1. BioHurler

BioHurler

Clinical trial started on October 23, 2014

Synopsis

Hurler disease - MPS I (mucopolysaccharidosis I) - is an inherited lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase, a lysosomal enzyme normally required for the breakdown of certain complex carbohydrates known as glycosaminoglycans (GAGs). If the enzyme is not present in sufficient quantities, the normal breakdown of GAGs is incomplete or blocked. The cell is then unable to excrete the carbohydrate residues and they accumulate in the lysosomes of the cell. This accumulation disrupts the cell's normal functioning and gives rise to the clinical manifestations of the disease.

New methods, such as mass spectrometry provide a good chance of characterizing specific metabolicalterations in the blood (plasma) of affected patients that will allow us to diagnose the disease earlier in the future, with higher sensitivity and specificity.

Therefore, it is the goal of this study to identify and validate a new biochemical marker from the plasma of affected patients helping to benefit other patients by an early diagnosis and thereby with earlier treatment.

Examining saliva samples will allow us to determine whether measurement is feasible in saliva samples and will further promote early detection of MPS1 disease.


Background information

What is Hurler Syndrome?

The incidence of MPS I is estimated to be at about 1 in 100,000 births. It is inherited in an autosomal recessive manner, affects males and females equally, and in most cases both parents of an affected child are asymptomatic carriers of the disease. Children diagnosed with MPS I have historically been classified into one of three categories based on the severity of their symptoms and rate of disease progression. It has now become clear, however, that there is a wide spectrum of severity in MPS I, with much overlap between the categories.

  • Hurler Syndrome
    The most severe form of MPS I is characterized by progressive developmental delay and severe progressive physical problems. Death often occurs before 10 years of age.
  • Hurler-Scheie Syndrome
    The intermediate form of MPS I is characterized by normal or near normal intelligence but more severe physical symptoms than those with Scheie Syndrome.
  • Scheie Syndrome
    The attenuated form of MPS I is characterized by normal intelligence, usually normal height, and milder physical problems than Hurler-Scheie. These individuals potentially have a normal life span.

Patients present within the first year of life with musculoskeletal alterations including short stature, dysostosis multiplex, thoracic-lumbar kyphosis, progressive coarsening of the facial features including large head with bulging frontal bones, depressed nasal bridge with broad nasal tip and anteverted nostrils, full cheeks and enlarged lips, cardiomyopathy and valvular abnormalities, neurosensorial hearing loss, enlarged tonsils and adenoids, and nasal secretion. Developmental delay is usually observed between 12 and 24 months of life and is primarily in the speech realm with progressive cognitive and sensorial deterioration. Hydrocephaly can occur after the age of two. Diffuse corneal compromise leading to corneal opacity becomes detectable from three years of age. Other manifestations include organomegaly, hernias and hirsutism. MPS1 syndrome is caused by mutations in the IDUA gene (4p16.3) leading to complete deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate. Transmission is autosomal recessive. Early diagnosis is difficult because the first clinical signs are not specific, but it is very important to enable early treatment. Diagnosis is based on detection of increased urinary excretion of heparan and dermatan sulfate by 1, 9-dimethylmethylene blue (DMB) test and glycosaminoglycan (GAG) electrophoresis, and demonstration of enzymatic deficiency in leukocytes or fibroblasts. Genetic testing is available. Differential diagnoses include the milder form of mucopolysaccharidosis type 1, the MPS1-Scheie syndrome, although this form is associated with developmental delay with only slight cognitive impairment.

Although MPS1 disease is a pan-ethnic disorder, the prevalence of this autosomal-recessive disorder is elevated in countries with a higher frequency of consanguinity. Therefore, we estimate that every 400th newborn in Arabian countries may be eligible for inclusion due to high-grade suspicion of MPS1 disease, while approximately every 2000th newborn in a non-Arabian country may be eligible.