Elisa Scala

CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms

Background: Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterised by a wide spectrum of clinical manifestations. Both the classic form and preserved speech variant of Rett syndrome are due to mutations in the MECP2 gene. Several other variants of Rett syndrome have been described. In 1985, Hanefeld described a variant with the early appearance of convulsions. In this variant, the normal perinatal period is soon followed by the appearance of seizures, usually infantile spasms. We have observed two patients with signs of Rett syndrome showing acquired microcephaly and stereotypic midline hand movements. The disease started with generalised convulsions and myoclonic fits at 1.5 months in the first patient and with spasms at 10 days in the other, suggesting a diagnosis of the Hanefeld variant. In these patients, MECP2 point mutations and gross rearrangements were excluded by denaturing high performance liquid chromatography and real time quantitative PCR. The ARX and CDKL5 genes have been associated with West syndrome (infantile spasms, hypsarrhythmia, and mental retardation). Methods: Based on the clinical overlap between the Hanefeld variant and West syndrome, we analysed ARX and CDKL5 in the two girls. Results: We found frameshift deletions in CDKL5 in both patients; one in exon 5 (c.163_166delGAAA) and the other in exon 18 (c.2635_2636delCT). CDKL5 was then analysed in 19 classic Rett and 15 preserved speech variant patients, all MECP2 negative, but no mutations were found. Conclusion: Our results show that CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type.

Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant)

The preserved speech variant is the milder form of Rett syndrome: affected girls show the same stages of this condition and by the second half of the first decade are making slow progress in manual and verbal abilities. They walk without help, and may be able to make simple drawings and write a few words. Most of them can speak in sentences. Autistic behavior can often be observed. We previously described several cases in the pre-molecular era and subsequently reported a survey of 12 cases with MECP2 mutations. Seventeen new patients with the preserved speech variant and a proven MECP2 mutation have been clinically evaluated. Additional clinical data of our previously described cases are reported. These 29 preserved speech variant cases were compared with 129 classic Rett patients using a clinical severity score system including 22 different signs. There was both statistical and clinical evidence of the existence of this variant. On the basis of their abilities these girls can be distinguished as low-, intermediate- and high-functioning. Girls of the last two groups show a greater homogeneity: they speak in sentences, use their hands more easily, have normal somatic features, mild neurovegetative abnormalities, with autistic behavior in 76%, epilepsy in 30%, while girls of the first group are closer to classic Rett syndrome. The majority of patients carries either missense mutations (especially the p.R133C change) or late truncating mutations in the MECP2 gene. These results confirm the existence of this variant of Rett syndrome (Zappella variant), a clear example of progress of manual and verbal abilities, and not of a preserved speech and suggest corresponding diagnostic criteria.

MECP2 deletions and genotype–phenotype correlation in Rett syndrome

Rett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. MECP2 point mutations in exons 2–4 account for about 80% of classic Rett cases and for a lower percentage of variant patients. We investigated the genetic cause in 77 mutation‐negative Rett patients (33 classic, 31 variant, and 13 Rett‐like cases) by searching missed MECP2 defects. DHPLC analysis of exon 1 and MLPA analysis allowed us to identify the defect in 17 Rett patients: one exon 1 point mutation (c.47_57del) in a classic case and 16 MECP2 large deletions (15/33 classic and 1/31 variant cases). One identical intragenic MECP2 deletion, probably due to gonadal mosaicism, was found in two sisters with discordant phenotype: one classic and one “highly functioning” preserved speech variant. This result indicates that other epigenetic or genetic factors, beside MECP2, may contribute to phenotype modulation. Three out of 16 MECP2 deletions extend to the adjacent centromeric IRAK1 gene. A putative involvement of the hemizygosity of this gene in the ossification process is discussed. Finally, results reported here clearly indicate that MECP2 large deletions are a common cause of classic Rett, and MLPA analysis is mandatory in MECP2‐negative patients, especially in those more severely affected (Pu2009=u20090.044).