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Two affected boys in a Rett syndrome family: clinical and molecular findings
L Villard1, A Kpebe, C Cardoso
1INSERM U491, Faculté de Médecine La Timone, Marseille, France. laurent.villard@medecine.univ-mrs.fr
Insights
A methyl-CpG-binding protein 2 (MECP2) gene mutation caused severe neonatal encephalopathy in two boys. This MECP2 mutation was also found in their sister with Rett syndrome, highlighting its role in male neurodevelopmental disorders.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Two boys presented with severe neonatal encephalopathy and died before age one.
- Their sister exhibited classic Rett syndrome.
- Rett syndrome is often linked to MECP2 gene mutations.
Purpose of the Study:
- Investigate the genetic basis of severe neonatal encephalopathy in a family.
- Determine if MECP2 gene mutations are involved in affected males.
- Analyze the inheritance pattern of the mutation within the family.
Main Methods:
- Genetic sequencing to identify mutations in the MECP2 gene.
- Analysis of DNA from affected siblings and the mother.
- X-chromosome inactivation studies to assess allele expression.
Main Results:
- A missense mutation (T158M) in the MECP2 gene was identified in the affected sister and one affected brother.
- The mother was a carrier of the T158M mutation with skewed X-chromosome inactivation.
- The MECP2 mutation was traced to the grandpaternal X chromosome.
Conclusions:
- MECP2 gene mutations can cause severe neonatal encephalopathy in males.
- The absence of Rett syndrome phenotype in affected males does not exclude MECP2 mutations.
- Understanding MECP2 mutation variants is crucial for diagnosing neurodevelopmental disorders in both sexes.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
An MECP2 mutation can be identified in boys, even though they do not present a Rett syndrome phenotype.
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