Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.
BACKGROUND
Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot-Marie-Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis.


METHODS
The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1.


RESULTS
A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C).


CONCLUSIONS
Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.
Nelis
E
E
Molecular Genetics Department, Flanders Interuniversity Institute of Biotechnology, Belgium.
Erdem
S
S
Van Den Bergh
P Y K
PY
Belpaire-Dethiou
M-C
MC
Ceuterick
C
C
Van Gerwen
V
V
Cuesta
A
A
Pedrola
L
L
Palau
F
F
Gabreëls-Festen
A A W M
AA
Verellen
C
C
Tan
E
E
Demirci
M
M
Van Broeckhoven
C
C
De Jonghe
P
P
Topaloglu
H
H
Timmerman
V
V
D017668:Age of Onset; D001369:Axons / Q000473:pathology*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004594:Electrophysiology; D005190:Family; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009431:Neural Conduction / Q000502:physiology; D010375:Pedigree; D013497:Sural Nerve / Q000473:pathology; D014421:Turkey
C118663:GDAP protein; D009419:Nerve Tissue Proteins