heparitin-sulfate and Intellectual-Disability

Developmental disabilities are defined as disorders that result in the limitation of function due to impaired development of the nervous system; these disabilities can be present in the form of impairments in learning, language, behavior, or physical abilities. Examples of developmental disorders include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), cerebral palsy (CP), hearing loss, blindness, intellectual disability, and learning disability. Of these disorders, ASD prevalence was 18.5 per 1000 children (1 in 54) aged 8 in 2016. Current literature suggests that deficient levels of heparan sulfate (HS), an acidic and linear glycosaminoglycan (GAG), is likely causative of ASD. The cascading effect of deficient HS levels can offer compelling evidence for the association of HS with ASD. Deficient levels of HS lead to defective Slit/Robo signaling, which affects axonal guidance and dendritic spine formation. Defective Slit/Robo signaling leads to increased Arp2/3 activity and dendritic spine density, which has been observed in the brains of persons with ASD. Therefore, interventions that target HS and its associated pathways may be viable treatment options for ASD.

Topics: Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Autistic Disorder; Child; Heparitin Sulfate; Humans; Intellectual Disability

Glypicans are a family of cell surface heparan sulfate proteoglycans that play critical roles in multiple cell signaling pathways. Glypicans consist of a globular core, an unstructured stalk modified with sulfated glycosaminoglycan chains, and a glycosylphosphatidylinositol anchor. Though these structural features are conserved, their individual contribution to glypican function remains obscure. Here, we investigate how glypican 3 (GPC3), which is mutated in Simpson-Golabi-Behmel tissue overgrowth syndrome, regulates Hedgehog signaling. We find that GPC3 is necessary for the Hedgehog response, surprisingly controlling a downstream signal transduction step. Purified GPC3 ectodomain rescues signaling when artificially recruited to the surface of GPC3-deficient cells but has dominant-negative activity when unattached. Strikingly, the purified stalk, modified with heparan sulfate but not chondroitin sulfate, is necessary and sufficient for activity. Our results demonstrate a novel function for GPC3-associated heparan sulfate and provide a framework for the functional dissection of glycosaminoglycans by in vivo biochemical complementation. This article has an associated First Person interview with the first author of the paper.

Topics: Abnormalities, Multiple; Arrhythmias, Cardiac; Genetic Diseases, X-Linked; Gigantism; Glypicans; Heart Defects, Congenital; Hedgehog Proteins; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Intellectual Disability; Signal Transduction

Mucopolysaccharidoses (MPS) are characterized by mental retardation constantly present in the severe forms of Hurler (MPS I), Hunter (MPS II) and Sanfilippo (MPS III) diseases. On the contrary, mental retardation is absent in Morquio (MPS IV) and Maroteaux-Lamy (MPS VI) diseases and absent or only minimal in the attenuated forms of MPS I, II and III. Considering that MPS patients affected by mental disease accumulate heparan sulfate (HS) due to specific enzymatic defects, we hypothesized a possible correlation between urinary HS-derived glucosamine (GlcN) accumulated in tissues and excreted in biological fluids and mental retardation. 83 healthy subjects were found to excrete HS in the form of fragments due to the activity of catabolic enzymes that are absent or impaired in MPS patients. On the contrary, urinary HS in 44 patients was observed to be composed of high molecular weight polymer and fragments of various lengths depending on MPS types. On this basis we correlated mental retardation with GlcN belonging to high and low molecular weight HS. We demonstrate a positive relationship between the accumulation of high molecular weight HS and mental retardation in MPS severe compared to attenuated forms. This is also supported by the consideration that accumulation of other GAGs different from HS, as in MPS IV and MPS VI, and low molecular weight HS fragments do not impact on central nervous system disease.

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Glucosamine; Heparitin Sulfate; Humans; Infant; Intellectual Disability; Male; Molecular Weight; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis III; Reference Values; Young Adult

We report the case of a 28-year-old female subject affected by the attenuated phenotype of mucopolysaccharidosis type IIIA characterized by moderate slowly evolving mental retardation in which the urinary content of heparan sulfate was demonstrated as being substantially low compared to that found in patients with the severe phenotype.. The specific evaluation of macromolecular heparan sulfate by electrophoresis and the determination of related glucosamine in the urine were performed.. In our patient, the urinary macromolecular heparan sulfate content (4.2μg/mg creatinine) was ~7.5-times higher than in healthy subjects (0.56μg/mg creatinine±0.9 SD) while it was ~28-times lower compared to the severe mucopolysaccharidosis IIIA group (117μg/mg creatinine±44.8 SD). Furthermore, the urinary glucosamine (86.4μg/mg creatinine) was ~2.4-times greater than in healthy subjects (36.0μg/mg creatinine±18.2 SD) but ~2.4-times lower than in severe subjects (208.1μg/mg creatinine±55.0 SD).. The above data could reflect the reduced heparan sulfate storage in her tissues and organs, and in particular in the brain, consequently explaining her moderate mental retardation. Furthermore, the clinical presentation of patients with an attenuated form of MPS III confirms the need for a specific evaluation of urinary GAGs in all young and adult subjects showing a not well-defined or not particularly severe mental retardation, along with an early MPS diagnosis. Such investigation should also be associated with a more specific characterization of heparan sulfate.

