Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families

Abstract

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.

Clinical utility gene card for: Arterial tortuosity syndrome

“…This can be completed if needed by a semi-quantitative technique seeking for partial or complete deletions of the gene, as described. 1 As this disorder is recessive and frequently caused by homozygous mutations, denaturation-based screening techniques can be performed on equimolar mixtures of patient and control DNA.…”

“…In classical cases, clinical diagnosis can be strongly suggested by combining family history, physical examination, echocardiography and arterial imaging like angioMRI or CT. 1 Patients are often born from consanguineous marriages. They generally present at birth with facial dysmorphism including beaked nose, blepharophimosis, hypertelorism, downslanting palpebral fissures and a small mouth with retrognathism.…”

“…Inguinal hernias are frequent, but diaphragmatic hernias rarely occur. 1,6 Infants with ATS may develop dyspnoea revealing pulmonary hypertension, due to stenoses of the pulmonary arteries or branches, which can be confirmed by cardiovascular imaging (ultrasound, catheterisation, angioCT or angioMRI) showing truncal or branch stenosis of the pulmonary arteries followed by a dilated segment.…”

Update on the Diagnosis and Management of Inherited Aortopathies, Including Marfan Syndrome

“…A number of other genetic syndromes have been reported in association with aortic disease, including but not limited to: Weill-Marchesani syndrome (ADAMTS10 and FBN1) [13]; congenital contractural arachnodactyly (resembles MFS, is characterised by crumpled ears, scoliosis, joint contractures and FBN2 mutations) [14]; Noonan syndrome (mutations in the RAS-MAPK signalling pathway) [15,16]; Alagille syndrome (JAG1) [17] ; X-linked dominant periventricular nodular heteropia, EDS variant (FLNA) [18] and Shprintzen-Goldberg syndrome (SK1) [19].…”

Characterization and expression pattern analysis of the facilitative glucose transporter 10 gene (slc2a10) in Danio rerio

“…Loss-of-function mutations in the SLC2A10 gene lead to arterial tortuosity syndrome (ATS) (OMIM #208050) (Coucke et al, 2006;Drera et al, 2007, Callewaert et al, 2008a, Faiyaz-UlHaque et al, 2009Zaidi et al, 2009;Ritelli et al, 2009), a rare autosomal recessive connective tissue disorder characterized by tortuosity and elongation of the large and medium sized arteries, a propensity for aneurysm formation, vascular dissection, and pulmonary artery stenosis. Two mouse models for ATS were proposed, but they did not fully mimic the human syndrome, and the reported phenotypes of these mice remain inconclusive with respect to GLUT10 function (Callewaert et al, 2008b, Cheng et al, 2009.…”