A novel mutation in the lysyl hydroxylase 1 gene causes decreased lysyl hydroxylase activity in an Ehlers-Danlos VIA patient.
(57/257)
The clinical diagnosis of a patient with the phenotype of Ehlers-Danlos syndrome type VI was confirmed biochemically by the severely diminished level of lysyl hydroxylase (LH) activity in the patient's skin fibroblasts. A novel homozygous mutation, a single base change of T(1360)-->G in exon 13 of the LH1 gene, predicted to result in W446G, was identified in the patient's full-length cDNA. This was confirmed in genomic DNA from both the patient and her parents, who were heterozygous for the mutation. This mutation was introduced into an LH1-pAcGP67 baculoviral construct and expressed, in parallel with normal LH1, in an insect cell system. The loss of LH activity in the mutated recombinant construct confirmed the pathogenicity of this mutation. Although not in the major catalytic site, this mutation occurs in a highly conserved region of the LH1 gene and may contribute to loss of activity by interfering with normal folding of the enzyme. (+info)
Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation.
(58/257)
BACKGROUND: The Ehlers-Danlos syndrome (EDS) comprises a group of hereditary connective tissue disorders. Periventricular nodular heterotopia (PNH) is a human neuronal migration disorder characterised by seizures and conglomerates of neural cells around the lateral ventricles of the brain, caused by FLNA mutations. FLNA encodes filamin A, an actin binding protein involved in cytoskeletal organisation. The amino-terminal actin binding domain (ABD) of filamins contains two tandem calponin homology domains, CHD1 and CHD2. OBJECTIVE: To report clinical and genetic analyses in a Spanish family affected by a connective tissue disorder suggestive of EDS type III and PNH. METHODS: A clinical and molecular study was undertaken in the three affected women. Clinical histories, physical and neurological examinations, brain magnetic resonance imaging studies, and skin biopsies were done. Genetic analysis of the FLNA gene was undertaken by direct sequencing and restriction fragment length polymorphism analysis. RESULTS: Mutation analysis of the FLNA gene resulted in the identification of a novel mutation in exon 3 (c.383C-->T) segregating with the combination of both syndromes. This mutation results in a substitution of an alanine residue (A128V) in CHD1. CONCLUSIONS: The findings suggest that the Ala128Val mutation causes the dual EDS-PNH phenotype. This association constitutes a new variant within the EDS spectrum. This is the first description of a familial EDS-PNH association with a mutation in FLNA. (+info)
The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience.
(59/257)
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. (+info)
Detection and characterisation of an overmodified type III collagen by analysis of non-cutaneous connective tissues in a patient with Ehlers-Danlos syndrome IV.
(60/257)
The clinical and biochemical observations in a patient with a mild form of Ehlers-Danlos syndrome (EDS) type IV are described. The patient's skin fibroblasts produced markedly diminished amounts of type III collagen. SDS-polyacrylamide gel electrophoresis of collagens produced by cells obtained from other, non-cutaneous tissues showed two forms of collagen alpha 1(III) chains, a normal and a slow migrating, mutant form. Further analysis confirmed that the type III collagen molecules containing mutant alpha chains which were overmodified had a lower thermal stability and were poorly secreted into the extracellular medium. The protein defect was mapped by in situ cyanogen bromide digestion and was located in alpha 1(III) CB9, the C-terminal peptide of the collagen triple helix. This study shows that non-cutaneous connective tissues can be a useful source for the study of type III collagen defects in patients with EDS type IV. (+info)
Neurological manifestations of Ehlers-Danlos Syndrome.
(61/257)
Ehlers-Danlos Syndrome (EDS) is more identified for its cutaneous features but its neurological manifestations have not received the focused attention. Four patients of Ehlers-Danlos Syndrome (EDS) with neurological manifestations were evaluated for phenotypic data. These four men were from three families and two had consanguineous parentage. The mean age at onset and presentation of neurological symptoms were 10.5 years and 19 years respectively. Patient 1 presented with bilateral optic atrophy, sensorineural deafness, cerebellar ataxia and neuropathy. Patient 2 had marfanoid habitus, chorea and cerebellar ataxia. Patient 3 had action and percussion myotonia, wasting and weakness of sternocleidomastoid and distal limb muscles. Patient 4 had action myotonia, mirror movements of both hands and neuropathy. MRI of brain showed right parietal polymicrogyria. Neuroaxis involvement at multiple levels in EDS may have prognostic significance. (+info)
Periventricular heterotopia: new insights into Ehlers-Danlos syndrome.
(62/257)
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. (+info)
Ehlers-Danlos syndrome: correlation with headache disorders in a young woman.
(63/257)
Ehlers-Danlos syndrome is a rare inherited illness, which includes an autosomal dominant and also a recessive X-linked variant. Its main clinical characteristic is a generalised connective tissue involving collagen and elastin, causing fragile and hyperextensible skin, loose jointedness and bruising. Many clinical subtypes are described, each of a different severity degree pattern. The correlation of this syndrome and headache disorders is rare. In this paper we describe the case of a young woman with Type II (less severe) Ehlers-Danlos Syndrome and headache. (+info)
Ehlers Danlos syndrome in two siblings.
(64/257)
Two cases of Ehlers-Danlos syndrome affecting two real brothers are being reported. Both of them presented with features of atrophy and hyperextensibility of skin, hypermobility of joints and scarring at the sites of trauma. The elder brother also had kyphoscoliosis and hypogonadism with testicular failure. (+info)