Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency.

BACKGROUND: Musculocontractural Ehlers-Danlos Syndrome (mcEDS) is a rare connective tissue disorder caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE), both of which result in defective dermatan sulfate biosynthesis. Forty-one patients with mcEDS-CHST14 and three patients with mcEDS-DSE have been described in the literature. METHODS: Clinical, molecular, and glycobiological findings in three additional patients with mcEDS-DSE were investigated. RESULTS: Three patients from two families shared craniofacial characteristics (hypertelorism, blue sclera, midfacial hypoplasia), skeletal features (pectus and spinal deformities, characteristic finger shapes, progressive talipes deformities), skin features (fine or acrogeria-like palmar creases), and ocular refractive errors. Homozygous pathogenic variants in DSE were found: c.960T>A/p.Tyr320* in patient 1 and c.996dupT/p.Val333Cysfs*4 in patients 2 and 3. No dermatan sulfate was detected in the urine sample from patient 1, suggesting a complete depletion of DS. CONCLUSION: McEDS-DSE is a congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems, similar to the symptoms of mcEDS-CHST14. However, the burden of symptoms seems lower in patients with mcEDS-DSE.

Defect in dermatan sulfate in urine of patients with Ehlers-Danlos syndrome caused by a CHST14/D4ST1 deficiency.

PURPOSE: Dermatan sulfate (DS) plays a number of roles in a wide range of biological activities such as cell signaling and tissue morphogenesis through interactions with various extracellular matrix proteins including collagen. Mutations in the carbohydrate sulfotransferase 14 gene (CHST14) encoding CHST14/dermatan 4-O-sulfotransferase-1 (D4ST1), which is responsible for the biosynthesis of DS, cause a recently delineated form of Ehlers-Danlos syndrome (EDS, musculocontractural type 1), an autosomal recessive connective tissue disorder characterized by congenital malformations (specific craniofacial features, and congenital multiple contractures) and progressive fragility-related complications (skin hyperextensibility, bruisability, and fragility with atrophic scars; recurrent dislocations; progressive talipes or spinal deformities; and large subcutaneous hematomas). In an attempt to develop a diagnostic screening method for this type of EDS, the amount of DS in the urine of patients was analyzed. METHODS: Urinary DS was quantified by an anion-exchange chromatography after treatment with DS-specific degrading enzyme. RESULTS: DS was not detected in the urine of patients with homo- or compound heterozygous mutations in CHST14. These results suggest that the quantification of DS in urine is applicable to an initial diagnosis of DS-defective EDS. CONCLUSIONS: This is the first study to perform a urinary disaccharide compositional analysis of chondroitin sulfate (CS)/DS chains in patients with EDS caused by a CHST14/D4ST1 deficiency, and demonstrated the absence of DS chains. This result suggests systemic DS depletion in this disorder, and also proposes the usefulness of a urinary disaccharide compositional analysis of CS/DS chains as a non-invasive screening method for this disorder.

Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss.

We report on an autosomal-recessive variant of Ehlers-Danlos syndrome (EDS) characterized by severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment, and normal pyridinoline excretion in urine. Clinically, the disorder shares many features with the kyphoscoliotic type of EDS (EDS VIA) and Ullrich congenital muscular dystrophy. Linkage analysis in a large Tyrolean kindred identified a homozygous frameshift mutation in FKBP14 in two affected individuals. Based on the cardinal clinical characteristics of the disorder, four additional individuals originating from different European countries were identified who carried either homozygous or compound heterozygous mutations in FKBP14. FKBP14 belongs to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases). ER-resident FKBPs have been suggested to act as folding catalysts by accelerating cis-trans isomerization of peptidyl-prolyl bonds and to act occasionally also as chaperones. We demonstrate that FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. Furthermore, indirect immunofluorescence of FKBP14-deficient fibroblasts indicated an altered assembly of the extracellular matrix in vitro. These findings suggest that a disturbance of protein folding in the ER affecting one or more components of the extracellular matrix might cause the generalized connective tissue involvement in this disorder. FKBP14 mutation analysis should be considered in all individuals with apparent kyphoscoliotic type of EDS and normal urinary pyridinoline excretion, in particular in conjunction with sensorineural hearing impairment.

The kyphoscoliotic type of Ehlers-Danlos syndrome (type VI): differential effects on the hydroxylation of lysine in collagens I and II revealed by analysis of cross-linked telopeptides from urine.

The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS type VIA) (OMIM 225400) is an autosomal recessive connective tissue disorder that results from mutations in the lysyl hydroxylase 1 gene (PLOD1) causing underhydroxylation of lysine residues in tissue collagens, particularly of skin. Previous studies have shown that the pool of collagen cross-linking amino acids, hydroxylysyl pyridinoline (HP) and lysyl pyridinoline (LP) excreted in urine has an abnormally low HP/LP ratio, which is diagnostic of the condition. Here we isolated cross-linked peptides containing these residues from the urine of a child with EDS VIA homozygous for a mutation that results in a stop codon and effective null expression of PLOD1 enzyme activity. Peptides that had originated from bone type I collagen and cartilage type II collagen were identified. A cross-linked N-telopeptide fraction that is derived from bone type I collagen contained only LP, no HP, which means that the helical lysines at residues 930 of alpha 1(I) and 933 of alpha 2(I) of the collagen triple-helix had not been hydroxylated. The equivalent peptide fraction from a normal child's urine gave a ratio of HP to LP of 1.5:1 typical for normal bone collagen. A second cross-linked peptide that is derived from the C-telopeptide domain of cartilage type II collagen showed both HP and LP in a 2:1 ratio, compared with 18:1 for the equivalent peptide from a normal child's urine. The results show that in EDS VIA, bone type I collagen is more markedly underhydroxylated than cartilage type II collagen, at least at those helical sites that form cross-links. The residual fraction of HP found in the urine of EDS VI patients therefore appears to be contributed in significant part by the degradation products of cartilage. Since PLOD1 is null, other PLOD genes must be responsible for the helical hydroxylation activity that results in HP. The presented approach of analyzing urinary cross-linked C-telopeptide fragments of type II collagen may allow the detection of chondrodysplasias due to genetic defects in lysyl hydroxylase isoforms active in cartilage.

