Spondylo-ocular Syndrome Research Articles

Spondylo-ocular syndrome: anaesthetic concerns and considerations for a novel genetic syndrome – a case report

Spondylo-ocular syndrome: anaesthetic concerns and considerations for a novel genetic syndrome – a case report

Xylosyltransferase-Deficiency in Human Dermal Fibroblasts Induces Compensatory Myofibroblast Differentiation and Long-Term ECM Reduction.

Desbuquois dysplasia type 2 (DBQD2) and spondylo-ocular syndrome (SOS) are autosomal recessive disorders affecting the extracellular matrix (ECM) and categorized as glycosaminoglycan (GAG) linkeropathies. Linkeropathies result from mutations within glycosyltransferases involved in the synthesis of the tetrasaccharide linker, a linker between the core protein of proteoglycan (PG) and GAG. DBQD2 and SOS are caused by the isolated mutations of the xylosyltransferase (XT) isoforms. In this work, we successfully generated XYLT1- as well as XYLT2-deficient GAG linkeropathy model systems in human dermal fibroblasts using a ribonucleoprotein-based CRISPR/Cas9-system. Furthermore, it was possible to generate a complete XYLT-knockdown. Short- and long-term XT activity deficiency led to the mutual reduction in all linker transferase-encoding genes, suggesting a potential multienzyme complex with mutual regulation. Fibroblasts compensated for ECM misregulation initially by overexpressing ECM through the TGFβ1 signaling pathway, akin to myofibroblast differentiation patterns. The long-term reduction in one XT isoform induced a stress response, reducing ECM components. The isolated XYLT1-knockout exhibited α-smooth muscle actin overexpression, possibly partially compensated by unaltered XT-II activity. XYLT2-knockout leads to the reduction in both XT isoforms and a strong stress response with indications of oxidative stress, induced senescence and apoptotic cells. In conclusion, introducing XYLT-deficiency revealed temporal and isoform-specific regulatory differences.

Japanese medaka Olpax6.1 mutant as a potential model for spondylo-ocular syndrome

Japanese medaka Olpax6.1 mutant as a potential model for spondylo-ocular syndrome

Spondyloocular Syndrome: A Report of an Additional Family and Phenotypic Spectrum Delineation.

Spondyloocular syndrome (SOS, OMIM # 605822) is a rare genetic disorder characterized by osseous and ocular manifestations, including generalized osteoporosis, multiple long bones fractures, platyspondyly, dense cataracts and retinal detachment, and dysmorphic facial features, with or without short stature, cardiopathy, hearing impairment, and intellectual disability. Biallelic mutations in the XYLT2 gene (OMIM * 608125), encoding the xylosyltransferase II, were shown to be responsible for this disease. To date, 22 cases with SOS have been described, with varying clinical presentations and a yet-to-be-established genotypic-phenotypic correlation. Two patients from a consanguineous Lebanese family that presented with SOS were included in this study. Whole exome sequencing revealed a novel homozygous nonsense mutation in XYLT2 (p.Tyr414*) in these patients. We review all previously reported cases with SOS, describe the second nonsense mutation in XYLT2, and contribute to a better delineation of the phenotypic spectrum of the disease.

Abstract #1180788: Spondylo-ocular Syndrome --A rare bone disease

Spondylo-ocular syndrome is a rare genetic disorder. Clinical findings include osteoporosis, eye abnormalities including cataract, keratoconus, glaucoma, etc. and hearing abnormalities. The syndrome was reported in 2015 as genetic defect in XYLT-2 gene. Almost eleven different variants have been reported so far from European Australia, Turkey and Pakistan. Mostly spondylo-ocular syndrome is seen in consanguineous marriages.

