Biomarker for Sanfilippo Type A-B-C-D Disease (BioSanfilippo)

Study Overview
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Brief Summary
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Development of a new MS-based biomarker for the ear-ly and sensitive diagnosis of Sanfilippo Disease Type A-B-C-D from blood (plasma)

Detailed Description
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The Mucopolysaccharidoses (MPS Disorders) are a group of rare genetic disorders caused by the deficiency of one of the lysosomal enzymes, resulting in an inability to metabolize complex carbohydrates (mucopolysaccharides) into simpler molecules. High concentrations of mucopolysaccharides in the cells of the central nervous system, including the brain, cause the neu-rological and developmental deficits that accompany these disorders. Lysosomal enzymes are found in the lysosome, a very small membrane-contained body (organelle) found in the cytoplasm of most cells. The lysosome is often called the waste disposal plant of the cell. The accumulation of these large, undegraded mucopolysaccharides in the cells of the body is the cause of a number of physical symptoms and abnormalities. MPS-III (Sanfilippo Syndrome) is one of seven MPS Disorders. It is an inborn error of metabolism that is transmitted as an autosomal recessive genetic disorder. MPS-lll has been categorized into four subtypes: MPS-III Type A, MPS-III Type B, MPS-III Type C, and MPS-III Type D depending on the gene defect (MPS3A - SGSH gene, MPS3B - NAGLU gene, MPS3C - HGSNAT, MPS3D - GNS gene). All types are associated with some degree of mental deterioration, but the severity depends on the particular type of MPS-lll. Several physical defects may be present, and the severity of these defects varies with the type of MPS-III. In the case of each type of MPS-III, abnormal amounts of a specific, chemically complex molecule is excreted in the urine. The excreted chemical is the same for each of the four types of MPS-III, since the defective gene involves a different step, and thus a different enzyme, in the deconstruction of the same mucopolysaccharide. By testing for one or another of these enzymes, the variant type may be readily identified. Symptoms Patients with Sanfilippo Syndrome (MPS Type III) usually appear normal at birth, but mental retardation and developmental delay is usually evident by age 3-5 years. Mental and motor development reaches a peak by 3-6 years of age after which behavioral disturbances and intellectual decline usually occur. However, hyperactivity and irritability may become obvious earlier. The following symptoms are usually apparent by approximately age 10: neurological deficits and signs, wobbly and erratic gait and difficulty walking (ataxia), hyperactivity (hyperkinetic syndrome), mental retardation, stiff joints, hernias, enlarged liver and/or spleen (hepatosplenomegaly).Growth is usually minimally affected; the head may be enlarged, and abnormal hairiness (hirsutism) may occur. Mild coarsening of facial features also characterizes this disorder. In some cases deafness may also occur. Causes All four varieties of MPS-III are autosomal recessive genetic disorders. The gene abnormalities associated with MSS-IIIA, MPS-IIIB, MPS-IIIC and MPS-IIID have been identified. The Gene Map Loci are as follows: MPS-IIIA --------- 17q25.3; SGSH gene MPS-IIIB --------- 17q21.2; NAGLU gene MPS-IIIC --------- 8p11.21; HGSNAT gene MPS-IIID --------- 12q14.3; GNS gene Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Official Title
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Biomarker for Sanfilippo Disease Type A-B-C-D AN INTERNATIONAL, MULTICENTER, EPIDEMIOLOGICAL PROTOCOL

Conditions
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Mental Retardation, Developmental Delay

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Informed consent will be obtained from the patient or the parents before any study related procedures. Patients of both genders older than 2 month The patient has a diagnosis of Sanfilippo Type A-B-C-D disease or a high-grade suspicion for Sanfilippo Type A-B-C-D disease High-grade suspicion present, if one or more inclusion criteria are valid: Positive family anamnesis for Sanfilippo Type A-B-C-D disease Dysostosis multiplex without identifiable cause Splenomegaly without identifiable cause Hepatomegaly without identifiable cause Heparan sulfate excretion in urine CNS involvement without identifiable cause EXCLUSION CRITERIA: No Informed consent from the patient or the parents before any study related procedures. Patients of both gender younger than 2 month No diagnosis of Sanfilippo Type A-B-C-D disease or no valid criteria for profound suspicion of Sanfilippo Type A-B-C-D disease

Ages Eligible for Study
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Minimum Age: 2 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Observation<br>Patients with Sanfilippo Type A-B-C-D disease or high-grade suspicion for Sanfilippo Type A-B-C-D disease | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Development of a new MS-based biomarker for the early and sensitive diagnosis of Sanfilippo Type A-B-C-D disease from plasma | New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood of affected patients that allow diagnosing in the future the disease earlier, with a higher sensitivity and specificity. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Testing for clinical robustness, specificity and long-term stability of the biomarker | the goal of the study to identify and validate a new biochemical marker from the blood of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sanfilippo Disease Type A-B-C-D, Biomarker