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Here, we report brain white matter alterations in individuals clinically and genetically diagnosed with periodontal Ehlers-Danlos syndrome, a rare disease characterized by premature loss of teeth and connective tissue abnormalities. Eight individuals of two families clinically diagnosed with periodontal Ehlers-Danlos syndrome were included in the present study and underwent general physical, dental, and neurological examination. Whole exome sequencing was performed, and all patients included in the study underwent MRI of the brain. Whole exome sequencing revealed heterozygous C1R mutations c.926G>T (p.Cys309Phe, Family A) and c.149_150TC>AT (p.Val50Asp, Family B). All adult individuals (n = 7; age range 31 to 68 years) investigated by MRI had brain white matter abnormalities. The MRI of one investigated child aged 8 years was normal. The MRI pattern was suggestive of an underlying small vessel disease that is progressive with age. As observed in other leukoencephalopathies related to microangiopathies, the extent of the white matter changes was disproportionate to the neurologic features. Medical history revealed recurrent headaches or depression in some cases. Neurological examination was unremarkable in all individuals but one had mild cognitive decline and ataxia and experienced a seizure. The observation that periodontal Ehlers-Danlos syndrome caused by missense mutations in C1R is consistently associated with a leukoencephalopathy opens a new pathogenic link between the classical complement pathway, connective tissue, brain small vessels, and brain white matter abnormalities.
Ehlers-Danlos syndrome is a rarely encountered connective tissue disorder characterized by skin hyper-elasticity, joint hyper-flexibility, and vasculature fragility. We report a 41-year-old female presenting with scalp swelling following minor head trauma. The patient presented with a large cephalohematoma that despite compressive measures and Factor IX administration continued to progress, necessitating transfer for definitive surgical intervention. The patient underwent surgical evacuation of approximately 1 liter of blood, followed by drain placement and compression dressing. This case underscores the importance for emergency physicians to recognize the potential vascular catastrophes these patients may present with following even minor injury.
tenascin-X (TNX) is an extracellular matrix glycoprotein whose absence leads to Ehlers-Danlos Syndrome (EDS). TNX-deficient EDS patients present with joint hypermobility and muscle weakness attributable to increased compliance of the extracellular matrix. We hypothesized that in response to the increased compliance of the extracellular matrix in TNX-deficient EDS patients, intracellular adaptations take place in the elastic properties of the giant muscle protein titin.
Ehlers-Danlos syndrome (EDS) is a heterogeneous heritable connective tissue disorder with various neurological manifestations, including chronic pain. The neurological manifestations in EDS are often regarded as being caused by the associated musculoskeletal disorders or polyneuropathy. Here, we present two patients with hypermobile EDS (hEDS), presenting with relapsing central nervous system (CNS) manifestations. Although the two patients showed relapsing signs of CNS manifestations like multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), they were unique in that they had widespread opioid-dependent chronic pain, which is not consistent with the symptoms of MS/NMOSD. Unexpectedly, the serious pain of unknown origin was remarkably mitigated by plasmapheresis, and magnetic resonance imaging (MRI) examinations conducted for one of the patients were negative. Collectively, we speculate that hEDS may be more susceptible to 'normal-appearing imaging, neuroimmunologically justified, autoimmune-mediated encephalomyelitis (NINJA).' Analysis of the presented cases and an additional three patients with EDS with chronic pain indicates that treatable immune-mediated mechanisms deserve considerations for neurological symptoms observed in hEDS.
Ehlers-Danlos syndrome (EDS) is a rare genetic connective tissue condition that is poorly understood in relation to lactation. As diagnostic methods improve, prevalence has increased. EDS, a disorder that impacts connective tissue, is characterized by skin extensibility, joint hypermobility, and fragile tissue which can affect every organ and body system leading to complications during pregnancy, delivery, and the postpartum period. Traits of this disease can cause mild to severe physiologic and functional obstacles during lactation. Unfortunately, there is little clinical evidence and minimal guidance for lactation management, and providers may feel uncomfortable and hesitant to address these concerns with patients due to a lack of readily available resources on the subject and inexperience with such patients. This narrative review describes and discusses the types of EDS, identifying symptoms, considerations, and precautions for care providers to implement during lactation and breastfeeding.
