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Mucopolysaccharidosis Type II and the G374sp Mutation.

ABSTRACT: Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a rare, X-linked disease caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, which catalyses a step in the catabolism of glycosaminoglycans resulting in accumulation of heparan and dermatan sulfate in many organs and tissues. This accumulation favors the appearance of neurologic involvement, severe airway obstruction, skeletal deformities, and cardiomyopathy, especially mitral and aortic valve regurgitation. In severe cases, obstructive airway disease and cardiac failure due to valvular dysfunction are the most common causes of death within the second decade of life. However, in mild cases, intelligence remains normal, stature is almost normal and death usually occurs due to cardiac failure in the fourth decade of life. We report the presentation, diagnosis, management, and outcome of 2 siblings with MPS II and the G374sp mutation at the nucleotide c.1246 of the gene encoding for the iduronate-2-sulfatase.

SUBMITTER: Martinez-Quintana E

PROVIDER: S-EPMC3666454 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Mucopolysaccharidosis Type II and the G374sp Mutation.

Martínez-Quintana E E Rodríguez-González F F

Molecular syndromology 20130213 4

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a rare, X-linked disease caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, which catalyses a step in the catabolism of glycosaminoglycans resulting in accumulation of heparan and dermatan sulfate in many organs and tissues. This accumulation favors the appearance of neurologic involvement, severe airway obstruction, skeletal deformities, and cardiomyopathy, especially mitral and aortic valve regurgitati ...[more]

PMID: 23801937

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Osteoarthropathy in mucopolysaccharidosis type II.

Project description:IntroductionMucopolysaccharidosis type II (MPS type II, Hunter syndrome) is a rare (~ 1/1500.000), X-linked inherited disorder (affects boys) due to deficiency of the lysosomal enzyme iduronate sulfatase (Xq.28). The complex clinical picture includes osteoarthropathy with a tendency to flexion stiffness and disability. In our country, the specific diagnosis and enzyme replacement therapy (ERT), are recently available in the Center for Genetic Pathology Cluj.ObjectivesAssessment of clinical features, radiological and imaging of osteoarthropathy in MPS type II and their evolution under ERT.Material and methodsThe study included 9 male patients with a suggestive clinical picture of MPS type II; the diagnosis was confirmed by enzymatic assay and the patients were treated with ERT. Osteoarthropathy was assessed before treatment: a) clinical tests (joint goniometry, walking test) and b) radiology (X-rays of the hand and wrist, spine and pelvis), bone densitometry in five patients. Clinical tests were repeated after therapy.ResultsChronic osteoarthropathy was present in all patients. Joint mobility was reduced with quasi stationary trend after 12 months of treatment. The walking test was improved after treatment. Radiological assessment revealed: hand bones changes, delayed bone age, vertebral changes, pelvis changes, kipho-scoliosis and aseptic necrosis of the femoral head in 100%, 88%, 88%, 55% and 11% respectively. Bone mineral density was normal in five of the nine patients evaluated.ConclusionsChronic osteoarthropathy with flexion stiffness is an essential component of the clinical picture of MPS type II. ERT allows an improvement/arrest of evolution (depending on disease severity and time of initiating therapy).

| S-EPMC4462490 | biostudies-literature

Presentation and Treatments for Mucopolysaccharidosis Type II (MPS II; Hunter Syndrome).

Project description:IntroductionMucopolysaccharidosis Type II (MPS II; Hunter syndrome) is an X- linked lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS). IDS deficiency leads to primary accumulation of dermatan sulfate (DS) and heparan sulfate (HS). MPS II is both multi-systemic and progressive. Phenotypes are classified as either attenuated or severe (based on absence or presence of central nervous system impairment, respectively).Areas coveredCurrent treatments available are intravenous enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), anti-inflammatory treatment, and palliative care with symptomatic surgeries. Clinical trials are being conducted for intrathecal ERT and gene therapy is under pre-clinical investigation. Treatment approaches differ based on age, clinical severity, prognosis, availability and feasibility of therapy, and health insurance.This review provides a historical account of MPS II treatment as well as treatment development with insights into benefits and/or limitations of each specific treatment.Expert opinionConventional ERT and HSCT coupled with surgical intervention and palliative therapy are currently the treatment options available to MPS II patients. Intrathecal ERT and gene therapy are currently under investigation as future therapies. These investigative treatments are critical to address the limitations in treatment of the central nervous system (CNS).

| S-EPMC5693349 | biostudies-literature

Cognitive, medical, and neuroimaging characteristics of attenuated mucopolysaccharidosis type II.

