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Concept: Hunter syndrome

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Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by deficiency of iduronate 2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs) in tissues of affected individuals, progressive disease, and shortened lifespan. Currently available enzyme replacement therapy (ERT) requires lifelong infusions and does not provide neurologic benefit. We utilized a zinc finger nuclease (ZFN)-targeting system to mediate genome editing for insertion of the human IDS (hIDS) coding sequence into a “safe harbor” site, intron 1 of the albumin locus in hepatocytes of an MPS II mouse model. Three dose levels of recombinant AAV2/8 vectors encoding a pair of ZFNs and a hIDS cDNA donor were administered systemically in MPS II mice. Supraphysiological, vector dose-dependent levels of IDS enzyme were observed in the circulation and peripheral organs of ZFN+donor-treated mice. GAG contents were markedly reduced in tissues from all ZFN+donor-treated groups. Surprisingly, we also demonstrate that ZFN-mediated genome editing prevented the development of neurocognitive deficit in young MPS II mice (6-9 weeks old) treated at high vector dose levels. We conclude that this ZFN-based platform for expression of therapeutic proteins from the albumin locus is a promising approach for treatment of MPS II and other lysosomal diseases.

Concepts: DNA, Gene, Genetics, Lysosomal storage disease, Therapy, Fabry disease, Mucopolysaccharidosis, Hunter syndrome

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Mucopolysaccharidosis I (MPS I) is a metabolic disorder caused by α-L-Iduronidase (IDUA) deficiency, resulting in lysosomal accumulation of heparan (HS) and dermatan sulphate (DS). This has been reported in microglia, yet currently the effect of IDUA deficiency on T cells and dendritic cells (DC) and their functionality in disease pathogenesis remains unclear.

Concepts: Mitochondrion, Lysosomal storage disease, Dendritic cell, Lysosome, Dermatan sulfate, Mucopolysaccharidosis, Hunter syndrome, Hurler syndrome

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Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficiency of the enzyme α-galactosidase. It exhibits a wide clinical spectrum that may lead to a delayed or even missed diagnosis and the real incidence can be underestimated. We report the cases of two unrelated Italian families in whom Fabry disease was incidentally diagnosed in two females. In both families, the risk for other lysosomal disorders was known about other members affected respectively by fucosidosis or Mucopolysaccharidosis I (MPSI) Hurler/Scheie. Some subjects were simultaneously heterozygous for Fabry and the other lysosomal deficiency. Our study demonstrates that the risk for more than one lysosomal storage disorder can occur in a family pedigree. The diagnosis of Fabry in female probands represents a diagnostic challenge, as symptoms and signs can be variably present due to the random X-chromosome inactivation.

Concepts: Lysosomal storage disease, Fabry disease, Mucopolysaccharidosis, Lysosomal storage diseases, Hunter syndrome, Sanfilippo syndrome, Mucolipidosis, X-inactivation

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Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder that is progressive and involves multiple organs and tissues. While enzyme replacement therapy (ERT) with idursulfase has been shown to improve many somatic features of the disease, some such as dysostosis multiplex and cardiac valve disease appear irreversible once established, and little is known about the preventative effects of ERT in pre-symptomatic patients. We report on two siblings with severe MPS II caused by an inversion mutation with recombination breakpoints located within the IDS gene and its adjacent pseudogene, IDS-2. The siblings initiated treatment with idursulfase at 3.0years (older brother) and 4months (younger brother) of age, and we compared their outcomes following 2years of treatment. At the start of treatment, the older brother showed typical features of MPS II, including intellectual disability. After 34months of ERT, his somatic disease was stable or improved, but he continued to decline cognitively. By comparison, after 32months of ERT his younger brother remained free from most of the somatic features that had already appeared in his brother at the same age, manifesting only exudative otitis media. Skeletal X-rays revealed characteristic signs of dysostosis multiplex in the older brother at the initiation of treatment that were unchanged two years later, whereas the younger brother showed only slight findings of dysostosis multiplex throughout the treatment period. The younger brother’s developmental quotient trended downward over time to just below the normal range. These findings suggest that pre-symptomatic initiation of ERT may prevent or attenuate progression of the somatic features of MPS II. Follow-up in a larger number of patients is required to confirm the additive long-term benefits of ERT in pre-symptomatic patients.

Concepts: DNA, Lysosomal storage disease, Therapy, Initiation, Fabry disease, TheStart, Mucopolysaccharidosis, Hunter syndrome

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BACKGROUND: The mucopolysaccharidoses (MPS) comprise a group of inherited lysosomal storage disorders characterized by deficiencies in enzymes catalyzing the degradation of glycosaminoglycans. Impairment of pulmonary function is an important health problem for patients with MPS. However, there are few published reports on the prevalence and severity of pulmonary dysfunction in relation to age and treatment in this disorder. METHODS: To evaluate pulmonary function in patients with MPS, we performed spirometry in 35 patients (22 males and 13 females; 1 with MPS I, 12 with MPS II, 16 with MPS IVA, and 6 with MPS VI; mean age, 14.6 ± 5.9 years; age range, 6.4 years to 33 years). Forced vital capacity (FVC), forced expired volume in 1 sec (FEV(1) ), FEV(1) to FVC ratio (FEV1/FVC), peak expiratory flow (PEF), and mean forced expiratory flow during the middle half of FVC (FEF(25-75%) ) were measured. RESULTS: Mean FVC, FEV(1) , PEF, and FEF(25-75%) were 74.2%, 73.9%, 64.7%, and 37.1% of the predicted values, respectively. By spirometric classification, 32 patients (91%) had small airway disease (FEF(25-75%)  < 65%), 17 (48%) had restrictive lung disease, and 3 (9%) had obstructive lung disease. Percent predicted FVC, FEV(1) , and PEF, as well as FEV(1) /FVC, were all negatively correlated with age (P < 0.01), such that pubertal and post-pubertal patients had significantly lower values than younger patients. Of eight attenuated MPS II and VI patients who underwent follow-up pulmonary function testing after receiving enzyme replacement therapy (ERT) for 1.5-7.4 years, six showed improvements in % predicted FVC and five improved in % predicted FEV(1) . CONCLUSION: Our additional characterization of the types and prevalence of pulmonary function abnormalities seen in MPS patients should be useful for clinical care. Pediatr Pulmonol. © 2013 Wiley Periodicals, Inc.