Topics: Adult; Female; Heparitin Sulfate; Humans; Intellectual Disability; Mucopolysaccharidosis III; Phenotype

Sanfilippo B is a rare autosomal recessive mucopolysaccharidosis (MPS IIIB) caused by a deficiency of N-acetyl-alpha-D-glucosaminidase (NAGLU).. A mild mentally retarded elderly female patient is described with a slowly progressive dementia who had given birth to a daughter who developed normally.. Metabolic screening revealed an enhanced concentration of heparan sulfate in urine. Enzymatic assay demonstrated deficiency of N-acetyl-alpha-D-glucosaminidase. Mutations in the NAGLU gene were found. One mentally retarded and hospitalized elder brother was also found to have MPS IIIB, whereas a second brother, who had died earlier, is suspected to have had the same metabolic disorder. Prior to the development of dementia, both the patient and her brother showed autistic like features, signs of ideomotor apraxia and weakness in verbal comprehension.. Screening for metabolic disorders, in particular MPSes, should always be considered in patients with a history of mental deficit and dementia or progressive functional decline.

Topics: Acetylglucosaminidase; Alzheimer Disease; Atrophy; Brain; Chromosome Aberrations; Diagnosis, Differential; Female; Genes, Recessive; Heparitin Sulfate; Humans; Intellectual Disability; Magnetic Resonance Imaging; Middle Aged; Mucopolysaccharidosis III

Topics: Acetylglucosaminidase; Alzheimer Disease; Chromosome Aberrations; Diagnosis, Differential; Female; Genes, Recessive; Heparitin Sulfate; Humans; Intellectual Disability; Middle Aged; Mucopolysaccharidosis III; Phenotype; Social Adjustment

Multiple Sulfatase Deficiency (MSD) is a rare autosomal recessive disease in which the activities of all sulfatases are reduced; its estimated prevalence is 1:1.4 million births. The disease is caused by mutations in SUMF1, which encodes an enzyme involved in the post-translational modification of sulfatases. The MSD phenotype is a combination of the clinical features found in diseases resulting from a deficiency of the individual sulfatases; i.e., mucopolysaccharidosis II, IIIA, IIID, IVA and VI, metachromatic leukodystrophy, X-linked ichthyosis, and the X-linked recessive form of chondrodysplasia punctata. We describe herein the first case of a Brazilian patient with MSD. The case was initially diagnosed as having mucopolysaccharidosis (MPS), due to skeletal alterations, coarse facial features, and urinary excretion of dermatan sulfate and heparan sulfate. Later, after a detailed biochemical investigation, the diagnosis of MSD was established. The analysis of the SUMF1 showed the patient was a compound heterozygote for two novel mutations (p.R349G and p.F244S). This case illustrates the challenges in the diagnosis of a disease considered rare, such as MSD. We point out that the availability of therapy for certain MPS disorders necessitates correct disease assignment, and the need to exclude the likelihood of MSD.

Topics: Brain; Brazil; Child, Preschool; Dermatan Sulfate; Diagnosis, Differential; Heparitin Sulfate; Humans; Intellectual Disability; Male; Multiple Sulfatase Deficiency Disease; Mutation; Oxidoreductases Acting on Sulfur Group Donors; Sulfatases; Tomography, X-Ray Computed

Clinical heterogeneity for Sanfilippo B syndrome (MPS III B) in the same family has never been reported previously. We describe two clinically severe cases and one clinically mild case of MPS III B in a Neapolitan sibship. We could not detect N-acetyl-alpha-D-glucosaminidase activity in the sera of either the severe or mild cases. Mucopolysacchariduria mainly due to heparan sulfate excretion was consistently high in the severely affected patients and extremely variable in the mildly affected one.

Topics: Abnormalities, Multiple; Adult; Child; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Intellectual Disability; Male; Mucopolysaccharidoses; Mucopolysaccharidosis III

Topics: Adolescent; Adult; Brain; Child; Child, Preschool; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Iduronidase; Infant; Intellectual Disability; Liver; Male; Molecular Weight; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis III; Organ Specificity; Spleen; Sulfatases

