Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT02298712 |
| Other study ID # |
BHUR 06-2018 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 20, 2018 |
| Est. completion date |
February 28, 2021 |
Study information
| Verified date |
February 2023 |
| Source |
CENTOGENE GmbH Rostock |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Development of a new MS-based biomarker for the early and sensitive diagnosis of Hurler
disease from plasma. Testing for clinical robustness, specificity and long-term stability of
the biomarker.
Description:
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.
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. Types of MPS I.
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 allow 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.
New methods, like mass-spectrometry give a good chance to characterize specific metabolic
alterations in the blood (plasma) of affected patients that allow diagnosing in the future
the disease earlier, with a higher sensitivity and specificity.
Therefore it is the goal of the study to identify and validate a new biochemical marker from
the plasma of the affected patients helping to benefit other patients by an early diagnose
and thereby with an earlier treatment.
Though 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.
