heparitin-sulfate and Atrophy

To characterize the longitudinal natural history of disease progression in pediatric subjects affected with mucopolysaccharidosis (MPS) IIIB.. Sixty-five children with a confirmed diagnosis of MPS IIIB were enrolled into 1 of 2 natural history studies and followed for up to 4 years. Cognitive and adaptive behavior functions were analyzed in all subjects, and volumetric magnetic resonance imaging analysis of liver, spleen, and brain, as well as levels of heparan sulfate (HS) and heparan sulfate nonreducing ends (HS-NRE), were measured in a subset of subjects.. The majority of subjects with MPS IIIB achieved an apex on both cognition and adaptive behavior age equivalent scales between age 3 and 6 years. Development quotients for both cognition and adaptive behavior follow a linear trajectory by which subjects reach a nadir with a score <25 for an age equivalent of 24 months by age 8 years on average and by 13.5 years at the latest. All tested subjects (n = 22) had HS and HS-NRE levels above the normal range in cerebrospinal fluid and plasma, along with signs of hepatomegaly. Subjects lost an average of 26 mL of brain volume (-2.7%) over 48 weeks, owing entirely to a loss of cortical gray matter (32 mL; -6.5%).. MPS IIIB exists along a continuum based on cognitive decline and cortical gray matter atrophy. Although a few individuals with MPS IIIB have an attenuated phenotype, the majority follow predicted trajectories for both cognition and adaptive behavior.. ClinicalTrials.gov identifiers NCT02493998, NCT03227042, and NCT02754076.

Topics: Atrophy; Brain; Gray Matter; Heparitin Sulfate; Humans; Magnetic Resonance Imaging; Mucopolysaccharidosis III

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

Mucopolysaccharidosis (MPS) type I (alpha-iduronidase deficiency) is characterized by storage and massive urinary excretion of dermatan sulfate and heparan sulfate; it may be distinguished into three different subtypes based on age at onset and severity of the clinical symptoms. We report on progressive white matter involvement documented by serial MR imaging in a patient with the MPS type I, severe skeletal involvement and preserved mental capabilities (intermediate phenotype or Hurler/Scheie syndrome).The natural history of white matter abnormalities in patients with MPS is still unclear; based on the present study, it appears that degenerative changes of the white matter mimicking a leukodystrophy may mark the course of MPS type I. We also suggest that the degree of MR changes in patients with MPS does not always reflect their neurological impairment.

Topics: Adolescent; Atrophy; Bone and Bones; Bone Diseases, Metabolic; Brain; Cerebral Ventricles; Cognition Disorders; Dermatan Sulfate; Diagnosis, Differential; Female; Heparitin Sulfate; Humans; Iduronidase; Leukodystrophy, Globoid Cell; Magnetic Resonance Imaging; Mucopolysaccharidosis I; Nerve Fibers, Myelinated; Phenotype

This study shows that cotreatment with insulin-like growth factor-I (IGF-I) and glycosaminoglycans (GAGs) prevents the onset of neuromuscular deficit in the m/m mutant mouse. These mice show a mid-to-late-life onset of progressive paralysis of the hind limb, that is correlated with altered innervation and reduced nerve-evoked isometric twitch tension in the extensor digitorum longus (EDL) muscle. Almost 50% of EDL nerve endings are negative for antisynaptophysin staining, while retrograde labelling with beta-cholera-toxin coupled to type IV horseradish and quantitative histological analysis show a small loss of EDL and lumbar cord motor neurons. At 10 months of age also forelimb function evaluated as grip strength is significantly reduced. Animals treated either with glycosaminoglycans alone or with IGF-I alone at low and high doses showed only a partial improvement of their condition. However, cotreatment of m/m mice with IGF-I and GAGs fully prevented the neuromuscular abnormalities, the twitch tension loss, the motor neuron decrease and the reduction of forelimb grip strength.

Topics: Animals; Atrophy; Cell Count; Cholera Toxin; Dermatan Sulfate; Drug Therapy, Combination; Female; Fluorescent Dyes; Heparitin Sulfate; Horseradish Peroxidase; Insulin-Like Growth Factor I; Male; Mice; Mice, Neurologic Mutants; Motor Neurons; Muscle Fibers, Skeletal; Muscle, Skeletal; Nerve Degeneration; Neuromuscular Diseases; Neuroprotective Agents; Presynaptic Terminals; Rhodamines; Synaptophysin

We report a case of atrophoderma of Pasini and Pierini. We determined the glycosaminoglycan content in the involved skin. Dermatan sulfate content in the involved skin (1.88 micrograms uronic acid/mg dry skin) was greater than that in the uninvolved skin (1.05 micrograms uronic acid/mg dry skin). No significant differences in hyaluronic acid, chondroitin sulfate or heparan sulfate content between involved and uninvolved skin were observed. These results suggest that abnormal metabolism of dermatan sulfate may be involved in the pathogenesis of atrophoderma; this pattern has been observed in systemic or localized scleroderma.

Topics: Adult; Atrophy; Chondroitin Sulfates; Dermatan Sulfate; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Male; Pigmentation Disorders; Scleroderma, Localized; Scleroderma, Systemic; Skin; Uronic Acids