Glycosaminoglycans were isolated from the urines of 46 patients with mucopolysaccharidosis; 11 with Type I (Hurler), 8 with Type II (Hunter), 16 with Type III (Sanfilippo A and B), 9 with Type V (Scheie), one with Type VI (Marateaux-Lamy), and one unclassified. All 46 patients excreted in their urine excessive amounts of dermatan sulfate, heparan sulfate or both. In addition, patients of certain types excreted excessive amounts of chondroitin sulfates A and/or C. There is a trend in each type of the disease towards the same carbazole/orcinol ratio, glucosamine/galactosamine ratio and glycosaminoglycan composition. Molecular weight distribution of the urinary glycosaminoglycans by gel filtration from Sephadex G-200 is characteristic for each different type of mucopolysaccharidosis and is distinguished from normal controls and patients without mucopolysaccharidosis. Preparation of elution diagrams from Sephadex G-200 allows an estimation of the composition of the glycosamino-glycans. Practically all heparan sulfate and a sizable part of dermatan sulfate from the urinary glycosaminoglycans of all these patients have been highly degraded. In all the patients in which the specific enzyme defect was demonstrated, the assignment of the type of mucopolysaccharidosis, on the basis of the elution diagrams, was correct. Patients with mucopolysaccharidosis Type V displayed two conspicuously different types of elution patterns, suggesting heterogeneity. Indeed, only a portion of these patients showed alpha-L- iduronidase deficiency. Carriers had normal urinary glycosaminoglycan output and composition and exhibited normal elution diagrams.

Topics: Adolescent; Adult; Bone and Bones; Carbohydrate Metabolism, Inborn Errors; Child; Child, Preschool; Chondroitin; Dermatan Sulfate; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hypertrichosis; Infant; Intellectual Disability; Joint Diseases; Male; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis II; Retinitis Pigmentosa

Morphological and biochemical autopsy findings of a 12 year old girl with mucopolysaccharidosis type III (Sanfilippo's syndrome). The clinically suspected diagnosis was biochemically ascertained before the patients death. The autopsy findings obtained by biochemical and by light and electron microscopic investigations of different organs are compared with the results of other authors.

Topics: Autopsy; Central Nervous System; Child; Female; Fibroblasts; Genotype; Glucuronidase; Glycosaminoglycans; Heparin; Heparitin Sulfate; Hexosaminidases; Humans; Hydrolases; Intellectual Disability; Liver; Microscopy, Electron; Mucopolysaccharidoses; Syndrome

Topics: Cells, Cultured; Dermatan Sulfate; Female; Fibroblasts; Glucuronidase; Glycosaminoglycans; Heparitin Sulfate; Hepatomegaly; Humans; Infant; Infant, Newborn; Intellectual Disability; Jaundice, Neonatal; Molecular Weight; Mucopolysaccharidoses

Topics: Amniocentesis; Amniotic Fluid; Cells, Cultured; Female; Fetal Diseases; Fetus; Fibroblasts; Glycoside Hydrolases; Heparitin Sulfate; Humans; Inclusion Bodies; Intellectual Disability; Liver; Lyases; Microscopy, Electron; Mucopolysaccharidoses; Pregnancy; Prenatal Diagnosis; Sulfur Radioisotopes; Syndrome

Topics: Adolescent; Adult; Carbazoles; Carbohydrate Metabolism, Inborn Errors; Child; Chondroitin; Corneal Opacity; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Intellectual Disability; Male; Methods; Mucopolysaccharidoses; Resorcinols; Retinitis Pigmentosa; Uronic Acids

Topics: Adolescent; Blood Transfusion; Carbohydrate Metabolism, Inborn Errors; Chemical Precipitation; Child; Chromatography, Gel; Chromatography, Ion Exchange; Female; Galactosamine; Glucosamine; Glycosaminoglycans; Heparitin Sulfate; Humans; Intellectual Disability; Male; Molecular Weight; Plasma; Time Factors; Uronic Acids

Topics: Amyloidosis; Animals; Aorta; Carbohydrate Metabolism, Inborn Errors; Cattle; Chromatography, Ion Exchange; Dialysis; Electrophoresis; Galactosamine; Glucuronates; Glycosaminoglycans; Heparitin Sulfate; Hexosamines; Hexoses; Humans; Intellectual Disability; Intestines; Liver; Lung; Methods; Molecular Weight; Optical Rotation; Proteins; Uronic Acids

Topics: Ammonium Sulfate; Carbohydrate Metabolism, Inborn Errors; Chromatography; Chromatography, Gel; Chromatography, Ion Exchange; Drug Stability; Electrophoresis; Fibroblasts; Glycosaminoglycans; Half-Life; Heparitin Sulfate; Hexosaminidases; Humans; Intellectual Disability; Phenols; Skin; Sulfatases; Sulfates; Sulfur Isotopes; Sulfuric Acids

Topics: Carbohydrate Metabolism, Inborn Errors; Diagnosis, Differential; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Mucopolysaccharidosis I; Mucopolysaccharidosis IV

Topics: Carbohydrate Metabolism, Inborn Errors; Chondroitin; Chromatography, Thin Layer; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Intellectual Disability; Mucopolysaccharidoses; Mucopolysaccharidosis IV; Retinitis Pigmentosa