology; D009133:Muscular Atrophy / Q000209:etiology; D009154:Mutation / Q000235:genetics*; D009185:Myelin Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012189:Retrospective Studies; D012678:Sensation Disorders / Q000209:etiology; D013030:Spain / Q000453:epidemiology; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D000097002:Gap Junction beta-1 Protein; C118663:GDAP protein; C073687:PMP22 protein, human