The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable disorders affecting connective tissues. The mutations causing the various forms of EDS in humans are well characterized, but the genetic mutations causing EDS-like clinical pathology in dogs are not known, thus hampering accurate clinical diagnosis. Clinical analysis of two independent cases of skin hyperextensibility and fragility, one with pronounced joint hypermobility was suggestive of EDS. Whole-genome sequencing revealed de novo mutations of COL5A1 in both cases, confirming the diagnosis of the classical form of EDS. The heterozygous COL5A1 p.Gly1013ValfsTer260 mutation characterized in case 1 introduced a premature termination codon and would be expected to result in α1(V) mRNA nonsense-mediated mRNA decay and collagen V haploinsufficiency. While mRNA was not available from this dog, ultrastructural analysis of the dermis demonstrated variability in collagen fibril diameter and the presence of collagen aggregates, termed 'collagen cauliflowers', consistent with COL5A1 mutations underlying classical EDS. In the second case, DNA sequencing demonstrated a p.Gly1571Arg missense variant in the COL5A1 gene. While samples were not available for further analysis, such a glycine substitution would be expected to destabilize the strict molecular structure of the collagen V triple helix and thus affect protein stability and/or integration of the mutant collagen into the collagen V/collagen I heterotypic dermal fibrils. This is the first report of genetic variants in the COL5A1 gene causing the clinical presentation of EDS in dogs. These data provided further evidence of the important role of collagen V in dermal collagen fibrillogenesis. Importantly, from the clinical perspective, we showed the utility of DNA sequencing, combined with the established clinical criteria, in the accurate diagnosis of EDS in dogs.
Ehlers-Danlos syndromes (EDSs) are a group of rare monogenic conditions with strong heterogeneity and can be caused by 20 genes associating with the essence of the extracellular matrix (ECM). This study enrolled three cases with various subtypes of EDS. Clinical evaluation and genetic testing with whole-exome sequencing (WES) were performed. The clinical manifestations of all three patients were thoroughly monitored; and three de novo diagnostic variants, namely COL5A1: NM_001278074.1: c.4609-2A>C, COL3A1: NM_000090.3: c.3554G>T(p.Gly1185Val), and COL1A1: NM_000088.3: c.545G>T(p.Gly182Val) were identified from them, respectively. The findings in this study expanded the mutation spectrum of EDS and strengthened the efficiency of WES in the differential diagnosis on disorders with overlapping phenotypes and various pathogenesis.
Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant disease caused by aberrations in COL3A1, which encodes type III collagen. Sanger sequencing has limitations for diagnosis since exon deletion/duplication and splicing alterations are not uncommon in COL3A1. We report 2 patients with vEDS who were not diagnosed by conventional Sanger sequencing.
Mutations in the COL3A1 gene that encodes the chains of type III procollagen result in the vascular form of Ehlers-Danlos syndrome (EDS), EDS type IV, if they alter the sequence in the triple-helical domain. Although other fibrillar collagen-gene mutations that lead to allele instability or failure to incorporate proalpha-chains into trimers-and that thus reduce the amount of mature molecules produced-result in clinically apparent phenotypes, no such mutations have been identified in COL3A1. Furthermore, mice heterozygous for Col3a1 "null" alleles have no identified phenotype. We have now found three frameshift mutations (1832delAA, 413delC, and 555delT) that lead to premature termination codons (PTCs) in exons 27, 6, and 9, respectively, and to allele-product instability. The mRNA from each mutant allele was transcribed efficiently but rapidly degraded, presumably by the mechanisms of nonsense-mediated decay. In a fourth patient, we identified a point mutation, in the final exon, that resulted in a PTC (4294C-->T [Arg1432Ter]). In this last instance, the mRNA was stable but led to synthesis of a truncated protein that was not incorporated into mature type III procollagen molecules. In all probands, the presenting feature was vascular aneurysm or rupture. Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those of the vascular form of EDS. This suggests that the major effect of many of these dominant mutations in the "minor" collagen genes may be expressed through protein deficiency rather than through incorporation of structurally altered molecules into fibrils.
The vascular type of Ehlers-Danlos syndrome (EDS), EDS type IV (Online Mendelian Inheritance in Man [MIM] #130050) is characterized by thin, translucent skin, easy bruising, and arterial, intestinal, and/or uterine fragility during pregnancy, which may lead to sudden death. It is an autosomal dominant inherited disorder caused by type III procollagen gene (COL3A1: MIM #120180) mutations. Approximately 50% of the COL3A1 mutations are inherited from an affected parent, and 50% are de novo mutations. Each child of an affected individual has a 50% chance of inheriting the mutation and developing the disorder. Pregnant women with vascular EDS are at an increased risk of uterine and arterial rupture during the peripartum period, with high maternal morbidity and mortality rates. We report the first case of an asymptomatic 35-year-old woman at a risk of complications of vascular EDS who underwent presymptomatic evaluation during pregnancy. The sequencing results of both her brother and mother had a one-base-pair deletion, resulting in Glutamate at position 730 changing to Lysine and causing a frame shift and premature termination codon at 61 amino acids from the mutation position (p. Glu730Lysfs*61) on exon 32 of COL3A1. This deletion caused frameshift, leading to a premature termination codon (TAG) at 181 nucleotides downstream in exon 35, which could not be detected by previous total RNA (ribonucleic acid) method. Thus, she was at risk of complications of vascular EDS, and diagnostic testing was employed at 8 weeks of pregnancy to minimize the risk of developing vascular EDS-related complications. The negative presymptomatic diagnostic result allowed the patient to choose normal delivery at term. Vascular EDS is a serious disorder, with high mortality, especially in high-risk women with vascular EDS during pregnancy. The presymptomatic genetic testing of vascular EDS during pregnancy for a high-risk family can help with the early establishment of preventive measures.
