Ehlers-Danlos Syndrome Type IV Research Articles

44 Detecting conformational differences in Fragile Foal Syndrome carriers utilizing artificial intelligence

Conformation traits impact gait and performance, and as a result vary based on intended use of the horse. For example, a horse with longer legs can cover a greater distance per stride than one with shorter legs. Limb length, therefore, is advantageous for horses expected to travel long distances for extended periods of time but may not be for those who go short distances at top speeds. Fragile Foal Syndrome (FFS) in horses results from a sequence change in PLOD1, the same gene that causes Ehlers Danlos Syndrome type IV (EDS-IV) in humans, a condition that results in longer limbs. Based on the phenotype observed in EDS, we hypothesize that FFS in the carrier state may impact extremity length including the neck, forelimbs, and hindlimbs in horses. To measure conformation parameters, we first digitally labeled specific anatomical points on a video recording of a trotting horse using the software package DeepLabCut (DLC). Representative frames for each horse at the same point within the stride were extracted from the video. The X, Y coordinates of each anatomical label were used to quantify conformation geometry. Frame extraction was done with a custom designed graphical interface that ensured the user could identify the ideal frame matching an identical body position across all horses examined. X,Y coordinate output files were thenanalyzed with a custom gait parameter pipeline written in MatLab to calculate the neck, forelimb, and hindlimb length. Each measurement was scaled to account for the varying distance horses were from the camera. Pulled tail hair was utilized to extract DNA and genotype each horse using PCR-RFLP, then followed by Sanger Sequencing for confirmation. Conformational measures were compared between genotype categories (wild type vs, carrier) in JMP Pro. Preliminary results showed that FFS carriers (n = 7) had significantly longer forelimb (P = 0.0344, t-test), hindlimb (P = 0.0258, t-test), and neck (P = 0.0013, t-test) lengths compared with wild type horses (n = 7). Future work will increase the overall sample size and number of frames captured per individual to increase statistical power and allow investigation of more conformation traits including static joint angles and back lengths. Improved understanding of conformational phenotypes that may result from the FFS carrier genotype will inform future studies of equine physiology and connective tissue disorders, leading to better decision making for breeding, sales and training, and preventing injury and loss of foals to this disease.

Ehlers-Danlos syndrome type IV in association with a (c.970G>A) mutation in the COL3A1 gene.

The Ehlers-Danlos syndrome type IV (EDS-IV) is a hereditary, autosomal dominant disease that causes a defect in the procollagen III synthesis, which results in a structural modification in this protein. An awareness of the disease is of vital importance for the optimal outcome, since the affected individuals have a high risk of vascular, intestinal and uterine rupture. It's a disease with great clinical variability and the diagnosis is confirmed by detection of a mutation in the gene encoding collagen type III. The authors present a case report of a patient who appeared at the emergency ward with acute abdomen and hypovolemic shock after spontaneous aortic rupture. The diagnosis was confirmed after genetic study that identified a mutation in the (c.970G>A) in the COL3A1 gene, only reported once in the literature in a family with internal carotid dissections in some of its members. It's the first time that this mutation is reported in association with the EDS-IV. The authors also make a brief review of the clinical, genetic and molecular characteristics of this syndrome.

Surgical pitfalls in patients with Ehlers–Danlos type IV: A case of spontaneous sigmoid perforation in a 17-year-old male

Ehlers-Danlos syndrome (EDS) is a group of well described connective tissue disorders in which collagen production is impaired. The surgical management of affected individuals remains challenging, with no general consensus. We report a case of spontaneous sigmoid perforation in a 17-year-old Eurasian male, in whom we subsequently established the diagnosis of EDS type IV (EDS-IV). We review the literature to discuss the clinical features and diagnosis, and the recommended therapeutic management.

Germline TGF‐β receptor mutations and skeletal fragility: A report on two patients with Loeys–Dietz syndrome

Loeys-Dietz syndrome (LDS, OMIM # 609192) caused by heterozygous mutations in TGFBR1 and TGFBR2 has recently been described as an important cause of familial aortic aneurysms. These patients have craniofacial and skeletal features that overlap with the Marfan syndrome (MFS), and more importantly, have significant vascular fragility as is seen in MFS and Ehlers-Danlos syndrome Type IV (EDS-IV). The skeletal phenotype with respect to low bone mineral density and skeletal fragility is not clear. We present two patients with LDS with significant skeletal fragility. The first is a 17-year-old male who had talipes equinovarus, diaphragmatic and inguinal and herniae, aortic root dilatation necessitating surgical repair, craniofacial and skeletal dysmorphism consistent with LDS, and a history of numerous fragility fractures leading to significant skeletal deformity. He was found to be heterozygous for a c.923T > C transition in exon 4 of TGFBR2. The second is a 26-year-old male with submucous cleft palate, talipes equinovarus, pectus excavatum requiring surgery, inguinal hernia, and aneurysms in the ascending aorta, abdominal aorta, carotid, subclavian, vertebral and brachial arteries requiring surgical repairs. He also had craniofacial and skeletal dysmorphism consistent with LDS, multiple fractures in childhood, low bone mineral density, and was found to be heterozygous for a c.1561 T > C transition in exon 7 of TGFBR2. These case studies highlight the importance of paying close attention to fractures and bone density in patients with LDS. Osteopenia or osteoporosis may become increasingly important issues as earlier detection and treatment of the vascular complications of LDS improves life expectancy in these patients.

