Spinal manifestations in 12 patients with musculocontractural Ehlers‐Danlos syndrome caused by CHST14/D4ST1 deficiency (mcEDS‐<i>CHST14</i>)

Uehara, Mariko; Kosho, Tomoki; Yamamoto, Noriaki; Takahashi, Hideaki; Shimakura, Taketoshi; Nakayama, Jun; Kato, Hiroyuki; Takahashi, J.

doi:10.1002/ajmg.a.40507

Cited by 17 publications

(20 citation statements)

References 46 publications

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“…EDS caused by mutations in FKBP14 also shows myopathy and progressive kyphoscoliosis (Baumann et al, 2012). Here, we demonstrate that kyphosis, which is associated with myopathy in our mouse models, mirrors the mcEDS phenotype (Mendoza-Londono et al, 2012;Uehara et al, 2018;Uehara et al, 2020). Using Chst14 −/− mutant mice developed by CRISPR/Cas9 genome engineering, we were able to comprehensively investigate the pathological mechanisms associated with the loss of D4ST1 and DS chains.…”

Section: Disease Models and Mechanisms • Dmm • Accepted Manuscriptsupporting

confidence: 69%

A new mouse model of Ehlers-Danlos syndrome generated using CRISPR/Cas9-mediated genomic editing

Nitahara-Kasahara

Mizumoto

Inoue

et al. 2021

Disease Models &Amp; Mechanisms

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Musculocontractural Ehlers-Danlos syndrome (mcEDS) is caused by generalized depletion of dermatan sulfate (DS) due to biallelic pathogenic variants in CHST14 encoding dermatan 4-O-sulfotransferase 1 (D4ST1) (mcEDS-CHST14). Here, we generated mouse models for mcEDS-CHST14 carrying homozygous mutations (1 bp deletion or 6 bp insertion/10 bp deletion) in Chst14 through CRISPR/Cas9-genome engineering to overcome perinatal lethality in conventional Chst14-deleted knockout mice. DS depletion was detected in the skeletal muscle of these genome-edited mutant mice, consistent with loss of D4ST1 activity. The mutant mice showed common pathophysiological features, regardless of the variant, including growth impairment and skin fragility. Notably, we identified myopathy-related phenotypes. Muscle histopathology showed variation in fiber size and spread of the muscle interstitium. Decorin localized diffusely in the spread endomysium and perimysium of skeletal muscle, unlike in wild-type mice. The mutant mice showed lower grip strength and decreased exercise capacity compared to wild-type, and morphometric evaluation demonstrated thoracic kyphosis in mutant mice. The established CRISPR/Cas9-engineered Chst14 mutant mice would be a useful model to further our understanding of the mcEDS pathophysiology and in the development of novel treatment strategies.

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Section: Disease Models and Mechanisms • Dmm • Accepted Manuscriptsupporting

confidence: 69%

A new mouse model of Ehlers-Danlos syndrome generated using CRISPR/Cas9-mediated genomic editing

Nitahara-Kasahara

Mizumoto

Inoue

et al. 2021

Disease Models &Amp; Mechanisms

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“…Major diagnostic criteria for mcEDS- CHST14 are (1) multiple congenital contractures, characterised by adduction–flexion contractures and talipes equinovarus; (2) characteristic craniofacial features, evident at birth or in early infancy; and (3) characteristic cutaneous features including hyperextensibility, bruisability and fragility with atrophic scars and increased fine palmar creases 2. Thus far, 48 patients in 33 families have been reported,4–6 10 12–27 including six individuals from five families whose spinal manifestations were described 27. However, accurate prevalences of each feature/complication and detailed natural history data remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular features of 66 patients with musculocontractural Ehlers−Danlos syndrome caused by pathogenic variants inCHST14(mcEDS-CHST14)

et al. 2021

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BackgroundMusculocontractural Ehlers−Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated.MethodsWe collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations.ResultsSixty-six patients in 48 families (33 males/females; 0–59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype–phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE.ConclusionThis first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.

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“…It is unclear why kyphosis is more frequently observed in patients with MPS I. However, patients with Ehlers-Danlos syndrome (musculocontractural type 1), a disease caused by lack of dermatan sulfotransferase and subsequent abnormal DS sulfation levels [106], also characteristically develop thoracolumbar kyphosis [107]. This suggests an involvement of abnormal DS sulfation in kyphosis in patients with MPS I as well.…”

Section: Systemic Manifestations: Skin Kyphosis Corneal Clouding Valvular Heart Diseasementioning

confidence: 99%

Differences in MPS I and MPS II Disease Manifestations

Hampe

Yund

Orchard

et al. 2021

IJMS

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Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

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Spinal manifestations in 12 patients with musculocontractural Ehlers‐Danlos syndrome caused by CHST14/D4ST1 deficiency (mcEDS‐CHST14)

Cited by 17 publications

References 46 publications

A new mouse model of Ehlers-Danlos syndrome generated using CRISPR/Cas9-mediated genomic editing

A new mouse model of Ehlers-Danlos syndrome generated using CRISPR/Cas9-mediated genomic editing

Clinical and molecular features of 66 patients with musculocontractural Ehlers−Danlos syndrome caused by pathogenic variants inCHST14(mcEDS-CHST14)

Differences in MPS I and MPS II Disease Manifestations

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