Two affected boys in a Rett syndrome family: clinical and molecular findings.

The authors report a family in which two boys had severe neonatal encephalopathy of unknown origin. They both presented with the same condition and died of severe apnea before they were 1 year old. Their sister has a classic form of Rett syndrome. Because mutations in the methyl-CpG-binding protein 2 (MECP2) gene have been identified in 70 to 80% of the sporadic cases of Rett syndrome, the authors looked for a mutation in the MECP2 gene in this family. The authors identified a missense mutation (T158M) in the affected girl and subsequently showed that one of her affected brothers, for whom DNA was available, carried the same mutation. The mother of the patients is a carrier of the T158M mutation. X-chromosome inactivation studies showed that the mother has a completely skewed X-chromosome inactivation pattern that favors the expression of the normal allele; this explains why she does not exhibit any phenotypic manifestation. In addition, the MECP2 mutation appeared on the grandpaternal X chromosome in this family. An MECP2 mutation can be identified in boys, even though they do not present a Rett syndrome phenotype.