Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation.

Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process.

Reduced skin thickness: a new minor diagnostic criterion for the classical and hypermobility types of Ehlers-Danlos syndrome.

BACKGROUND: The diagnosis of Ehlers-Danlos syndrome (EDS) is mainly based on clinical criteria, although in some instances a sound molecular diagnosis is available. Clinical signs can be divided into two categories: one with high diagnostic specificity and the other with low specificity. Despite the fact that reduced skin thickness is one of the dermatological features in patients with EDS, this issue has not been analysed in greater detail. OBJECTIVES: To determine skin thickness in patients with the classical and the hypermobility types of EDS. METHODS: In 21 patients with classical type of EDS and in nine patients with hypermobility type of EDS, skin thickness was analysed at different body sites by cross-sectional b-mode scans obtained with a 20-MHz ultrasound system. RESULTS: We found a significant decrease in skin thickness in both types of EDS, which was highest at the chest and at the distal part of the lower leg. CONCLUSIONS: We propose that the reduced thickness of the dermis as determined by high-resolution 20-MHz ultrasound can be used as a new minor criterion in the diagnosis of the classical and the hypermobility types of EDS.

Familial coexistence of primary antiphospholipid syndrome and factor VLeiden.

The antiphospholipid syndrome (APS) is an autoimmune thrombophilic disorder in which thromboembolism and thrombocytopenia occur. The antiphospholipid antibodies in these patients may cause acquired activated protein C resistance, whereas hereditary activated protein C resistance results from a common single point mutation in coagulation factor V (factor VLeiden). In a family of 11 members with 4 normal subjects, autoimmune thrombocytopenia was documented in 6 patients. Three out of these were found to have thrombocytopenia associated with primary APS. In addition, these 3 subjects were also heterozygous for the factor VLeiden. Only in this group of individuals did life threatening thromboembolic complications occur, while other thrombocytopenic family members showed no thrombotic manifestations. Genetic studies revealed no linkage between APS and HLA class II alleles. Taken together, we present a family with autoimmune thrombocytopenia, which is associated with primary APS in at least 50% of thrombocytopenic individuals. The coexistence of both APS and factor VLeiden in thrombocytopenic subjects, led to an increased number of thrombotic events, suggesting a critical role of combined acquired and hereditary activated protein C resistance in the development of thrombosis in this family. Since no association between APS and specific HLA groups was found, other underlying risk factors for the development of APS must be considered.