Intra-familial phenotypic heterogeneity in adult onset vanishing white matter disease.
Vanishing white matter (VWM) disease, also known as childhood ataxia with central nervous system hypomyelination (CACH) syndrome, is an autosomal recessive transmitted leukodystrophy. Classically characterised by early childhood onset, adult onset formed with slower progression have been recently recognized. The course of neurological impairment is usually progressive with possible occasional episodes of acute deterioration following febrile illnesses or head trauma. Neurological features are dominated by cerebellar ataxia and spasticity with relatively preserved mental abilities. Brain MRI shows diffuse abnormal signal of the cerebral white matter and cystic degeneration. Mutations in one of the genes coding for the five subunits of the translation factor eukaryotic initiation factor 2B (eIF2B) have been identified. We report here on two sisters affected by adult onset VWM with variable phenotypic expression. The proband is remarkable by the very late age of the disease onset (age of 42). A homozygous p.Arg113His mutation in the eIF2Bvarepsilon gene was identified. This mutation had been recurrently associated with adult onset VWM establishing phenotype-genotype correlations. We will show an important intra-familial phenotypic variability and discuss it in the light of recent molecular progresses. External precipitating factors are contributing for some of the differences observed.
CHU Bordeaux, Fédération des Neurosciences Cliniques, Hôpital Pellegrin, 33076 Bordeaux, France. nathalie280906@gmail.com
Nathalie
N
Damon-Perriere
Patrice
P
Menegon
Anne
A
Olivier
Odile
O
Boespflug-Tanguy
Florence
F
Niel
Isabelle
I
Creveaux
Vincent
V
Dousset
Bruno
B
Brochet
Cyril
C
Goizet
D000328:Adult; D001259:Ataxia / Q000235:genetics / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics / Q000473:pathology*; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics*; D005192:Family Health; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D008279:Magnetic Resonance Imaging; D009154:Mutation; D010641:Phenotype
D020717:Eukaryotic Initiation Factor-2B