Early infantile onset ''congenital'' Rett syndrome variants: Swedish experience through four decades and mutation analysis.

The early infantile onset ''congenital'' variant of Rett syndrome presents with deviations of behavior from very early infancy. Here, we report on a clinical-genetic study in a collected series of 14 Swedish girls with early infantile onset Rett syndrome phenotype. The clinical diagnosis was based on symptom onset before the age of 6 months and the patients fulfilled 3 or more Rett variant criteria and 5 or more supportive criteria. Genotype-phenotype correlation studies in the CDKL5-gene have recently shown clinical associations to early infantile onset Rett variants. Mutation analyses for both the MECP2-gene and the CDKL5-gene were, therefore, performed. Of interest, we found a large deletion covering 2 exons in MECP2, which underlines the importance of MECP2 mutation screening even for the ''atypical'' early infantile onset variants of Rett syndrome. No early infantile onset Rett syndrome patients in this study had the previously well-known hotspot mutations in the MECP2-gene.

Rett syndrome: long-term clinical follow-up experiences over four decades.

Long-term clinical profiles of female patients with classic Rett syndrome are presented and exemplified by three cases, as experienced over four decades. Emphasized is the frequently surprisingly well-preserved eye contact and primitive memory, in contrast to a premature neuromuscular aging and often advanced peripheral atrophy, usually combined with dystonic-rigid signs that are predominantly right sided.

MECP2 abnormality phenotypes: clinicopathologic area with broad variability.

Rett syndrome is a neurodevelopmental disorder that occurs worldwide and predominantly affects girls. The MECP2 gene has been put forward as the underlying gene. Interestingly, other clinical presentations in addition to Rett syndrome have been reported to be the results of deviations in MECP2. This prompted us to outline a working hypothesis of how these diverse phenotypes are connected. Our aim was to summarize the clinical picture of deviations in MECP2 at this moment to obtain a comprehensive overview. Thus, we have attempted to create a gradient, starting at the left with the most severely affected MECP2-deviant subgroups, represented by boys who are diseased in the intrauterine phase or as neonates, and at the right, the most mildly affected subgroup, female asymptomatic carriers. In the center, with dominant numbers, we have placed classic Rett syndrome presentations, together with the late-onset Rett syndrome variant and preserved speech variant. In conclusion, we feel that it is important to emphasize that Rett syndrome is a strictly clinical diagnosis that is not identical to the far broader concept of MECP2 deviations.

Odd MECP2-mutated Rett variant-long-term follow-up profile to age 25.

A 25-year-old MECP2-mutated female with odd developmental and dyspraxic/ataxic features, followed up through two decades, is reported. She does not fit either the classical Rett syndrome or the criteria required for any Rett variant phenotypes so far described. Nevertheless, she belongs clinically to the latter group. This case deserves attention in order, among other things, to provide important clues to better understand the puzzling battery of neuroimpairments and behavioural abnormalities met in classical Rett phenotypes and Rett variants defined thus far.

Multiplex ligation-dependent probe amplification (MLPA) detects large deletions in the MECP2 gene of Swedish Rett syndrome patients.

Mutations in the methyl-CpG-binding protein-2 (MECP2) gene on Xq28 have been found to be a cause of Rett syndrome (RS). In a previous mutation screening, we found MECP2 mutations in 81% of Swedish classical Rett women. In this study, we have analyzed 22 patients for MECP2 deletions using multiplex-ligation-dependent probe amplification (MLPA). Clinically, 11 of the patients who were classical Rett women, 3 were forme fruste, 1 was congenital RS, and 7 were Rett variants. As inclusion criteria, we used DNA from patients in whom previous sequencing results showed no mutations in coding portions of the MECP2 gene. MLPA is a method based on multiplex PCR. In one PCR, as many as 40 probes are amplified with the same primers. The specificity of the amplification products is determined by the site-specific hybridization of each probe construct, prior to amplification. Each PCR product has a unique length, which makes it possible to identify it by size separation. In 3 of 11 (27%) classical Rett women, we detected large deletions in MECP2 using MLPA. All these patients had deletions covering two exons; in 2 cases the deletion involved exons 3 and 4 and, in one case, exons 1 and 2 were missing. In the forme fruste, congenital and Rett-variant patients, we found no large deletions. We have found that MLPA is useful when it comes to finding large deletions compromising whole exons in MECP2. Used as a complementary method to DNA sequencing, it revealed new MECP2 mutations in classical RS patients.

Clinical manifestations and stages of Rett syndrome.

The presentation and clinical diagnosis of Rett syndrome at various ages and stages are reviewed. In addition to the classical form, variability in phenotype between different atypical Rett forms is given. Obligatory, supportive, and differential diagnostic criteria are summarized. Long-term follow-up findings in ageing Rett women are addressed.

Subtelomeric rearrangements detected in patients with idiopathic mental retardation.

A screening for submicroscopic rearrangements was performed in 111 patients with idiopathic mental retardation (MR) using fluorescence in situ hybridization (FISH) probes from the subtelomeric regions of all chromosome arms. Ten cryptic rearrangements were found (9%): five de novo deletions; one unbalanced de novo translocation; three unbalanced inherited translocations; and one unbalanced recombinant chromosome, inherited from a parent with a pericentric inversion. In addition, 50 of the patients were screened for interstitial rearrangements with spectral karyotyping (SKY), but no aberrations were found. However, SKY detected the subtelomeric rearrangement in three of the four unbalanced translocations. Dysmorphic features were present in all patients with detected subtelomeric rearrangements.