Epilepsy as the first presentation of arterial tortuosity syndrome in a young girl: a case report.
ABSTRACT: Arterial tortuosity syndrome (ATS) is an extremely rare autosomal recessive connective tissue disorder characterized by tortuosity and elongation of all major arteries. We report a clinical case of a girl with this rare condition, who initially presented with epilepsy. DSA or MRA revealed a severe arterial tortuosity. EEG showed epileptiform discharge in right frontotemporal hemisphere. Here, we report the first case of ATS presenting with epilepsy. We discussed the possible clinical implications of this rare clinical presentation. Moreover, we suggest that some patients presenting with epilepsy might need serious cerebral vascular evaluation and ATS needs to be considered in the differential diagnosis.
Project description:Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder caused by mutations in the solute carrier family 2 member 10 (SLC2A10) gene encoding a glucose/ascorbic acid transporter. The clinical features of ATS are mild-to-severe tortuosity of the large and medium arteries throughout the body, accompanied by dysmorphisms and joint laxity. Vascular changes in different parts of the body lead to stenosis and/or aneurysms requiring difficult surgical procedures. Here we present two new patients with ATS from two unrelated families. Patient 1 presented at 10 years of age with headache and typical physical appearance, delicate skeleton, large visible pulsation of the carotid arteries in the neck, and joint laxity. On computed tomography (CT) angiography she had severe tortuosity of the aortal branches and cerebral arteries, but no significant tortuosity of the pulmonary arteries. Two cousins of the girl carried the same homozygous c.254T>C, p.(Leu85Pro) mutation in SLC2A10, however, they additionally had a severe involvement of the pulmonary vessels. Patient 2 was a 9-year-old girl diagnosed with severe tortuosity and stenosis of the pulmonary arteries and progressive myocardiopathy. Her physical appearance was very similar to Patient 1, except that she also had growth retardation. After long-term follow-up by cardiologists, she underwent cardiac surgery abroad, with an unfavorable outcome. Homozygosity for the c.685C>T, p.(Arg229*) mutation in the SLC2A10 gene was detected. Consanguinity was disclosed within both families. Our findings confirm the intrafamilial phenotype variability of ATS. A novel finding is the severe tortuosity of cerebral arteries causing migraine that has not been described before in a child with ATS.
Project description:BACKGROUND: Arterial tortuosity syndrome (ATS) (OMIM #208050) is a rare autosomal recessive connective tissue disorder characterized by tortuosity and elongation of the large and medium-sized arteries, propensity to aneurysms formation, vascular dissection, and pulmonary arteries stenosis. ATS is caused by mutations in SLC2A10 gene, encoding for the facilitative glucose transporter 10 (GLUT10). So far, 17 SLC2A10 mutations have been reported in 32 families, two of which were Italian with a total of five patients. Here we present the clinical and molecular characterization of two novel Italian paediatric ATS patients. METHODS: The exons and intronic flanking regions of SLC2A10 gene were amplified and direct sequencing was performed. RESULTS: In both patients, the involvement of major- and medium-sized arteries was characteristic; the nonvascular connective tissue manifestations were mild and not pathognomic of the disorder. Both patients, born from non-consanguineous parents, were heterozygous for two different SLC2A10 mutations, three of which were recurrent and one was novel (p.Arg231Trp). This mutation is localized at the endofacial loop between the transmembrane domains 6 and 7 of GLUT10. CONCLUSION: Two novel ATS patients were characterized at clinical and molecular level. Overall, four ATS unrelated families are known in Italy so far. Though ATS clinical delineation improved in the last years, further works in the comprehension of disease presentation and complications onset, particularly in paediatric age, and on ATS molecular basis are needed to add new insights for diagnosis and prevention strategies for related complications.
Project description:Arterial Tortuosity Syndrome (ATS) is a very rare autosomal recessive connective tissue disorder (CTD) characterized by tortuosity and elongation of the large- and medium-sized arteries and a propensity for aneurysm formation and vascular dissection. During infancy, children frequently present the involvement of the pulmonary arteries (elongation, tortuosity, stenosis) with dyspnea and cyanosis. Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint hypermobility, skeletal abnormalities, and keratoconus. ATS is typically described as a severe disease with high rate of mortality due to major cardiovascular malformations. ATS is caused by mutations in the SLC2A10 gene, which encodes the facilitative glucose transporter 10 (GLUT10). Approximately 100 ATS patients have been described, and 21 causal mutations have been identified in the SLC2A10 gene.We describe the clinical findings and molecular characterization of three new ATS families, which provide insight into the clinical phenotype of the disorder; furthermore, we expand the allelic repertoire of SLC2A10 by identifying two novel mutations. We also review the ATS patients characterized by our group and compare their clinical findings with previous data.Our data confirm that the cardiovascular prognosis in ATS is less severe than previously reported and that the first years of life are the most critical for possible life-threatening events. Molecular diagnosis is mandatory to distinguish ATS from other CTDs and to define targeted clinical follow-up and timely cardiovascular surgical or interventional treatment, when needed.
