Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disease, characterized by widespread arterial involvement with elongation, tortuosity, and aneurysms of the large and middle-sized arteries. Recently, SLC2A10 mutations were identified in this condition. This gene encodes the glucose transporter GLUT10 and was previously suggested as a candidate gene for diabetes mellitus type 2. A total of 12 newly identified ATS families with 16 affected individuals were clinically and molecularly characterized. In addition, extensive cardiovascular imaging and glucose tolerance tests were performed in both patients and heterozygous carriers. All 16 patients harbor biallelic SLC2A10 mutations of which nine are novel (six missense, three truncating mutations, including a large deletion). Haplotype analysis suggests founder effects for all five recurrent mutations. Remarkably, patients were significantly older than those previously reported in the literature (P=0.04). Only one affected relative died, most likely of an unrelated cause. Although the natural history of ATS in this series was less severe than previously reported, it does indicate a risk for ischemic events. Two patients initially presented with stroke, respectively at age 8 months and 23 years. Tortuosity of the aorta or large arteries was invariably present. Two adult probands (aged 23 and 35 years) had aortic root dilation, seven patients had localized arterial stenoses, and five had long stenotic stretches of the aorta. Heterozygous carriers did not show any vascular anomalies. Glucose metabolism was normal in six patients and eight heterozygous individuals of five families. As such, overt diabetes is not related to SLC2A10 mutations associated with ATS.

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Background Mutations in TRPV4, a gene that encodes a Ca 2+ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. Objectives and methods To examine TRPV4 mutation spectrum and phenotypeÀgenotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. Results TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. Conclusion The TRPV4 mutation spectrum in MD and SMDK, which showed genotypeÀphenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

Background: Pseudoxanthoma elasticum (PXE) is an heritable connective tissue disorder with clinical manifestations of the ocular, dermal, and cardiovascular system. The purpose of this study was to investigate the prevalence of symptomatic intracranial aneurysms (IAs) and ischaemic stroke (IS) in PXE. Methods: The records of 100 patients with PXE were retrieved. All patients were contacted and data on complications were collected. The literature was reviewed regarding PXE, ISs, and IAs. Results: No patient with PXE had a symptomatic IA as presenting symptom. One patient presented with an IS. During follow-up of 94 of the 100 patients (mean follow-up 17.1 years, range 1–49 years), none presented a symptomatic IA (3,168 retrospective patient observation years and 1,602 prospective patient observation years). Upper gastrointestinal haemorrhage during follow-up occurred in 17 patients, in 1 patient during aspirin use. One patient has IS as presenting symptom and a recurrence during follow-up, and 7 patients had IS during follow-up. All were caused by small-vessel disease. The relative risk of IS in PXE under 65 years compared with the general population was 3.6 (95% confidence interval 3.3–4.0). Conclusions: On the basis of the currently available data, an association between symptomatic IAs and PXE is unlikely. However, the incidence of IS, due to small-vessel disease, was increased. Antiplatelet therapy in patients with PXE may lead to a high incidence of upper gastrointestinal haemorrhages.