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

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

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)

Study Overview

• Status: Withdrawn
• Conditions: Developmental Delay; Mental Retardation

Detailed Description

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.

• Study Type: Observational

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt, 89075
    • Children's Hospital, Faculty of Medicine, Ain Shams University
• Germany
  • Rostock, Germany, 18055
    • Centogene AG
• India
  • Mumbai, India, 400705
    • Navi Mumbai Institute of Research In Mental And Neurological Handicap (NIRMAN)
  • Kerala
    • Cochin, Kerala, India, 682041
      • Amrita Institute Of Medical Sciences & Research Centre
• Sri Lanka
  • Colombo 8, Sri Lanka, 00800c
    • Lady Ridgeway Hospital for Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with Sanfilippo Type A-B-C-D disease or high-grade suspicion for Sanfilippo Type A-B-C-D disease

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Observation; 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?

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

Collaborators and Investigators

• Sponsor: CENTOGENE GmbH Rostock

Publications and helpful links

Helpful Links

• Centogene is one of the leading laboratories focusing on genetic testing for rare hereditary disorders. We now offer more than 2200 routine genetic and biochemical tests.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 20, 2018
• Primary Completion (ACTUAL): February 28, 2021
• Study Completion (ACTUAL): February 28, 2021

Study Registration Dates

• First Submitted: October 23, 2014
• First Submitted That Met QC Criteria: November 19, 2014
• First Posted (ESTIMATE): November 24, 2014

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2023
• Last Update Submitted That Met QC Criteria: February 9, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Biomarker; Sanfilippo Disease Type A-B-C-D
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurodevelopmental Disorders; Intellectual Disability
• Other Study ID Numbers: BSF01-2014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No