Project description:The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, has not been previously studied in systematic manner. In contrast to the "severe" phenotype, the "attenuated" phenotype does not present with behavioral or cognitive impairment; however, the presence of mild behavior and cognitive impairment that might impact long-term functional outcomes is unknown. Previously, significant MRI abnormalities have been found in MPS II. Recent evidence suggests white matter abnormalities in many MPS disorders.As the initial cross-sectional analysis of a longitudinal study, we studied the association of brain volumes and somatic disease burden with neuropsychological outcomes, including measures of intelligence, memory, and attention in 20 patients with attenuated MPS II with a mean age of 15.8. MRI volumes were compared to 55 normal controls.While IQ and memory were average, measures of attention were one standard deviation below the average range. Corpus callosum volumes were significantly different from age-matched controls, differing by 22%. Normal age-related volume increases in white matter were not seen in MPS II patients as they were in controls. Somatic disease burden and white matter and corpus callosum volumes were significantly associated with attention deficits. Neither age at evaluation nor age at starting treatment predicted attention outcomes.Despite average intelligence, attention is compromised in attenuated MPS II. Results confirm an important role of corpus callosum and cortical white matter abnormality in MPS II as well as the somatic disease burden in contributing to attention difficulties. Awareness by the patient and caregivers with appropriate management and symptomatic support will benefit the attenuated MPS II patient.

| S-EPMC4312717 | biostudies-literature

RNA-Seq profiling of brain in Mucopolysaccharidosis type II mouse model

Project description:Lysosomal Storage Disorders (LSDs) are a group of about 50 metabolic disorders, sharing the inability to degrade specific endolysosomal substrates. This results in failure of cellular functions in many organ systems including brain in most patients, which show a progressive neurodegeneration. In this study we performed an RNA-Seq analysis of two brain areas (cerebral cortex and midbrain/diencephalon/hippocampus) of the mouse model for Mucopolysaccharidosis type II, a neurodegenerative LSD.

2017-05-19 | GSE95224 | GEO

Severe tracheal and bronchial collapse in adults with type II mucopolysaccharidosis.

Project description:Mucopolysaccharidosis type II (MPSII) patients frequently suffer from dyspnoea caused by restrictive airway disease due to skeletal abnormalities as well as glycosaminoglycans (GAG) accumulation at different levels of the airway, including the trachea. In this study we describe the extent of the tracheal and bronchial narrowing, the changes in airway diameter during respiration and the effects of these obstructions on respiratory function in adult MPSII patients.Five adult MPSII patients (mean age 40 years) were included. Pulmonary function tests and in- and expiratory chest CT scans were obtained. Cross-sectional areas of trachea and main bronchi were measured at end-inspiration and -expiration and percentage collapse was calculated.There was diffuse narrowing of the entire intra-thoracic trachea and main bronchi and severe expiratory collapse of the trachea in all patients. At 1 cm above the aortic arch the median % collapse of the trachea was 68 (range 60 to 77%), at the level of the aortic arch 64 (range 21-93%), for the main bronchi this was 58 (range 26-66%) on the left and 44 (range 9-76%) on the right side. The pulmonary function tests showed that this airway collapse results in obstructive airway disease in all patients, which was severe (forced expiratory volume <50% of predicted) in four out of five patients.In adult MPS II patients, central airways diameters are strikingly reduced and upon expiration there is extensive collapse of the trachea and main bronchi. This central airways obstruction explains the severe respiratory symptoms in MPSII patients.

| S-EPMC4845328 | biostudies-literature

Brain RNA-Seq Profiling of the Mucopolysaccharidosis Type II Mouse Model.

Project description:Lysosomal storage disorders (LSDs) are a group of about 50 genetic metabolic disorders, mainly affecting children, sharing the inability to degrade specific endolysosomal substrates. This results in failure of cellular functions in many organs, including brain that in most patients may go through progressive neurodegeneration. In this study, we analyzed the brain of the mouse model for Hunter syndrome, a LSD mostly presenting with neurological involvement. Whole transcriptome analysis of the cerebral cortex and midbrain/diencephalon/hippocampus areas was performed through RNA-seq. Genes known to be involved in several neurological functions showed a significant differential expression in the animal model for the disease compared to wild type. Among the pathways altered in both areas, axon guidance, calcium homeostasis, synapse and neuroactive ligand-receptor interaction, circadian rhythm, neuroinflammation and Wnt signaling were the most significant. Application of RNA sequencing to dissect pathogenic alterations of complex syndromes allows to photograph perturbations, both determining and determined by these disorders, which could simultaneously occur in several metabolic and biochemical pathways. Results also emphasize the common, altered pathways between neurodegenerative disorders affecting elderly and those associated with pediatric diseases of genetic origin, perhaps pointing out a general common course for neurodegeneration, independent from the primary triggering cause.

| S-EPMC5454982 | biostudies-literature

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment.

