Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.

␤-Cell transcription factor genes are important in the pathophysiology of the ␤-cell, with mutations in hepatocyte nuclear factor (HNF)-1␣, HNF-4␣, insulin promoter factor (IPF)-1, HNF-1␤, and NeuroD1/BETA2, all resulting in early-onset type 2 diabetes. We assessed the relative contribution of these genes to early-onset type 2 diabetes using linkage and sequencing analysis in a cohort of 101 families (95% U.K. Caucasian). The relative distribution of the 90 families fitting maturityonset diabetes of the young (MODY) criteria was 63% HNF-1␣, 2% HNF-4␣, 0% IPF-1, 1% HNF-1␤, 0% NeuroD1/ BETA2, and 20% glucokinase. We report the molecular genetic and clinical characteristics of these patients T ranscription factor genes play a crucial role in the normal development and function of the ␤-cell (1). This is highlighted by the identification of mutations in ␤-cell transcription factors as a cause of early-onset type 2 diabetes-most notably the distinct subtype maturity-onset diabetes of the young (MODY). MODY is characterized by an autosomal dominant mode of inheritance, ␤-cell dysfunction, and a young age of diagnosis (usually before 25 years) (2). Mutations in the transcription factors hepatocyte nuclear factor (HNF)-1␣ (3), HNF-4␣ (4), insulin promoter factor (IPF)-1 (5), HNF-1␤ (6), and NeuroD1 (7) all cause early-onset diabetes. These genes form crucial links in the cascade of transcription factors that control the appropriate expression of ␤-cell genes, such as insulin and GLUT2 (1,8,9).Mutations in different transcription factor genes appear to result in different clinical presentations. HNF-1␣ mutations are highly penetrant, with 63% of mutation carriers having diabetes by the age of 25 years, 78.6% by 35 years, and 95.5% by 55 years (10). Mutations in HNF-1␣ result in progressive ␤-cell dysfunction with increasing treatment requirements and greater risk of complications with age (11,12). Mutations in HNF-4␣ result in a similar progressive deterioration of ␤-cell function but appear to be associated with a later age of diagnosis (13-16). The predominant feature of patients with HNF-1␤ mutations appears to be renal dysfunction, which is often diagnosed before diabetes (6,(17)(18)(19). Mutations in IPF-1 (PDX-1) are not a common cause of MODY (20)(21)(22). Only one MODY family published to date has an IPF-1 mutation that clearly cosegregates with diabetes (5), although the average age at diagnosis in this family (35 years) was somewhat older than that in families with HNF mutations. The mutation in this family (P63fsdelC) had a severe dominant-negative effect in vitro (23). Two recent studies suggest that missense mutations in the coding region of the IPF-1 gene are more likely to represent predisposing alleles in more common forms of type 2 diabetes (24,25) rather than highly penetrant disease-causing alleles. Mutations in the NeuroD1/BETA2 gene have recently been reported as being associated with type 2 diabetes in two families, one of which meets MODY criteria (7). Studies of the HNF-3␤ (26-28) and NkX2.2 (29) ...

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The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting.

Mutations in the CDKL5 gene (also known as STK9) have recently been shown to cause early onset epilepsy and severe mental retardation (ISSX or West syndrome). Patients with CDKL5 mutations sometimes also show features similar to those seen in Rett Syndrome (RTT). We have screened the CDKL5 gene in 94 patients with RTT or a RTT-like phenotype who had tested negative for MECP2 mutations (13 classical RTT female subjects, 25 atypical RTT female subjects, 40 RTT-like female and 16 RTT-like male subjects; 33 of the patients had early onset seizures). Novel pathogenic CDKL5 mutations were identified in three girls, two of whom had initially been diagnosed with the early onset seizure variant of RTT and the other with early onset seizures and some features of RTT. In addition, the 33 patients with early seizures were screened for the most common mutations in the ARX gene but none were found. Combining our three new cases with the previously published cases, 13/14 patients with CDKL5 mutations presented with seizures before the age of 3 months.