An association between bilateral keratoconus in a patient with spondyloocular syndrome and xylosyltransferase II gene mutation

Spondyloocular syndrome (SOS) is a rare autosomal-recessive disorder. Since 2015, SOS has been linked to mutations in xylosyltransferase II (XYLT2) locus. Phenotypic features could affect multiple systems, such as sight, hearing, or bones. Herein, we report a case of SOS with multiple bone fractures without trauma, bilateral cataracts, and sensorineural hearing loss. Mutations in XYLT2 gene were detected, and the diagnosis of SOS was made. At the age of 8, the patient presented with progressive vision loss. Slit-lamp examination revealed inferior steepening, apical scarring, and thinning of the cornea. Due to keratoconus suspicion, a corneal tomography was done, confirming the diagnosis of keratoconus. We present the first case of bilateral keratoconus in a patient with SOS.

A Novel Homozygous Frameshift Variant in XYLT2 Causes Spondyloocular Syndrome in a Consanguineous Pakistani Family.

We report on three new patients with spondyloocular syndrome (SOS) in a consanguineous Pakistani family. All three patients present progressive generalized osteoporosis, short stature, recurrent fractures, hearing loss and visual impairments. WES revealed a novel homozygous frameshift variant in exon 11 of XYLT2 (NG 012175.1, NP_071450.2) resulting in loss of evolutionary conserved amino acid sequences (840 – 865/865) at C-terminus p.R840fs∗115. Sanger Sequencing confirmed the presence of the novel homozygous mutation in all three patients while the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern. Only nine variants worldwide have previously been reported in XYLT2 in patients with SOS phenotype. These three patients with novel homozygous variant extend the genotypic and phenotypic spectrum of SOS.

Intrafamilial variability of XYLT2-related spondyloocular syndrome

Spondyloocular syndrome is characterized by generalized osteoporosis, multiple fractures and severe ocular findings. The causative XYLT2 mutations have recently been identified with the use of whole exome sequencing. We report on two siblings with spondyloocular syndrome who presented with varying clinical severity. A novel XYLT2 missense mutation was detected in a region evolutionary conserved across the species. This report along with the previous reports demonstrates that variable expressivity may be possible even within the same family. These two siblings with a novel mutation further expand the clinical and mutational spectrum of spondyloocular syndrome.

Homozygous XYLT2 variants as a cause of spondyloocular syndrome.

Spondyloocular syndrome (SOS) is a rare autosomal recessive, skeletal disorder. Two recent studies have shown that it is the result of biallelic sequence variants in the XYLT2 gene with pleiotropic effects in multiple organs, including retina, heart muscle, inner ear, cartilage, and bone. The XYLT2 gene encodes xylosyltransferase 2, which catalyzes the transfer of xylose (monosaccharide) to the core protein of proteoglycans (PGs) leading to initiating the process of PG assembly. SOS was originally characterized in 2 families A and B of Iraqi and Turkish origin, respectively. Using DNA from affected members of the same 2 families, we performed whole exome sequencing, which revealed 2 novel homozygous missense variants (c.1159C > T, p.Arg387Trp) and (c.2548G > C, p.Asp850His). Our findings extend the body of evidence that SOS is caused by homozygous variants in the XYLT2 gene. In addition, this report has extended the phenotypic description of SOS by adding follow-up data from 5 affected individuals in one of the two families, presented here.

Abnormal Proteoglycan Synthesis Due to Gene Defects Causes Skeletal Diseases with Overlapping Phenotypes.

In recent years, massively parallel sequencing technologies have helped us to identify novel disease genes and solve the mysteries behind rare diseases. Today, we know that some diseases with many overlapping and distinct clinical features, as presented in this review, can be caused by mutations in genes that encode enzymes playing crucial roles at different steps of the exact same pathway. In this review, we exclusively focused on 5 genes - XYLT1, XYLT2, B4GALT7, B3GALT6, and B3GAT3 - that encode enzymes involved in the biosynthesis of the common tetrasaccharide linker region of proteoglycans and review the associated diseases, also referred to as linkeropathies, by summarizing the cases reported in literature. Since proteoglycans are essential macromolecules in development, signaling and homeostasis of many tissues and organs, mutations in these genes can affect many organs; including bone, cartilage, eyes, ears, heart, and skin. Short stature, developmental delay, facial dysmorphism, and skeletal dysplasias are some of the common features observed in patients with mutations in these genes. Among these genes, XYLT2 mutations cause a relatively distinct phenotype, the so-called spondyloocular syndrome, which is characterized by clinical presentation of a very severe childhood-onset primary osteoporosis, cataract, and hearing impairment. The full phenotype spectrum of diseases mentioned here is likely to expand with additional clinical reports and further molecular studies.

