Triple-barrelled aortic dissection in Ehlers-Danlos syndrome.
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ABSTRACT:
SUBMITTER: Einstein AJ
PROVIDER: S-EPMC1861105 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AIMS:The vascular type of Ehlers-Danlos syndrome (EDS IV) is an autosomal-dominant disorder characterized by thin translucent skin and extensive bruising. Patients with EDS IV have reduced life expectancy (median 45-50 years) due to spontaneous rupture of arteries (particularly large arteries) or bowel. EDS IV results from mutation of the COL3A1 gene, which encodes the pro-?(1) chains of type III collagen that is secreted into the extracellular matrix, e.g. by smooth muscle cells. A mouse model of EDS IV produced by targeted ablation of Col3a1 has been of limited use as only 10% of homozygous animals survive to adulthood, whereas heterozygous animals do not die from arterial rupture. We report a novel, exploitable model of EDS IV in a spontaneously generated mouse line. METHODS AND RESULTS:Mice were identified by predisposition to sudden, unexpected death from dissection of the thoracic aorta. Aortic dissection inheritance was autosomal-dominant, presented at an early age (median, 6 weeks) with incomplete penetrance, and had a similar sex ratio bias as EDS IV (2:1, male:female). Molecular genetic analysis demonstrated that the causal mutation is a spontaneous 185 kb deletion, including the promoter region and exons 1-39, of the Col3a1 gene. As in EDS IV, aortic dissection was not associated with elevated blood pressure, aneurysm formation, or infection, but may result from aberrant collagen fibrillogenesis within the aortic wall. CONCLUSION:This novel, exploitable mouse line that faithfully models the vascular aspects of human EDS IV provides an important new tool for advancing understanding of EDS IV and of aortic dissection in general.
| S-EPMC3058731 | biostudies-literature
Project description:Ehlers-Danlos syndrome type IV, the vascular type of Ehlers-Danlos syndromes (EDS), is an inherited connective tissue disorder defined by characteristic facial features (acrogeria) in most patients, translucent skin with highly visible subcutaneous vessels on the trunk and lower back, easy bruising, and severe arterial, digestive and uterine complications, which are rarely, if at all, observed in the other forms of EDS. The estimated prevalence for all EDS varies between 1/10,000 and 1/25,000, EDS type IV representing approximately 5 to 10% of cases. The vascular complications may affect all anatomical areas, with a tendency toward arteries of large and medium diameter. Dissections of the vertebral arteries and the carotids in their extra- and intra-cranial segments (carotid-cavernous fistulae) are typical. There is a high risk of recurrent colonic perforations. Pregnancy increases the likelihood of a uterine or vascular rupture. EDS type IV is inherited as an autosomal dominant trait that is caused by mutations in the COL3A1 gene coding for type III procollagen. Diagnosis is based on clinical signs, non-invasive imaging, and the identification of a mutation of the COL3A1 gene. In childhood, coagulation disorders and Silverman's syndrome are the main differential diagnoses; in adulthood, the differential diagnosis includes other Ehlers-Danlos syndromes, Marfan syndrome and Loeys-Dietz syndrome. Prenatal diagnosis can be considered in families where the mutation is known. Choriocentesis or amniocentesis, however, may entail risk for the pregnant woman. In the absence of specific treatment for EDS type IV, medical intervention should be focused on symptomatic treatment and prophylactic measures. Arterial, digestive or uterine complications require immediate hospitalisation, observation in an intensive care unit. Invasive imaging techniques are contraindicated. Conservative approach is usually recommended when caring for a vascular complication in a patient suffering from EDS type IV. Surgery may, however, be required urgently to treat potentially fatal complications.
| S-EPMC1971255 | biostudies-literature
Project description:Pathogenic variants in the lysyl-hydroxylase-1 gene (PLOD1) are responsible for the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS). The disease is classically responsible for severe hypotonia at birth, progressive kyphoscoliosis, generalised joint hypermobility and scleral fragility. Arterial fragility is an important feature of the disease, but its characterisation remains limited. We report the clinical history of a 41-year-old woman who presented repeated arterial accidents, which occurred in previously normal medium size arteries within a limited time span of 2 years. Molecular investigations revealed compound heterozygosity for two PLOD1 gene deletions of exons 11-12 and 14-15. Arterial fragility is an important characteristic of kyphoscoliotic EDS. It manifests as spontaneous arterial rupture, dissections and dissecting aneurysms which may occur even during early childhood. This fragility is particularly likely to manifest during surgical intervention. Early medical management and surveillance may be indicated, but its modalities remain to be defined.