Project description:Mucopolysaccharidosis type II (MPS II, Hunter syndrome) was first described by Dr. Charles Hunter in 1917. Since then, about one hundred years have passed and Hunter syndrome, although at first neglected for a few decades and afterwards mistaken for a long time for the similar disorder Hurler syndrome, has been clearly distinguished as a specific disease since 1978, when the distinct genetic causes of the two disorders were finally identified. MPS II is a rare genetic disorder, recently described as presenting an incidence rate ranging from 0.38 to 1.09 per 100,000 live male births, and it is the only X-linked-inherited mucopolysaccharidosis. The complex disease is due to a deficit of the lysosomal hydrolase iduronate 2-sulphatase, which is a crucial enzyme in the stepwise degradation of heparan and dermatan sulphate. This contributes to a heavy clinical phenotype involving most organ-systems, including the brain, in at least two-thirds of cases. In this review, we will summarize the history of the disease during this century through clinical and laboratory evaluations that allowed its definition, its correct diagnosis, a partial comprehension of its pathogenesis, and the proposition of therapeutic protocols. We will also highlight the main open issues related to the possible inclusion of MPS II in newborn screenings, the comprehension of brain pathogenesis, and treatment of the neurological compartment.

| S-EPMC7072947 | biostudies-literature

Clinical and Genetic Characteristics of Romanian Patients with Mucopolysaccharidosis Type II.

Project description:BACKGROUND:Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare X-linked disorder caused by deficiency of iduronate-2-sulfatase (I2S) enzyme, which leads to the accumulation of partially digested glycosaminoglycans (GAGs) in the lysosomes and induces multisystemic alteration (coarse facial features; skeletal dysplasia; hepatosplenomegaly; joint stiffness and contractures; heart, lung, vision, and hearing disability; profound neurological decline).The purpose of this study is to present the clinical and genetic characteristics of Romanian patients with Hunter syndrome and the genotype-phenotype correlation. MATERIAL AND METHODS:15 unrelated patients, with MPS II ranging from mild (4 subjects) to severe phenotype (11 subjects) aged 2 to 20 years, were evaluated clinically, cognitive development, enzyme assay and molecular analysis. RESULTS:The molecular analysis of the 15 unrelated Romanian MPS II patients has identified 15 different mutations (2 major genetic defects (13%) and 13 minor genetic defects (87%)): microdeletions and point mutations (missense, nonsense), seven of them described for the first time-deletion encompassing 3 to exon 7; c823G>T, pD275Y; c.1600A>C (pN534H); c.102_10delAG (p.D5Cfs*11); c.448_471del (p.P150_P157del); c.421delA (p.I141Yfs*72); and c.419-1G>C. The major genetic defects were correlated with a severe course of disease. CONCLUSION:This is the first study on the clinical and molecular characterization of the MPS II Romanian patients. This study supports the evidence of the mutational heterogeneity of the I2S gene as well as the difficulty to correlate genotype and phenotype in the patients with MPS II.

| S-EPMC5413445 | biostudies-literature

Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I.

Project description:BackgroundMucopolysaccharidosis type I (MPSI) is a rare autosomal recessive disorder caused by a deficiency of α-l-iduronidase (IDUA) encoded by the IDUA gene. We examined the mutation spectrum of the IDUA gene to explain the clinical, biochemical, and molecular features in 21 Iranian patients with MPSI.MethodsSanger sequencing was used to measure the IDUA gene sequence in the coding region and exon-intron boundaries. We recorded the clinical findings of studied patients at the first diagnosis of disease and then during the treatment and follow-up.ResultsFive different missense disease-causing mutations were determined in our patient groups, indicating 90.48% of detection rate. The most widespread mutation was the p.Y109H, occurring in 15.625% of all alleles, which was reported for the first time in our study. Other frequent mutations were as follows: p.Ser157Pro (12.5%), p.Gly84Arg (12.5%), p.Asp257His (9.375%), and p.Asp301Glu (9.375%). Three ones of them were new missense mutations: p.Ser157Pro, p.Asp257His, and p.Asp301Glu.DiscussionThe results of this study explain the different spectrum of IDUA gene mutations in our patients with MPSI. We introduced here 32 different variants including four new variants: p.Y109H (15.625%), p.S157P (12.5%), p.D257H (9.375%), and p.D301E (9.375%). In this series, there was no relationship between the happening of clinical features and genotype variations and biochemical findings.

| S-EPMC6805319 | biostudies-literature

Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II.

Project description:Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an inherited X-linked recessive disease caused by deficiency of iduronate-2-sulfatase (IDS), resulting in the accumulation of the glycosaminoglycans (GAG) heparan and dermatan sulfates. Mouse models of MPS II have been used in several reports to study disease pathology and to conduct preclinical studies for current and next generation therapies. Here, we report the generation and characterization of an immunodeficient mouse model of MPS II, where CRISPR/Cas9 was employed to knock out a portion of the murine IDS gene on the NOD/SCID/Il2rγ (NSG) immunodeficient background. IDS-/- NSG mice lacked detectable IDS activity in plasma and all analyzed tissues and exhibited elevated levels of GAGs in those same tissues and in the urine. Histopathology revealed vacuolized cells in both the periphery and CNS of NSG-MPS II mice. This model recapitulates skeletal disease manifestations, such as increased zygomatic arch diameter and decreased femur length. Neurocognitive deficits in spatial memory and learning were also observed in the NSG-MPS II model. We anticipate that this new immunodeficient model will be appropriate for preclinical studies involving xenotransplantation of human cell products intended for the treatment of MPS II.

| S-EPMC10705040 | biostudies-literature

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