[Excretion of pyridinoline with urine in children with Ehlers-Danlos syndrome and Marfan's syndrome and the effect of beta blocker and complex vitamin therapy on it]. / Ekskretsiia piridinolina s mochoi u detei s sindromami Elersa-Danlo i Marfana i vliianie na nee terapii beta-adrenoblokatorom i kompleksom vitaminov.

Excretion of pyridinoline and polypeptide-bound hydroxyproline with urine was studied in 27 children with hereditary impairment of connective tissue. At the same time, effects of beta-adrenoblocking agents and vitamin complex, prescribed during preoperation period before thoracoplasty in hereditary chest deformation, were investigated. Clinical efficiency of the treatment depended distinctly on the initial value of ratios pyridinoline/creatinine and polypeptide-bound hydroxyproline/creatinine. Total positive effect of the therapeutic course, considering also echocardiographic examination and postoperational complications, was observed in 44% of patients with Ehlers-Dunlop syndrome and in 75% of patients with Marfan syndrome.

[Effect of therapy with beta-adrenoblockers and vitamin complexes on indices of oxyproline excretion in various hereditary connective tissue diseases]. / Vliianie terapii beta-adrenoblokatorom i kompleksom vitaminov na pokazateli ékskretsii oksiprolina pri nekotorykh nasledstvennykh bolezniakh soedinitel'noi tkani.

Excretion of hydroxyproline with urine was studied in 16 children (5-14 years old) with Marphan-Like syndrome and Marphan, Ehlers-Dunlos and Larson syndromes after therapy involving propranolol and a complex of vitamins (ascorbic acid, riboflavin and pyridoxine) and recommended on the basis of echocardiographic analyses. The therapeutic course appears to cause quantitative and qualitative correction of collagen and apparently of elastin fibrilles development. Depending on initial patterns of hydroxyproline excretion and the syndrome form the correction could be complete or partial, while positive effect of the treatment was stable or provisional. The data obtained suggest that the complex treatment developed might be applied as a preoperative therapy of the patients with Marphan-like syndrome as well as with syndromes of Marphan and Ehlers-Dunlos before thoracoplastics caused by hereditary chest deformation and by impairments of cardiovascular system.

[Urinary excretion of hydroxyproline in funnel chest deformity]. / Ekskretsiia oksiprolina s mochoi pri voronkoobraznoi deformatsii grudnoi kletki.

Excretion of hydroxyproline with urine was studied in 16 children with localized form of funnel chest deformation simultaneously with Marfan and Ehlers-Danlos syndromes, in 9 children with the localized form of deformation within 6-8 months after thorax surgical plastic operation as well as in 3 children with Ehlers-Danlos syndrome but without funnel chest deformation. Funnel chest deformation of the II-III degree, independently of its form, was accompanied by a decrease of total hydroxyproline in urine as compared with healthy children of the similar age. The hydroxyproline excretion was normalized after thoracoplastic operation in the children with localized form of the chest deformation. In Ehlers-Danlos syndrome, independently on presence or absence of the chest deformation, relative content of free hydroxyproline was increased in urine, while the peptide-bound amino acid was decreased (peptides with molecular mass above 700 daltons); this phenomenon appears to be a characteristic property of the syndrome.

Variations in human urinary O-hydroxylysyl glycoside levels and their relationship to collagen metabolism.

Two O-hydroxylysyl glycosides, Hyl-Gal-Glc and Hyl-Gal, have been isolated from normal human urine and shown to be identical to two glycosides isolated from alkaline hydrolysates of collagen. A relatively sample and reproducible analytical procedure has been devised to measure the levels of these glycosides in human urine. By the use of this procedure it was shown that a normal diet has only a small effect on 24-hr urinary excretion levels of these glycosides indicating an endogenous origin. Urinary glycoside levels appear to be highest in children, roughly paralleling collagen turnover as indicated by urinary hydroxyproline levels. Collagen turnover equivalents calculated from urinary hydroxylysyl glycoside levels were found to be significantly larger than collagen turnover equivalents calculated from urinary hydroxyproline levels. This suggests that urinary glycosides are more quantitative indicators of collagen metabolism than urinary hydroxyproline. The ratio of Hyl-Gal-Glc to Hyl-Gal was measured in urines of diseased as well as normal individuals and a bimodal distribution was found. Alkaline hydrolysates of different human connective tissue collagens showed that only bone collagen, of the collagens examined, had a low ratio of Hyl-Gal-Glc to Hyl-Gal compared to human urine. Other collagens examined had higher ratios than found in human urine. On the basis of these results it is postulated that the bimodal distribution of glycoside ratios represents two populations of collagen turnover, the lower ratio population having a high bone collagen turnover, the lower ratio population having a high bone collagen turnover relative to the second population. Examination of the types of subjects making up the two populations supports this hypothesis. These data suggest that urinary O-hydroxylysyl glycoside excretion, in addition to providing a more quantitative estimate of collagen turnover than urinary hydroxyproline, may prove to be of value as a specific means of studying the metabolism of bone collagen.