Girls with a classic disease course, more moderate symptoms and congenital forms,
severe encephalopathy, retardation of unknown cause in boys,
mother of affected girl with a known mutation.
Rett Syndrome - MECP2
Clinical Features
The Rett syndrome was first described in 1966 and is one of the commonest causes of severe mental retardation in girls. After apparently normal development during the first 6 to 8 months of life developmental stagnation occurs, followed by a rapid regression in language and motor skills. The hallmark of the disease is the loss of purposeful hand use and its replacement by stereotyped hand movements. The developmental abnormality of the CNS leads to microcephaly with severe mental retardation and withdrawal. Ataxia, sleep and respiratory abnormalities may occur. Approx. 1/3 of the affected individuals show epileptic seizures, nearly all patients have typical EEG changes. Age at onset, disease course and the severity of single symptoms may vary considerably between individuals.
Genetic Information
In most cases Rett syndrome is caused by de novo mutations and deletions of the so-called MECP2 (Methyl-CPG-binding protein 2) gene, which is located on the X chromosome (Xq28). In rare cases inheritance is X-linked dominant, i.e. a mutation on one of the two parental X chromosomes leads to Rett syndrome in girls. The phenotype is influenced by the type of mutation and the pattern of X-chromosome inactivation. Females who have a mutation but have favorably skewed X-chromosome inactivation may have mild symptoms or none at all. For a long time, a mutation in males was considered to be associated with intrauterine lethality. More recently, also in males mutations of the MECP2 gene were detected associated with a wide range of highly variable symptoms from mental retardation without the characteristics of Rett syndrome up to severe lethal encephalopathy.
Prevalence
In females approx. 1 : 10 000 to 1 : 15 000, presumably even higher due to the variability of the clinical phenotype. Prevalence among severely retarded girls up to 1 : 4.
Diagnostic
Indication
Method
All exons of the gene as well as the flanking regions are analyzed by DHPLC and, if necessary, subsequent sequencing. Small deletions in exon 4 are detected by fragment length analysis. Deletions of single or several exons are detected by quantitative PCR.
Sample Requirement
2 to 4 ml of EDTA blood
Duration
4 weeks