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Patients with Hunter Syndrome Diagnosed Early in Life Differ Clinically from Those Diagnosed Later

Muenzer - Speaker World Symposium 2017Joseph Muenzer, MD, PhD

February 18, 2017—San Diego, California—Patients diagnosed with mucopolysaccharidosis type II (Hunter disease) later in life may have different clinical characteristics than those diagnosed earlier, though with significant morbidity.

This conclusion, based on results of a review of data from the Hunter Outcomes Study, was presented at the 13th Annual WORLDSymposium, from February 13–18.

Joseph Muenzer, MD, PhD, of the University of North Carolina, Chapel Hill, explained that individuals with the severe form of mucopolysaccharidosis type II (Hunter syndrome) are rarely diagnosed before 1–2 years of age. Patients with the attenuated form are typically diagnosed later.

He said, “Hunter syndrome is a rare genetic disorder with progressive neurological disease in the severe form. No treatment is available for this disease.”

Mucopolysaccharidosis II, 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.

Intravenous enzyme replacement therapy with idursulfase is efficacious for somatic manifestations of Hunter syndrome.

Using data from the Hunter Outcomes Study global observational registry, clinical characteristics and surgical history of prospective patients age ≥5 years at diagnosis (“late diagnosis”) were compared with those of patients age <5 years (“early diagnosis”).

As of January 2016, 204/947 patients were age ≥5 years at diagnosis and 609/947 <5 years (median ages [P10; P90]: 6.6 [5.0; 15.3] and 2.7 [0.7; 4.1] years, respectively). Median ages at symptom onset were 3.0 (0.5;7.0) and 1.3 (0.3;3.3) years.

Joint stiffness, hernia, and facial features consistent with Hunter syndrome were common in both groups (189/200 [95%] vs 537/602 [89%]; 174/198 [88%] vs 475/599 [79%]; 189/200 [95%] vs 563/602 [94%], respectively).

Cognitive impairment and behavioural problems, however, were less common in the late- than the early-diagnosis group (81/196 [41%] vs 398/597 [67%]; 73/196 [37%] vs 375/598 [63%], respectively).

Median numbers of surgeries per patient were similar in both groups (four [one; nine] and five [one;10], respectively). First surgery, however, occurred later in the late- than the early-diagnosis group (4.0 [0.2;16.8] vs 2.3 [0.2;7.6] years, respectively).

Hernia repair, carpal tunnel decompression and cervical decompression were more common in the late- (n=204) than in the early-diagnosis group (n=609; 58% vs 48%; 36% vs 26%; 5% vs 2%, respectively).

Conversely, ear tube insertions and adenoidectomies were less common in the late- than in the early-diagnosis group (46% vs 55%; 42% vs 56%). Fourteen percent (28/204) of patients in the late-diagnosis group and 18% (111/609) in the early-diagnosis group had died.

Dr. Muenzer concluded that patients diagnosed with Hunter syndrome later in life may have different clinical characteristics than those diagnosed younger, though with significant morbidity.

Further analysis is required to delineate these differences and explore whether longer follow-up time is a factor in delineating clinical characteristics of mucopolysaccharidosis in these children.

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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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