Concepts: Pulmonology, Asthma, Respiratory physiology, Lysosomal storage disease, Chronic obstructive pulmonary disease, Spirometry, Mucopolysaccharidosis, Hunter syndrome

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We devised iduronate-2-sulfatase (IDS) enzyme activity assays by combining fluorometric substrate and LC-MS/MS based detection.

Concepts: Enzyme, Mass spectrometry, Assay, Enzyme assay, Hunter syndrome

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Mucopolysaccharidosis type II (MPS II) is a rare X-linked genetic disorder caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), leading to impaired catabolism of ubiquitous polysaccharides and abnormal accumulation of these undegraded substrates in the lysosome. Like many lysosomal storage diseases, MPS II is characterized by both somatic and central nervous system (CNS) involvement. Intravenous enzyme replacement therapy can improve somatic manifestations of MPS II, but systemic IDS does not cross the blood-brain barrier and therefore cannot address CNS disease. In this study, an adeno-associated virus (AAV) serotype 9 vector carrying the IDS gene was injected into the cerebrospinal fluid (CSF) of IDS deficient mice, a model of MPS II. Treated mice exhibited dose-dependent IDS expression and resolution of brain storage lesions, as well as improvement in long-term memory in a novel object recognition test. These findings suggest that delivery of AAV vectors into CSF could serve as a platform for efficient, long-term enzyme delivery to the CNS, potentially addressing this critical unmet need for patients with MPS II and many related lysosomal enzyme deficiencies.

Concepts: Central nervous system, Nervous system, Genetics, Brain, Lysosomal storage disease, Cerebrospinal fluid, Mucopolysaccharidosis, Hunter syndrome

2

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease. Affected individuals have disease ranging from attenuated to severe with significant disease burden, disability, and premature death. Early treatment with enzyme replacement therapy and/or stem cell transplantation can reduce disease progression and improve outcomes. However, diagnosis is often delayed, particularly for patients with attenuated phenotypes. We conducted a survey of 168 patients and 582 physicians to explore health care seeking patterns and familiarity of physicians with MPS I symptoms. Patients with attenuated MPS I typically first presented with stiff joints or hernia/bulging abdomen, and patients with severe disease with noisy/difficult breathing, or hernia/bulging abdomen. There was a mean delay from time of symptom presentation to diagnosis of 2.7 years for patients with attenuated disease, with a mean of 5 physicians consulted before receiving a correct diagnosis. MPS I was most commonly misidentified by physicians as rheumatoid arthritis (48-72%), with a wide variety of suspected diseases, including lupus.

Concepts: Medicine, Disease, Lysosomal storage disease, Physician, Mucopolysaccharidosis, Lysosomal storage diseases, Hunter syndrome, Hurler syndrome

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Neonatal bone marrow transplantation (nBMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth thus preventing tissue damage. We tested this concept in mucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of α-L-iduronidase (IDUA). MPS IH is characterized by a broad spectrum of clinical manifestations including severe progressive skeletal abnormalities. Although BMT increases the life span of MPS IH patients, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal bone marrow into newborn MPS I mice, soon after birth, can prevent skeletal dysplasia. We observed that nBMT was effective at restoring IDUA activity and clearing elevated glycosaminoglycans in blood and multiple organs. At 37 weeks of age, we observed an almost complete normalization of all bone tissue parameters using radiographic, micro-CT, biochemical, and histological analyses. Overall, the magnitude of improvements correlated with the extent of hematopoietic engraftment. We conclude that BMT at a very early stage in life markedly reduces signs and symptoms of MPS I before they appear.

Concepts: Bone, Bone marrow, Lysosomal storage disease, Genetic disorders, Mucopolysaccharidosis, Lysosomal storage diseases, Hunter syndrome, Hurler syndrome

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Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase. Early bone involvement leads to decreased growth velocity and short stature in nearly all patients. Our analysis aimed to investigate the effects of enzyme replacement therapy (ERT) with idursulfase (Elaprase) on growth in young patients with mucopolysaccharidosis type II. Analysis of longitudinal anthropometric data of MPS II patients (group 1, n = 13) who started ERT before 6 years of age (range from 3 months to 6 years, mean 3.6 years, median 4 years) was performed and then compared with retrospective analysis of data for MPS II patients naïve to ERT (group 2, n = 50). Patients in group 1 received intravenous idursulfase at a standard dose of 0.58 mg/kg weekly for 52-288 weeks. The course of average growth curve for group 1 was very similar to growth pattern in group 2. The average value of body height in subsequent years in group 1 was a little greater than in group 2, however, the difference was not statistically significant. In studied patients with MPS II, idursulfase did not appear to alter the growth patterns.

Concepts: Mode, Lysosomal storage disease, Human height, Arithmetic mean, Mean, Mucopolysaccharidosis, Hunter syndrome, Iduronate-2-sulfatase