Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy (original) (raw)
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Impact of ERT and Follow up of 17 Patients from the Same Family with Mild form of MPS II
2021
Background: Mucopolysaccharidosis type II, also known as Hunter syndrome, is a rare X-linked recessive disorder caused by deficiency of the lysosomal enzyme iduronate-2- sulfatase (IDS), leading to progressive accumulation of glycosaminoglycans (GAGs) in several organs. Over the years, Enzyme Replacement Therapy (ERT) has provided significant benefit for patients, retarding natural progression of the disease.Results: We evaluated 17 patients from the same family with a mild form of MPS type II; proband had developed acute decompensated heart failure refractory to clinical measurements at 23 years and needed a rather urgent heart transplant; however, he died from surgery complications shortly after the procedure. Nevertheless, subsequently to his tragic death, 16 affected male relatives were detected after biochemical tests identifying low or absent activity of IDS enzyme and confirmed by molecular analysis of IDS gene.Following diagnosis, different options of treatment were decided:...
Journal of Inherited Metabolic Disease, 2014
Introduction No published clinical trial data are available to inform the use of enzyme replacement therapy (ERT) in patients with the severe (neuropathic) phenotype of mucopolysaccharidosis II (MPS II). Current guidelines recommend ERT administered intravenously be used on a trial basis in this population. Aims/methods A retrospective chart review was conducted at five international centers for this case series of 22 patients with neuropathic MPS II who received intravenous idursulfase 0.5 mg/kg weekly for at least 2 consecutive years. We collected data about urinary glycosaminoglycan levels, adverse events, and the following somatic signs/symptoms: skeletal disease, joint range of motion, liver/spleen size, respiratory infections, cardiac disease, diarrhea, skin/hair texture, and hospitalizations. Results The age at diagnosis was 2 months to 5 years, and the age at idursulfase initiation was between 18 months and 21 years. One of 22 patients experienced improvements in seven somatic signs/symptoms; 17/22 experienced improvements in five to six somatic signs/symptoms; and 4/22 experienced improvements in four somatic signs/symptoms. None experienced fewer than four improvements. No new safety concerns arose. Infusion-related reactions were experienced by 4/22 patients but were successfully managed using accepted strategies. Conclusions Long-term treatment with idursulfase was associated with improvements in somatic manifestations in this Communicated by: Frits Wijburg Electronic supplementary material The online version of this article (
Presentation and treatments for Mucopolysaccharidosis Type II (MPS II; Hunter Syndrome)
Expert Opinion on Orphan Drugs, 2017
Introduction-Mucopolysaccharidosis 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 covered-Current 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 opinion-Conventional 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).
Molecular Genetics and Metabolism, 2007
Mucopolysaccharidosis II (MPS II; Hunter syndrome) is an X-linked metabolic disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S), which catalyzes the catabolism of glycosaminoglycans (GAG) by cleaving the O-linked sulfate from dermatan sulfate and heparan sulfate. Recently, enzyme replacement therapy (ERT) with recombinant human I2S (Elapraseä (idursulfase), Shire Human Genetic Therapies, Inc.), has been approved in the US and European Union for the treatment and management of MPS II. The purpose of the studies presented here was to describe some of the preclinical development of idursulfase using the I2S knockout mouse model of MPS II designed to study the effect of dose and various dosing regimens of idursulfase on urine and tissue GAG levels. Urine and tissue samples were collected prior to idursulfase treatment and periodically throughout each study and analyzed for GAGs. The presence of anti-idursulfase antibodies in the mice serum after idursulfase use was also determined. Results showed that idursulfase, at several doses and at several dosing frequencies, caused a reduction in tissue and urine GAG levels in a dose-dependent manner. These studies also demonstrated that after IV administration, idursulfase is biologically active in the IdS-KO mouse model and is transported to key target tissues, reaching the lysosomes in an active form, and degrading the accumulated GAG. In conclusion, these results indicated that ERT with idursulfase produced in a human cell line could be useful in the treatment and management of MPS II, and were used in the design of clinical studies to evaluate the efficacy of idursulfase in MPS II patients.
Profile of idursulfase for the treatment of Hunter syndrome
Research and Reports in Endocrine Disorders, 2015
Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulfatase (IDS). Enzyme replacement therapy (ERT) with recombinant human IDS, available since 2005, is currently the most appropriate treatment for this progressive, multisystemic, chronic, and life-threatening disease. Efficacy and safety of therapy with idursulfase have been assessed in several clinical trials, and confirmed in many clinical reports. Long-term follow-up of patients receiving ERT has demonstrated the importance of an early onset of treatment with idursulfase, before irreversible pathological changes occur. Intravenously administered idursulfase is not able to cross the blood-brain barrier, so neurological signs and symptoms cannot benefit from ERT, still remaining a major challenge in the treatment of MPS II.
Journal of investigational allergology & clinical immunology, 2011
Hunter syndrome or type II mucopolysaccharidosis is a rare lysosomal storage disease of X-linked recessive inheritance. It is characterized by a lack of the enzyme iduronate 2 sulfatase (I2S), which leads to the accumulation of glycosaminoglycans in many cells and tissues, resulting in myocardiopathy, airway obstruction, skeletal deformities, and severe and progressive neurologic disturbances. Those affected often die in the second decade of life [1]. Until the appearance of enzyme replacement therapy, there were few therapeutic options that had a signifi cative impact on the natural course of the disease. Nowadays, however, it is possible to compensate for the enzymatic loss with idursulfase, a purifi ed form of I2S produced using DNA recombinant technology in a continuous human cell line [2]. However, the administration of idursulfase is associated with infusion-related hypersensitivity reactions in a high percentage of patients [3]. Table. Proposed 8-hour Desensitization Protocol for Idursulfase a Dilution Concentration Preparation Infusion Rate Duration 1 1/1000 (0.000012 mg/mL) 10 mL of dilution #2 in 1st hour: 10 mL/hr 2 hr 90 mL of NS 2nd hour: 90 mL/hr 2 1/100 (0.00012 mg/mL) 10 mL of dilution #3 in 1st hour: 10 mL/hr 2 hr 90 mL of NS 2nd hour: 90 mL/hr 3 1/10 (0.0012 mg/mL) 10 mL of dilution #4 in 1st hour: 10 mL/hr 2 hr 90 mL of NS 2nd hour: 90 mL/hr 4 Basal (0.012 mg/mL) 12 mg (6 mL) of idursulfase 1st hour: 10 mL/hr 2 hr in 94 mL of NS 2nd hour: 90 mL/hr a The patient should receive 0.5 mg/kg weekly. Each ampule contains 6 mg of idursulfase diluted in 3 mL of normal saline (NS). The dilutions shown here were calculated according to the patient´s body weight (24 kg) and prepared in progressive steps from dilution #4. Thirty minutes before initiating the protocol, we administered 1 mg of intravenous clemastine. To prepare individual protocols, the dose should be calculated according to specifi c body weight. The total volume of dilution #4 should be 100 mL.