Project description:GLUT10 belongs to a family of transporters that catalyze the uptake of sugars/polyols by facilitated diffusion. Loss-of-function mutations in the SLC2A10 gene encoding GLUT10 are responsible for arterial tortuosity syndrome (ATS). Since subcellular distribution of the transporter is dubious, we aimed to clarify the localization of GLUT10. In silico GLUT10 localization prediction suggested its presence in the endoplasmic reticulum (ER). Immunoblotting showed the presence of GLUT10 protein in the microsomal, but not in mitochondrial fractions of human fibroblasts and liver tissue. An even cytosolic distribution with an intense perinuclear decoration of GLUT10 was demonstrated by immunofluorescence in human fibroblasts, whilst mitochondrial markers revealed a fully different decoration pattern. GLUT10 decoration was fully absent in fibroblasts from three ATS patients. Expression of exogenous, tagged GLUT10 in fibroblasts from an ATS patient revealed a strict co-localization with the ER marker protein disulfide isomerase (PDI). The results demonstrate that GLUT10 is present in the ER.
Project description:Ascorbate requiring Fe2+/2-oxoglutarate-dependent dioxygenases located in the nucleoplasm have been shown to participate in epigenetic regulation of gene expression via histone and DNA demethylation. Transport of dehydroascorbic acid is impaired in the endomembranes of fibroblasts from arterial tortuosity syndrome (ATS) patients, due to the mutation in the gene coding for glucose transporter GLUT10. We hypothesized that altered nuclear ascorbate concentration might be present in ATS fibroblasts, affecting dioxygenase activity and DNA demethylation. Therefore, our aim was to characterize the subcellular distribution of vitamin C, the global and site-specific changes in 5-methylcytosine and 5-hydroxymethylcytosine levels, and the effect of ascorbate supplementation in control and ATS fibroblast cultures. Diminished nuclear accumulation of ascorbate was found in ATS fibroblasts upon ascorbate or dehydroascorbic acid addition. Analyzing DNA samples of cultured fibroblasts from controls and ATS patients, a lower global 5-hydroxymethylcytosine level was found in ATS fibroblasts, which could not be significantly modified by ascorbate addition. Investigation of the (hydroxy)methylation status of specific regions in six candidate genes related to ascorbate metabolism and function showed that ascorbate addition could stimulate hydroxymethylation and active DNA demethylation at the PPAR-? gene region in control fibroblasts only. The altered DNA hydroxymethylation patterns in patient cells both at the global level and at specific gene regions accompanied with decreased nuclear accumulation of ascorbate suggests the epigenetic role of vitamin C in the pathomechanism of ATS. The present findings represent the first example for the role of vitamin C transport in epigenetic regulation suggesting that ATS is a compartmentalization disease.
Project description:Arterial tortuosity manifests in many conditions, including hypertension, genetic mutations predisposing to thoracic aortopathy, and vascular aging. Despite evidence that tortuosity disrupts efficient blood flow and that it may be an important clinical biomarker, underlying mechanisms remain poorly understood but are widely appreciated to be largely biomechanical. Many previous studies suggested that tortuosity may arise via an elastic structural buckling instability, but the novel experimental-computational approach used here suggests that tortuosity arises from mechanosensitive, cell-mediated responses to local aberrations in the microstructural integrity of the arterial wall. In particular, computations informed by multimodality imaging show that aberrations in elastic fiber integrity, collagen alignment, and collagen turnover can lead to a progressive loss of structural stability that entrenches during the development of tortuosity. Interpreted in this way, microstructural defects or irregularities of the arterial wall initiate the condition and hypertension is a confounding factor.
Project description:Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder caused by loss-of-function mutations in SLC2A10, which encodes facilitative glucose transporter 10 (GLUT10). The role of GLUT10 in ATS pathogenesis remains an enigma, and the transported metabolite(s), i.e. glucose and/or dehydroascorbic acid, have not been clearly elucidated. To discern the molecular mechanisms underlying the ATS aetiology, we performed gene expression profiling and biochemical studies on skin fibroblasts. Transcriptome analyses revealed the dysregulation of several genes involved in TGF? signalling and extracellular matrix (ECM) homeostasis as well as the perturbation of specific pathways that control both the cell energy balance and the oxidative stress response. Biochemical and functional studies showed a marked increase in ROS-induced lipid peroxidation sustained by altered PPAR? function, which contributes to the redox imbalance and the compensatory antioxidant activity of ALDH1A1. ATS fibroblasts also showed activation of a non-canonical TGF? signalling due to TGFBRI disorganization, the upregulation of TGFBRII and connective tissue growth factor, and the activation of the ?v?3 integrin transduction pathway, which involves p125FAK, p60Src and p38 MAPK. Stable GLUT10 expression in patients' fibroblasts normalized redox homeostasis and PPAR? activity, rescued canonical TGF? signalling and induced partial ECM re-organization. These data add new insights into the ATS dysregulated biological pathways and definition of the pathomechanisms involved in this disorder.
