Genotype-phenotype correlation in vanishing white matter disease.
OBJECTIVE
Vanishing white matter (VWM) is an autosomal recessive leukoencephalopathy characterized by slowly progressive ataxia and spasticity with additional stress-provoked episodes of rapid and major deterioration. The disease is caused by mutations in the genes encoding the subunits of eukaryotic initiation factor 2B, which is pivotal in translation of mRNAs into proteins. The disease onset, clinical severity, and disease course of VWM vary greatly. The influence of genotype and gender on the phenotype is unclear.


METHODS
From our database of 184 patients with VWM, we selected those with the following mutations in the gene EIF2B5: p.Arg113His in the homozygous state (n = 23), p.Arg113His in the compound-heterozygous state (n = 49), p.Thr91Ala in the homozygous state (n = 8), p.Arg113His/p.Arg339any (n = 9), and p.Thr91Ala/p.Arg339any (n = 7). We performed a cross-sectional observational study. Evaluated clinical characteristics were gender, age at onset, age at loss of walking without support, and age at death. Means, male/female ratios, and Kaplan-Meier curves were compared.


RESULTS
Patients homozygous for p.Arg113His had a milder disease than patients compound heterozygous for p.Arg113His and patients homozygous for p.Thr91Ala. Patients with p.Arg113His/p.Arg339any had a milder phenotype than patients with p.Thr91Ala/p.Arg339any. Overall, females tended to have a milder disease than males.


CONCLUSIONS
The clinical phenotype in VWM is influenced by the combination of both mutations. Females tend to do better than males.
van der Lei
H D W
HD
Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.
van Berkel
C G M
CG
van Wieringen
W N
WN
Brenner
C
C
Feigenbaum
A
A
Mercimek-Mahmutoglu
S
S
Philippart
M
M
Tatli
B
B
Wassmer
E
E
Scheper
G C
GC
van der Knaap
M S
MS
D000328:Adult; D003430:Cross-Sectional Studies; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D005838:Genotype; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology; D006801:Humans; D056784:Leukoencephalopathies / Q000150:complications / Q000235:genetics / Q000473:pathology; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011336:Probability; D012737:Sex Factors; D016019:Survival Analysis
D020717:Eukaryotic Initiation Factor-2B