Article

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

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Human Mutation (Impact Factor: 5.05). 01/2008; 29(1):150-8. DOI: 10.1002/humu.20623
Source: PubMed

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.

Download full-text

Full-text

Available from: Bert Callewaert, Jul 05, 2015
0 Followers
 · 
352 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Age-related morphological changes of the aorta, including dilatation and elongation, have been reported. However, rotation has not been fully investigated. We focused on the rotation of the ascending aorta and investigated its relationship with tortuosity. One hundred and two consecutive patients who underwent computed tomography coronary angiography were studied. The angle at which the en face view of the volume-rendered image of the right coronary aortic sinus (RCS) was obtained without foreshortening was defined as the rotation index. It was defined as zero if the RCS was squarely visible in the frontal view, positive if it rotated clockwise toward the left anterior oblique (LAO) direction, and negative if it rotated counter-clockwise toward the right anterior oblique (RAO) direction. The tortuosity was evaluated by measuring the biplane tilt angles formed between the ascending aorta and the horizontal line. The mean rotation index, posterior tilt angle viewed from the RAO direction (αRAO), and anterior tilt angle viewed from the LAO direction (αLAO) were 4.8 ± 16.3, 60.7 ± 7.0°, and 63.6 ± 9.0°, respectively. Although no correlation was observed between the rotation index and the αLAO (β = −0.0761, P = 0.1651), there was a significant negative correlation between the rotation index and αRAO (β = −0.1810, P < 0.0001). In multivariate regression analysis, the rotation index was an independent predictor of the αRAO (β = −0.1274, P = 0.0008). Clockwise rotation of the proximal ascending aorta exacerbates the tortuosity by tilting the aorta toward the posterior direction. Clin. Anat., 2014. © 2014 Wiley Periodicals, Inc.
    Clinical Anatomy 11/2014; 27(8). DOI:10.1002/ca.22452 · 1.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.
    Human Mutation 01/2013; 34(1). DOI:10.1002/humu.22165 · 5.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder, mainly characterized by tortuosity and elongation of the large- and medium-sized arteries with predisposition to stenoses and aneurysms. ATS is caused by mutations in the SLC2A10 gene, encoding for the facilitative glucose transporter 10 (GLUT10) and is described typically in pediatric patients. We report on a 51-year-old woman, originally ascertained because of unexplained widespread chronic pain and positive family history of aortic malformation. The main findings included aged appearance, congenital joint hypermobility, joint instability complications, chronic fatigue syndrome, progressive painful joint stiffness, abdominal hernias, pelvic prolapses, multiple cardiac valve prolapses, varicose veins, easy bruising, and gingival recession. Vascular imaging revealed kinking and anomalous origin of the aortic arch branches, marked tortuosity of the aorta, pulmonary and most middle arteries, and a small aneurysm of the splenic artery. SLC2A10 analysis disclosed homozygosity for the novel c.1411+1G>A splice mutation, leading to a 41 amino acids GLUT10 internal deletion. Expression study by immunofluorescence using healthy control cells showed lack of membrane internalization of GLUT10 in patient's skin fibroblasts. This report describes the first splice-site SLC2A10 mutation and increases to 19 the repertoire of known mutations in this gene. Comparison with the few previously published adult patients with ATS contributes to the natural history of this condition, which is probably under diagnosed within the expanding family of inherited connective tissue disorders.
    American Journal of Medical Genetics Part A 05/2012; 158A(5):1164-9. DOI:10.1002/ajmg.a.35266 · 2.05 Impact Factor