(1) Background: Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by joint hypermobility and skin hyperextensibility with atrophic scarring. Many cEDS individuals carry variants in either the COL5A1 or COL5A2 genes. Mosaicism is relatively common in heritable connective tissue disorders but is rare in EDS. In cEDS, a single example of presumed gonosomal mosaicism for a COL5A1 variant has been published to date. (2) Methods: An 8-year-old girl with cEDS was analyzed by next-generation sequencing (NGS). Segregation was performed by Sanger sequencing in her unaffected parents. In the father, the mosaicism of the variant was further analyzed by targeted NGS and droplet digital PCR (ddPCR) in the blood and by Sanger sequencing in other tissues. (3) Results: The NGS analysis revealed the novel germline heterozygous COL5A1 c.1369G>T, p.(Glu457*) variant in the proband. Sanger chromatogram of the father's blood specimen suggested the presence of a low-level mosaicism for the COL5A1 variant, which was confirmed by NGS and estimated to be 4.8% by ddPCR. The mosaicism was also confirmed by Sanger sequencing in the father's saliva, hair bulbs and nails. (4) Conclusions: We described the second case of cEDS caused by paternal gonosomal mosaicism in COL5A1. Parental mosaicism could be an issue in cEDS and, therefore, considered for appropriate genetic counseling.
Heterozygous missense or in-frame insertion/deletion mutations in complement 1 subunits C1r and C1s cause periodontal Ehlers-Danlos Syndrome (pEDS), a specific EDS subtype characterized by early severe periodontal destruction and connective tissue abnormalities like easy bruising, pretibial haemosiderotic plaques, and joint hypermobility. We report extensive functional studies of 16 C1R variants associated with pEDS by in-vitro overexpression studies in HEK293T cells followed by western blot, size exclusion chromatography and surface plasmon resonance analyses. Patient-derived skin fibroblasts were analyzed by western blot and Enzyme-linked Immunosorbent Assay (ELISA). Overexpression of C1R variants in HEK293T cells revealed that none of the pEDS variants was integrated into the C1 complex but cause extracellular presence of catalytic C1r/C1s activities. Variants showed domain-specific abnormalities of intracellular processing and secretion with preservation of serine protease function in the supernatant. In contrast to C1r wild type, and with the exception of a C1R missense variant disabling a C1q binding site, pEDS variants had different impact on the cell: retention of C1r fragments inside the cell, secretion of aggregates, or a new C1r cleavage site. Overexpression of C1R variants in HEK293T as well as western blot analyses of patient fibroblasts showed decreased levels of secreted C1r. Importantly, all available patient fibroblasts exhibited activated C1s and activation of externally added C4 in the supernatant while control cell lines secreted proenzyme C1s and showed no increase in C4 activation. The central elements in the pathogenesis of pEDS seem to be the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that independently of microbial triggers can activate the classical complement cascade.
The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD-EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13(G64D), in which Gly at amino acid position 64 is replaced by Asp, and ZIP13(ΔFLA), which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13(G64D) and ZIP13(ΔFLA) protein levels are decreased by degradation via the valosin-containing protein (VCP)-linked ubiquitin proteasome pathway. The inhibition of degradation pathways rescued the protein expression levels, resulting in improved intracellular Zn homeostasis. Our findings uncover the pathogenic mechanisms elicited by mutant ZIP13 proteins. Further elucidation of these degradation processes may lead to novel therapeutic targets for SCD-EDS.
Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by hyperextensible skin, joint hypermobility and soft tissue fragility. For molecular diagnosis, targeted exome sequencing was performed on a 9-year-old male patient who was clinically suspected to have EDS. The patient presented with progressive kyphoscoliosis, joint hypermobility and hyperextensible skin without scars. Ultimately, classical EDS was diagnosed by identifying a novel, mono-allelic mutation in COL5A2 [NM_000393.3(COL5A2_v001):c.682G>A, p.Gly228Arg].
