Callewaert, B. L. et al. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum. Mutat. 29, 150-158

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Human Mutation (Impact Factor: 5.14). 01/2008; 29(1):150-8. DOI: 10.1002/humu.20623
Source: PubMed


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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    • "The wall characteristics (Apter et al., 1966; Lakatta, 2003; Patel and Deeb, 2008) and genetic factors (Callewaert et al., 2008; Allaire et al., 2009) also have associations with aortic remodeling. The consequent structural change of the aorta could adversely affect shear stress and wall tension, which could further exacerbate aortic remodeling and trigger the development of aortic diseases (Dobrin et al., 1988; Wenn and Newman, 1990; Callewaert et al., 2008; Poullis et al., 2008). Continuous investigations of the age-related aortic remodeling and its additional impact on aortic diseases are important. "
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    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 · 1.33 Impact Factor
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    • "This contrasts with FBLN4-deficient cutis laxa where vascular complications can severely reduce life expectancy and skin features are often less pronounced [Dasouki et al., 2007; Renard et al., 2010]. Also, in the cardiovascular system, both LTBP4-and FBLN5-deficient patients may present with peripheral pulmonary artery stenosis, a nonspecific feature that also occurs in related entities as FBLN4 deficiency and arterial tortuosity syndrome [Callewaert et al., 2008; Renard et al., 2010]. Supravalvular aortic stenosis has been reported in FBLN5 deficiency [Elahi et al., 2006; "
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    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 · 5.14 Impact Factor
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    • "It has been shown that perturbations in the TGF beta pathway contribute to the pathogenesis of some of the above-mentioned disorders. Despite the dramatic vascular phenotype and associated morbidities [3-6] ATS and LDS are reported to have a natural history permitting survival of several patients to adulthood [2,5-7]. ARCL Type I is characterized by cutis laxa, pulmonary emphysema, umbilical and inguinal hernias and gastrointestinal and vesico-urinary tract diverticuli, described in association with mutations of fibulin-5 [8] [GenBank:BC022280.1] and fibulin-4 [9] [GenBank:AF109121.1]. "
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    ABSTRACT: Background: Vascular elasticity is crucial for maintaining hemodynamics. Molecular mechanisms involved in human elastogenesis are incompletely understood. We describe a syndrome of lethal arteriopathy associated with a novel, identical mutation in the fibulin 4 gene (FBLN4) in a unique cohort of infants from South India. Methods: Clinical characteristics, cardiovascular findings, outcomes and molecular genetics of twenty-two infants from a distinct population subgroup, presenting with characteristic arterial dilatation and tortuosity during the period August 2004 to June 2011 were studied. Results: Patients (11 males, 11 females) presented at median age of 1.5 months, belonging to unrelated families from identical ethno-geographical background; eight had a history of consanguinity. Cardiovascular features included aneurysmal dilatation, elongation, tortuosity and narrowing of the aorta, pulmonary artery and their branches. The phenotype included a variable combination of cutis laxa (52%), long philtrum-thin vermillion (90%), micrognathia (43%), hypertelorism (57%), prominent eyes (43%), sagging cheeks (43%), long slender digits (48%), and visible arterial pulsations (38%). Genetic studies revealed an identical c.608A > C (p. Asp203Ala) mutation in exon 7 of the FBLN4 gene in all 22 patients, homozygous in 21, and compound heterozygous in one patient with a p. Arg227Cys mutation in the same conserved cbEGF sequence. Homozygosity was lethal (17/21 died, median age 4 months). Isthmic hypoplasia (n = 9) correlated with early death (≤4 months). Conclusions: A lethal, genetic disorder characterized by severe deformation of elastic arteries, was linked to novel mutations in the FBLN4 gene. While describing a hitherto unreported syndrome in this population subgroup, this study emphasizes the critical role of fibulin-4 in human elastogenesis.
    Orphanet Journal of Rare Diseases 09/2012; 7(1):61. DOI:10.1186/1750-1172-7-61 · 3.36 Impact Factor
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