| S-EPMC6040561 | biostudies-literature
Project description:Vascular Ehlers-Danlos syndrome (EDS) type IV is the most severe form of EDS. In many cases the disease is caused by a point mutation of Gly in type III collagen. A slower folding of the collagen helix is a potential cause for over-modifications. However, little is known about the rate of folding of type III collagen in patients with EDS. To understand the molecular mechanism of the effect of mutations, a system was developed for bacterial production of homotrimeric model polypeptides. The C-terminal quarter, 252 residues, of the natural human type III collagen was attached to (GPP)7 with the type XIX collagen trimerization domain (NC2). The natural collagen domain forms a triple helical structure without 4-hydroxylation of proline at a low temperature. At 33 °C, the natural collagenous part is denatured, but the C-terminal (GPP)7-NC2 remains intact. Switching to a low temperature triggers the folding of the type III collagen domain in a zipper-like fashion that resembles the natural process. We used this system for the two known EDS mutations (Gly-to-Val) in the middle at Gly-910 and at the C terminus at Gly-1018. In addition, wild-type and Gly-to-Ala mutants were made. The mutations significantly slow down the overall rate of triple helix formation. The effect of the Gly-to-Val mutation is much more severe compared with Gly-to-Ala. This is the first report on the folding of collagen with EDS mutations, which demonstrates local delays in the triple helix propagation around the mutated residue.
| S-EPMC3696688 | biostudies-literature
Project description:Classical Ehlers-Danlos syndrome (EDS) is a heritable disorder characterized by joint hypermobility, skin hyperextensibility, and abnormal wound healing. The majority of affected individuals have alterations in 1 of the 2 type V collagen genes, COL5A1 and COL5A2. The most common mechanism is COL5A1 haploinsufficiency due to instability of the transcript of one allele. In dermal fibroblasts from our population of 76 individuals with clinical features of classical EDS, there were 21 (29.5%) with decreased expression of one COL5A1 allele, consistent with published estimates of the frequency of null alleles. We identified the causative mutation in nine of these cell strains (mutations for seven others had been previously described), and found two nonsense mutations, five splice mutations, and two insertion/deletions. The same type of genomic change at splice sites can have different effects at the RNA level and the outcome could not be predicted from the primary genomic DNA alteration.
| S-EPMC3827857 | biostudies-literature
Project description:Ehlers-Danlos syndrome (EDS), hypermobility type, is probably the most common EDS type, as well as the most common heritable connective tissue disorder. Bladder dysfunction is a rare clinical manifestation of EDS and manifests itself as primary nocturnal enuresis. We present a 10-year-old boy referred to the paediatrics nephrology consultation due to primary nocturnal enuresis and day time symptoms of urinary urgency. During the appointment, a tendency to joint hypermobility was noted. On evaluation the skin was hyperextensible and the Beighton score was positive. The genetic testing revealed a variant of the COL5A1 gene not yet described in the literature.
| S-EPMC7021119 | biostudies-literature
Project description:Nature often employs similar mechanisms to complete similar tasks, thus the evolution of homologous proteins across various organ systems to perform similar but slightly different functions. In this respect, disorders attributed to specific genetic mutations, while initially thought to be restricted in function and purpose, may provide broad insight into general cellular and molecular mechanisms of development and maintenance. One such example can be seen in the brain malformation, periventricular heterotopia (PH), which is characterized by very specific nodules of neurons that line the lateral ventricles beneath the cerebral cortex. PH is seen as a disorder of neuronal migration and can be caused by mutations in filamin A (FLNA), which encodes an actin-binding protein that regulates the cytoskeleton and cell motility. Recent advances in our understanding of the genetic causes of PH suggest that mutations in this gene, however, are also associated with the connective tissue disorder, Ehlers-Danlos syndrome (EDS), in which affected individuals present with joint and skin hyperextensibility and vascular problems including aortic dissection, excessive bleeding and bruisability. While much still remains unknown regarding the mechanistic role of FLNA in giving rise to PH and EDS, a common cellular and molecular basis likely gives rise to these two seemingly unrelated clinical disorders.
| S-EPMC1288408 | biostudies-literature
Project description:Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1+/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1+/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vascular Ehlers-Danlos syndrome.
2022-02-16 | GSE196753 | GEO
Project description:Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable connective tissue disorders whose primary clinical features include soft and extensible skin, articular hypermobility and tissue fragility. EDS type VIIC or 'human dermatosparaxis' is an autosomal recessive disease characterized by severe skin fragility and sagging redundant skin (major criteria) with a soft, doughy texture, easy bruising, premature rupture of fetal membranes and large hernias (minor criteria). Dermatosparaxis (meaning 'tearing of skin'), which has been described in several non-human species, is a disorder of the connective tissue resulting from a deficiency of the enzyme that cleaves the registration peptide off the N-terminal end of collagen after it has been secreted from fibroblasts. We describe a Mexican case from consanguineous parents with all the phenotypical characteristics previously described, plus skeletal abnormalities.
| S-EPMC3362267 | biostudies-literature
Project description:We report the first observation of a patient with contgenital chylous ascites (CCA) and Ehlers-Danlos syndrome type VI due to primary lymphatic defect with additional vascular anomaly. CCA is a rare condition, and there is limited understanding of its pathophysiology and treatment options. We also review the patient's treatment course mitigated with octreotide and total parenteral nutritional support, as there are no current established guidelines for CCA. Early recognition of possible association with Ehlers-Danlos syndrome is important for quick intervention and successful management of pediatric patients.
| S-EPMC5226192 | biostudies-literature