J Hum Genet.
2013 Jan 31. doi: 10.1038/jhg.2012.152. [Epub ahead of print]
Department of Pediatrics, Peking University First Hospital, Beijing, China.
delineate the phenotype and genotype in Chinese children with type I
Alexander disease (AxD) and the parental origin of de novo glial
fibrillary acidic protein (GFAP) mutations. Twenty-two children with
clinically diagnosed type I AxD were followed up for 1.66-6.62 years.
Allele-specific PCR was used for the analysis of parental origin of the
allele harboring the de novo mutation. Phenotype of these patients were
consistent with type I AxD described in other population, with
developmental delay (motor delay in 81.82%, cognitive delay in 63.64%),
macrocephaly (100%), seizures (95.45%), paroxysmal deterioration
(27.27%) and typical brain magnetic resonance imaging (100%).
Progression was slower than reported. At 8.55 years of age (5.29-13.25),
all patients who underwent the second follow-up were alive. Eleven
heterozygous missense mutations of GFAP were identified in 21 patients,
with three novel mutations. Reported hot spot mutations, p.R79, p.R239
and p.R88, were also identified in Chinese patients. Mutations were de
novo in all but one case. The mother of a proband was demonstrated to be
a presymptomatic patient with type II AxD with a p.R79H mutation.
Ninety percent of de novo mutations were on the paternal allele
demonstrated by allele-specific PCR. This is the largest follow-up study
on Chinese children with AxD. The phenotypes of these patients are
consistent with reports in other populations. GFAP mutations were
identified in 95.46% of Chinese children with clinically diagnosed type I
AxD. Our data suggested a male germ-line transmission.Journal of Human
Genetics advance online publication, 31 January 2013;