Project description:BACKGROUND:Clinical evidence suggests that the currently recommended approach to estimate the risk of aortic dissection in Marfan syndrome (MFS) is not reliable enough. Therefore, we investigated the possible role of visceral arterial tortuosity in the risk stratification. METHODS AND RESULTS:Splenic and renal arteries of 37 MFS patients and 74 age and gender matched control subjects were segmented using CT angiography imaging. To measure tortuosity, distance metric (DM), sum of angles metric (SOAM), inflection count metric (ICM), and the ratio of ICM and SOAM (ICM/SOAM) were calculated. DM of the splenic, right and left renal artery was significantly higher in MFS patients than in controls (2.44 [1.92-2.80] vs. 1.75 [1.57-2.18] p?<?0.001; 1.16 [1.10-1.28] vs. 1.11 [1.07-1.15] p?=?0.011; 1.40 [1.29-1.70] vs. 1.13 [1.09-1.23] p <?0.001, respectively). A similar tendency for ICM and an opposite tendency for SOAM were observed. ICM/SOAM was significantly higher in the MFS group compared to controls in case of all three arteries (73.35 [62.26-93.63] vs. 50.91 [43.19-65.62] p?< 0.001; 26.52 [20.69-30.24] vs. 19.95 [16.47-22.95] p?<?0.001; 22.81 [18.64-30.96] vs. 18.38 [15.29-21.46] p?<?0.001, respectively). MFS patients who underwent aortic root replacement had increased right and left renal DM and ICM/SOAM compared to MFS patients without surgery. CONCLUSION:To our knowledge this is the first demonstration of increased arterial tortuosity in MFS on visceral arteries. Visceral arterial tortuosity, dominated by curves of lower frequency but higher amplitude according to the observed opposite tendency between the DM and SOAM metrics, could be a possible new predictor of serious manifestations of MFS.
Project description:BACKGROUND/PURPOSE:The purpose of this study was to evaluate the utility and efficacy of combined low-dose, time-resolved (TR) and single-phase high-resolution (HR) contrast-enhanced MRA (CE-MRA) as a pre-angiographic study for spinal vascular disease. MATERIALS AND METHODS:Seventeen consecutive patients with suspected spinal vascular disease were retrospectively reviewed. All patients underwent combined low-dose TR CE-MRA and three-dimensional single-phase HR CE-MRA at 3 Tesla, followed by conventional spinal digital subtraction angiography (DSA) within 90 days. Six patients underwent additional spinal MRA and DSA for treatment follow-up. Spinal lesions were analyzed in terms of presence, disease type, laterality, spinal level, and number of arterial feeders. RESULTS:Low-dose TR CE-MRA helped proper localization of subsequent HR CE-MRA in two patients with high or low level of the lesion. For initial detection of spinal vascular disease, sensitivity, specificity and accuracy of CE-MRA were 93.3% (n = 14/15), 100% (n = 3/3), and 94.4% (n = 17/18), respectively. In characterization of dural arteriovenous fistula (AVF), perimedullary AVF, spinal cord arteriovenous malformation (AVM), and extraspinal AVM, CE-MRA correctly characterized in 86.7% (n = 13/15) among the positive findings, and in 88.9% (n = 16/18) among the several patients including negative results. CE-MRA showed matched per-case localization of arterial feeders within 1 vertebral level in 80% (n = 12/15), and matched per-lesion localization in 78.3% (n = 18/23). CONCLUSION:Combined low-dose TR CE-MRA and single-phase HR CE-MRA at 3 Tesla was an effective and accurate non-invasive tool for the pre-angiographic evaluation of spinal vascular diseases in a single session.
Project description:Pulmonary hypertension (PH) can result in vascular pruning and increased tortuosity of the blood vessels. In this study we examined whether automatic extraction of lung vessels from contrast-enhanced thoracic computed tomography (CT) scans and calculation of tortuosity as well as 3D fractal dimension of the segmented lung vessels results in measures associated with PH. In this pilot study, 24 patients (18 with and 6 without PH) were examined with thorax CT following their diagnostic or follow-up right-sided heart catheterisation (RHC). Images of the whole thorax were acquired with a 128-slice dual-energy CT scanner. After lung identification, a vessel enhancement filter was used to estimate the lung vessel centerlines. From these, the vascular trees were generated. For each vessel segment the tortuosity was calculated using distance metric. Fractal dimension was computed using 3D box counting. Hemodynamic data from RHC was used for correlation analysis. Distance metric, the readout of vessel tortuosity, correlated with mean pulmonary arterial pressure (Spearman correlation coefficient: ? = 0.60) and other relevant parameters, like pulmonary vascular resistance (? = 0.59), arterio-venous difference in oxygen (? = 0.54), arterial (? = -0.54) and venous oxygen saturation (? = -0.68). Moreover, distance metric increased with increase of WHO functional class. In contrast, 3D fractal dimension was only significantly correlated with arterial oxygen saturation (? = 0.47). Automatic detection of the lung vascular tree can provide clinically relevant measures of blood vessel morphology. Non-invasive quantification of pulmonary vessel tortuosity may provide a tool to evaluate the severity of pulmonary hypertension.ClinicalTrials.gov NCT01607489.