Endovascular treatment for a spontaneous rupture of the posterior tibial artery in a patient with Ehlers-Danlos syndrome Type IV: Report of a case

This report presents the case of a 27-year-old woman with a history of Ehlers-Danlos syndrome Type IV (EDS-IV) who suffered from acute compartment syndrome caused by the spontaneous rupture of the posterior tibial artery. Bleeding control was achieved by endovascular embolization. A fasciotomy was successfully performed without any trouble with hemorrhaging. Endovascular treatment could therefore represent the ideal option for treating infrapopliteal lesions, particularly for EDS-IV patients.

The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: A 30-year experience

Ehlers-Danlos syndrome type IV (EDS-IV) results from abnormal procollagen III synthesis and leads to arterial, intestinal, and uterine rupture. The purpose of this study was to review the spectrum, management, and clinical outcome of EDS-IV patients. We retrospectively reviewed the clinical data of 31 patients (15 male and 16 female) with a clinical diagnosis of EDS-IV treated over a 30-year period (1971 to 2001). Biochemical confirmation was obtained in 24 patients, and mutation of the COL3A1 gene was confirmed in 11 patients. The study excluded patients with other connective tissue dysplasias. The mean age at the time of diagnosis was 28.5 +/- 11 years (range, 10 to 53 years). Twenty-four patients developed 132 vascular complications; of these, 85 were present either before or at the time of the initial evaluation, and 47 complications occurred during a median follow-up of 6.3 years (range, 0.5 to 26 years). Survival free of vascular complications was 90% at age 20 years, 39% at 40 years, and 20% at age 60 years. Fifteen patients underwent 30 operative interventions for vascular complications, including arterial reconstruction (n = 15), simple repair or ligation (n = 4), coil embolization (n = 3), splenectomy (n = 2), and abdominal decompression, nephrectomy, graft thrombectomy, vein stripping and thoracoscopy (n = 1 each). Three hospital deaths occurred from exsanguinating hemorrhage: two after operative interventions and one because of a ruptured splenic artery. Procedure-related morbidity was 46%, including a 37% incidence of postoperative bleeding and a 20% need for re-exploration. The incidence of late graft-related complications was 40% of arterial reconstructions, including 4 anastomotic aneurysms, 1 fatal anastomotic disruption, and 1 graft thrombosis. Patient survival was 68% at age 50 years and 35% at age 80 years. Of the 12 deaths during the study period, 11 were associated with vascular or graft-related complications. Operative mortality in patients with vascular complications of EDS-IV was not excessively high, but the incidence of postoperative bleeding complications and late graft-related problems was significant. Despite successful repair of vascular complications, survival was shortened because of secondary vascular or graft-related complications.

Management of spontaneous colonic perforation in ehlers-danlos syndrome type IV

A 14-year-old girl with a family history of fatal colonic rupture, presented with a 2-day history of abdominal pain and signs of peritonitis. At laparotomy, a full-thickness perforation of the sigmoid colon was found, which was exteriorized as a loop colostomy. Subsequently, molecular studies of the patient’s cultured fibroblasts found a point mutation in the COL3A1 gene, confirming a diagnosis of Ehlers-Danlos syndrome type IV (EDS-IV). Four and a half years later, a total abdominal colectomy and ileoproctostomy were performed, restoring intestinal continuity. At 5 years follow-up, the patient has had no further complications. Although spontaneous colonic perforation is a well-reported manifestation of EDS-IV, a consensus on the surgical management of this complication in EDS-IV has yet to be determined. Given the high rate of reperforation in EDS-IV when the colon is left in place and the low incidence of reported small bowel and rectal perforations, subtotal colectomy is a reasonable treatment. Primary anastomosis and avoidance of an end-ileostomy was possible in this young patient, with no evidence of anastomotic leakage nor reperforation to date. Lifelong close follow-up should be continued in these patients, because the natural history of this anatomy in EDS-IV is not known.