Homozygosity for Frameshift Mutations in XYLT2 Result in a Spondylo-Ocular Syndrome with Bone Fragility, Cataracts, and Hearing Defects

Heparan and chondroitin/dermatan sulfated proteoglycans have a wide range of roles in cellular and tissue homeostasis including growth factor function, morphogen gradient formation, and co-receptor activity. Proteoglycan assembly initiates with a xylose monosaccharide covalently attached by either xylosyltransferase I or II. Three individuals from two families were found that exhibited similar phenotypes. The index case subjects were two brothers, individuals 1 and 2, who presented with osteoporosis, cataracts, sensorineural hearing loss, and mild learning defects. Whole exome sequence analyses showed that both individuals had a homozygous c.692dup mutation (GenBank: NM_022167.3) in the xylosyltransferase II locus (XYLT2) (MIM: 608125), causing reduced XYLT2 mRNA and low circulating xylosyltransferase (XylT) activity. In an unrelated boy (individual 3) from the second family, we noted low serum XylT activity. Sanger sequencing of XYLT2 in this individual revealed a c.520del mutation in exon 2 that resulted in a frameshift and premature stop codon (p.Ala174Profs(∗)35). Fibroblasts from individuals 1 and 2 showed a range of defects including reduced XylT activity, GAG incorporation of (35)SO4, and heparan sulfate proteoglycan assembly. These studies demonstrate that human XylT2 deficiency results in vertebral compression fractures, sensorineural hearing loss, eye defects, and heart defects, a phenotype that is similar to the autosomal-recessive disorder spondylo-ocular syndrome of unknown cause. This phenotype is different from what has been reported in individuals with other linker enzyme deficiencies. These studies illustrate that the cells of the lens, retina, heart muscle, inner ear, and bone are dependent on XylT2 for proteoglycan assembly in humans.

Spondylo‐ocular syndrome: A new entity involving the eye and spine

Spondylo‐ocular syndrome: A new entity involving the eye and spine

Spondylo-ocular syndrome: a new entity with crystalline lens malformation, cataract, retinal detachment, osteoporosis, and platyspondyly

PurposeTo define a new clinical entity in a consanguineous family with six children affected by a spondylo-ocular syndrome, including cataract, crystalline lens malformation, retinal detachment, osteoporosis, and platyspondyly. To analyze candidate genes of connective tissue disorders as a possible underlying disorder and to demonstrate especially the ocular phenotype. DesignObservational case series. MethodsConsanguineous parents, one unaffected sibling and five affected children with clinical features of spondylo-ocular syndrome, were demonstrated. Clinical examination, radiologic, laboratory, and cytogenetic as well as moleculargenetic analyses were performed. The segregation of flanking marker alleles of three collagen genes and the interval for osteoporosis-pseudoglioma syndrome were analyzed. Two microsatellite markers located within Pax6CA/GT region were tested for homozygosity. ResultsOn laboratory investigation a normal excretion of amino acids, mucopolysaccharides, and oligosaccharides could be found. The karyotype was normal. Complete radiologic examination in one index patient revealed a generalized moderate osteoporosis, platyspondyly with fish bone appearance, and greatly enlarged intervertebral spaces. The candidate genes known to be in Stickler syndrome as well as linkage to the osteoporosis-pseudoglioma syndrome candidate region could be excluded. None of the affected showed homozygosity for the Pax6 microsatellite markers. ConclusionsWe conclude that the phenotype and the clinical features in this family defines a new Mendelian disorder. It remains to be seen what kind of molecule shared by eye and bone is involved.