TNXB-related classical-like Ehlers-Danlos syndrome (TNXB-clEDS) is an ultrarare type of Ehlers-Danlos syndrome due to biallelic null variants in TNXB, encoding tenascin-X. Less than 30 individuals have been reported to date, mostly of Dutch origin and showing a phenotype resembling classical Ehlers-Danlos syndrome without atrophic scarring. TNXB-clEDS is likely underdiagnosed due to the complex structure of the TNXB locus, a fact that complicates diagnostic molecular testing. Here, we report two unrelated Italian women with TNXB-clEDS due to compound heterozygosity for null alleles in TNXB. Both presented soft and hyperextensible skin, generalized joint hypermobility and related musculoskeletal complications, and chronic constipation. In addition, individual 1 showed progressive finger contractures and shortened metatarsals, while individual 2 manifested recurrent subconjunctival hemorrhages and an event of spontaneous rupture of the brachial vein. Molecular testing found the two previously unreported c.8278C > T p.(Gln2760*) and the c.(2358 + 1_2359 - 1)_(2779 + 1_2780 - 1)del variants in Individual 1, and the novel c.1150dupG p.(Glu384Glyfs*57) and the recurrent c.11435_11524+30del variants in Individual 2. mRNA analysis confirmed that the c.(2358 + 1_2359 - 1)_(2779 + 1_2780 - 1)del variant causes a frameshift leading to a predicted truncated protein [p.(Thr787Glyfs*40)]. This study refines the phenotype recently delineated in association with biallelic null alleles in TNXB, and adds three novel variants to its mutational repertoire. Unusual digital anomalies seem confirmed as possibly peculiar of TNXB-clEDS, while vascular fragility could be more than a chance association also in this Ehlers-Danlos syndrome type.
β4GalT7 is a transmembrane Golgi enzyme, encoded by B4GALT7, that plays a pivotal role in the proteoglycan linker region formation during proteoglycan biosynthesis. Defects in this enzyme give rise to a rare autosomal recessive form of Ehlers-Danlos syndrome (EDS), currently known as 'spondylodysplastic EDS (spEDS-B4GALT7)'. This EDS subtype is mainly characterized by short stature, hypotonia and skeletal abnormalities, thereby illustrating its pleiotropic importance during human development. Insights into the pathogenic mechanisms underlying this disabling disease are very limited, in part due to the lack of a relevant in vivo model. As the majority of mutations identified in patients with spEDS-B4GALT7 are hypomorphic, we generated zebrafish models with partial loss of B4galt7 function, including different knockdown (morphant) and mosaic knockout (crispant) b4galt7 zebrafish models and studied the morphologic, functional and molecular aspects in embryonic and larval stages. Morphant and crispant zebrafish show highly similar morphological abnormalities in early development including a small, round head, bowed pectoral fins, short body-axis and mild developmental delay. Several craniofacial cartilage and bone structures are absent or strongly misshapen. In addition, the total amount of sulfated glycosaminoglycans is significantly diminished and particularly heparan and chondroitin sulfate proteoglycan levels are greatly reduced. We also show impaired cartilage patterning and loss of chondrocyte organization in a cartilage-specific Tg(Col2a1aBAC:mcherry) zebrafish reporter line. The occurrence of the same abnormalities in the different models confirms these are specifically caused by B4galt7 deficiency. A disturbed actin pattern, along with a lack of muscle tone, was only noted in morphants in which translation of b4galt7 was blocked. In conclusion, we generated the first viable animal models for spEDS-B4GALT7, and show that in early development the human spEDS-B4GALT7 phenotype is faithfully mimicked in these zebrafish models. Our findings underscore a key role for β4GalT7 in early development of cartilage, bone and muscle. These models will lead to a better understanding of spEDS-B4GALT7 and can be used in future efforts focusing on therapeutic applications.
We investigated 4 European domestic shorthair kittens with skin lesions consistent with the dermatosparaxis type of the Ehlers-Danlos syndrome, a connective tissue disorder. The kittens were sired by the same tomcat but were born by 3 different mothers. The kittens had easily torn skin resulting in nonhealing skin wounds. Both clinically and histologically, the skin showed thin epidermis in addition to inflammatory changes. Changes in collagen fibers were visible in electron micrographs. The complete genome of an affected kitten was sequenced. A one base pair duplication leading to a frameshift in the candidate gene ADAMTS2 was identified, p.(Ser235fs*3). All 4 affected cats carried the frameshift duplication in a homozygous state. Genotypes at this variant showed perfect cosegregation with the autosomal recessive Ehlers-Danlos syndrome phenotype in the available family. The mutant allele did not occur in 48 unrelated control cats. ADAMTS2 loss-of-function variants cause autosomal recessive forms of Ehlers-Danlos syndrome in humans, mice, dogs, cattle, and sheep. The available evidence from our investigation together with the functional knowledge on ADAMTS2 in other species allows to classify the identified ADAMTS2 variant as pathogenic and most likely causative variant for the observed Ehlers-Danlos syndrome.
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