Neurological presentation of Ehlers–Danlos syndrome type IV in a family with parental mosaicism

Ehlers-Danlos syndrome type IV (EDS-IV) is an autosomal-dominant disorder caused by a defect of type III collagen which leads to ruptures of arteries and hollow organs. Neurological presentation with muscle involvement and flexion contractures of the finger joints is uncommon. We clinically characterized seven members of a family with EDS-IV. The index patient, a young woman with an acrogeric face, suffered chronic muscle pain and cramps, Achilles tendon retraction, finger flexion contractures and seizures. The mother had similar features and had experienced an ischemic stroke. Biochemical study in cultured fibroblasts and molecular analysis of the COL3A1 gene led to the diagnosis of EDS-IV. A glycine substitution, p.G883V, within the triple helix of the alpha 1(III) chain, was found in the index patient and in the mother. The maternal grandfather and an aunt each had an abdominal aortic aneurysm, the rupture of which was the cause of death in the latter, at 40 years of age. Surprisingly, we found the mutation, as a mosaic, in the asymptomatic maternal grandmother. This expands the clinical spectrum of EDS type IV and confirms that in some families mosaicism can be identified as the source of the mutation.

Abnormal type III collagen produced by an exon-17-skipping mutation of the COL3A1 gene in Ehlers-Danlos syndrome type IV is not incorporated into the extracellular matrix.

A novel heterozygous mutation of the COL3A1 gene that encodes the alpha 1(III) chains of type III collagen was identified in a family with the acrogeric form of Ehlers-Danlos syndrome type IV (EDS-IV). Cultured dermal fibroblasts produced normal and shortened alpha 1(III) chains. The triple helix of the latter chain was shortened owing to a 33 amino acid deletion of Gly-184 to Pro-216. The corresponding region of cDNA lacked 99 base pairs from nucleotides 1051 to 1149. The deletions corresponded exactly to the normal sequence encoded by exon 17 of the COL3A1 gene. The proband was heterozygous for a T to G transversion at position +2 of intron 17, which resulted in skipping of exon 17. The splicing defect was not corrected by growing the fibroblasts at 33 degrees C and no other splicing variants were identified at 33 or 37 degrees C. The affected brother had the same mutation but his unaffected mother did not. Heterotrimeric type III collagen molecules containing normal and mutant chains were retained within the cell. The mutant homotrimeric molecules were modified and secreted normally and were thermally stable. These normal characteristics of the mutant homotrimers suggested that the loss of ten Gly-Xaa-Yaa triplets (where Gly-Xaa-Yaa is a repetitive amino acid triplet structure in which Xaa and Yaa are other amino acids, proline and hydroxyproline being more common in the Yaa position) did not adversely affect the formation and stability of the triple helix or the structural requirements for secretion. However, the mutant homotrimers were not incorporated into the extracellular matrix of an in vitro model of EDS-IV dermis. The EDS-IV phenotype in this family was probably due to a deficiency in the amount of normal type III collagen available for formation of the heterotypic collagen fibrils of the extracellular matrix. Intracellular and extracellular quality-control mechanisms prevented the incorporation of heterotrimeric and homotrimeric mutant type III collagen molecules into the cross-linked extracellular matrix.

A base substitution at a splice site in the COL3A1 gene causes exon skipping and generates abnormal type III procollagen in a patient with Ehlers-Danlos syndrome type IV.

The dermis of a child with Ehlers-Danlos syndrome type IV (EDS-IV) contained about 11% of the normal amount of type III collagen and cultured dermal fibroblasts produced a reduced amount of type III procollagen which was secreted poorly. Type III collagen produced by these cells contained normal and abnormal alpha-chains and cyanogen bromide peptides. The site of the structural defect in the abnormal alpha 1 (III) chains was localized to the region of Met797, which is at the junction of the two carboxyl-terminal CB5 and CB9 cyanogen bromide peptides. Chemical cleavage of heteroduplexes formed between EDS-IV mRNA and a normal cDNA clone covering the CB5 and CB9 region showed that about 100 nucleotides were mismatched. Sequencing of amplified and cloned cDNA spanning the mutant region revealed a 108 nucleotide deletion corresponding to amino acid residues Gly775 to Lys810. The deleted nucleotide sequence corresponded to sequences that, by analogy to the organization of the type I collagen genes, should be precisely encoded by exon 41 of the COL3A1 gene. Sequencing of amplified genomic DNA, prepared using disimilar amounts of primers specific for exons 41 and 42, displayed a base substitution (G-to-A) in the highly conserved GT dinucleotide of the 5' splice site of intron 41. Normal sequences were also obtained from the normal allele. It is likely that the GT-to-AT transition at the splice donor site of intron 41 generated an abnormally spliced mRNA in which sequences of exon 40 and 42 were joined together with maintenance of the reading frame. The corresponding peptide deletion included the cyanogen bromide cleavage site Met797-Pro798 and the mammalian collagenase cleavage site at Gly781-Ile782. These losses account for the resistance of EDS-IV collagen to cyanogen bromide and mammalian collagenase digestion. Cultured fibroblasts produced normal homotrimer, mutant homotrimer, and mixed heterotrimer type III collagen molecules. The mutant homotrimer molecules were the major pepsin-resistant species and about 69% of the alpha 1(III) mRNA was in the mutant form.