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Urinary Glycosaminoglycan Levels Appear to Drop by Over 100% in Children with Mucopolysaccharidosis Type II

Barbara Burton - Speaker World Symposium 2017

February 18, 2017—San Diego, California—Though patient numbers are low, findings indicate decreased urinary glycosaminoglycan levels following idursulfase therapy in children with mucopolysaccharidosis type II (Hunter syndrome).

This outcome of a study of data in the Hunter Outcome Survey, a global, observational registry, was reported at the 13th Annual WORLDSymposium, from February 13 – 18.

Barbara K. Burton, MD, of Northwestern University, Feinberg School of Medicine, Chicago, Illinois, explained that specific treatment for mucopolysaccharidosis type II (Hunter syndrome) is available in the form of intravenous enzyme replacement therapy.

Coinvestigator Joseph Muenzer, MD, PhD, of the University of North Carolina, Chapel Hill, explained, “Hunter syndrome is a rare genetic disorder with progressive neurological disease in the severe form. No treatment is available for this disease.”

Hunter syndrome primarily affects males (X-linked recessive). It interferes with the body's ability to break down and recycle specific mucopolysaccharides, also known as glycosaminoglycans. Hunter syndrome is one of several related lysosomal storage diseases called the mucopolysaccharide diseases. An estimated 2000 persons are afflicted with Hunter syndrome worldwide, 500 of whom live in the US.

In Hunter syndrome, the problem concerns the breakdown of two glycosaminoglycans: dermatan sulfate and heparan sulfate. The first step in the breakdown of dermatan sulfate and heparan sulfate requires the lysosomal enzyme I2S.

A definitive diagnosis of Hunter syndrome is made by measuring I2S activity in serum, white blood cells, or fibroblasts from a skin biopsy. In some patients with Hunter syndrome, analysis of the I2S gene can determine clinical severity. Prenatal diagnosis is routinely available by measuring I2S enzymatic activity in amniotic fluid or chorionic villus tissue.

In patients with Hunter syndrome, this enzyme is either partially or completely inactive. As a result, 12S builds up in cells throughout the body, particularly in tissues that contain large amounts of dermatan sulfate and heparan sulfate. As this build-up continues, it interferes with the way certain cells and organs function and leads to a number of serious symptoms. The rate of glycosaminoglycan build-up varies from patient to patient, resulting in a wide spectrum of abnormalities.

Idursulfase stabilises or improves many somatic features of mucopolysaccharidosis type II in patients age ≥5years. Tolerability and initial efficacy outcomes in patients starting idursulfase therapy at age 1.4–7.5 years have been shown to be similar to those of the first clinical studies but experience in patients age ≤18 months remains limited.

Diagnosis of mucopolysaccharidosis type II early in life is improving, requiring a need for a better understanding of the impact of early initiation of enzyme replacement therapy.

Dr. Burton and colleagues analysed data from patients enrolled in the Hunter Outcome Survey who started idursulfase at age ≤18 months (n=45 prospective patients; all male).

Patients were diagnosed at a median (P10, P90) age of 0.4 (0.0, 1.3) years. Symptom onset was at age 0.4 (0.0, 1.1) years. Almost half suffered cognitive impairment (48.8%; 20/41). Patients had received idursulfase for 53.3 (2.1, 91.9) months, starting at age 0.8 (0.2, 1.4) years.

Three individuals stopped enzyme replacement therapy and did not restart it. Sixteen patients started idursulfase at <6 months (median 0.3 [0.0,0.4] years). Urinary glycosaminoglycan measurements (dimethylmethylene blue spectrophotometric assay adjusted for urine creatinine; n=33) showed a trend toward a decrease from elevated baseline levels with idursulfase therapy.

Among those with data at both baseline and 1 year of idursulfase (n=11), urinary glycosaminoglycan levels dropped by −61.6% (−81.8, 44.1%). Between baseline and year 2 (n=9), the change was −73.5% (−87.7, 115.7%). Though patient numbers are low, the findings indicate decreased urinary glycosaminoglycan levels following idursulfase therapy in children with mucopolysaccharidosis type II (Hunter syndrome).

Additional follow-up and analysis of a range of clinical outcomes will further improve our understanding of early treatment with idursulfase.

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Molecular Genetics and Metabolism is a contribution to the understanding of the metabolic basis of disease. The journal publishes articles describing investigations that use the tools of biochemistry and molecular biology for studies of normal and diseased states. In addition to original research articles, occasional minireviews reporting timely advances as well as brief communications and letters to the editor are considered.

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