Biomarker for Metachromatic Leukodystrophy (BioMeta) Disease (BioMeta)

Biomarker for Metachromatic Leukodystrophy Disease AN INTERNATIONAL, MULTICENTER, EPIDEMIOLOGICAL PROTOCOL

Development of a new MS-based biomarker for the early and sensitive diagnosis of Metachromatic Leu-kodystrophy disease from blood (plasma)

Study Overview

• Status: Withdrawn
• Conditions: Muscle Weakness; Peripheral Neuropathy

Detailed Description

Metachromatic Leukodystrophy Disease (MLD) is one of a group of genetic disorders called the leukodystrophies. These diseases impair the growth or development of the myelin sheath, the fatty covering that acts as an insulator around nerve fibers. Myelin, which lends its colour to the white matter of the brain, is a complex substance made up of varying lipids (75%) and proteins (25%). The leukodystrophies are caused by genetic defects in myelin production or metabolization of the compounds of the myelin sheath. Each of the leukodystrophies is the result of a defect in the gene that controls one (and only one) of the enzymes responsible for creating or degrading a part of the myelin. MLD is caused by a deficiency of the enzyme arylsulfatase A. MLD is one of several lipid storage diseases, which results in the toxic build-up of fatty materials (lipids) in cells in the nervous system, liver, and kidneys. There are three forms of MLD: late infantile, juvenile, and adult. Onset of the late infantile form (the most common MLD) is typically between 12 and 20 months following birth. Affected children have difficulty walking after the first year of life. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Most children with this form of MLD die by age 5. The juvenile form of MLD (between 3-10 years of age) usually begins with impaired school performance, mental deterioration, and dementia and then develop symptoms similar to the infantile form but with slower progression. The adult form commonly begins after age 16 as a psychiatric dis-order or progressive dementia. Symptoms include impaired concentration, ataxia, seizures, dementia, and tremor. Due to consanguinity autosomalrecessive disorders such as MLD have higher prevalence in Arabian countries.

New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood (plasma) of affected patients that allow to diagnose in the future the disease earlier, with a higher sensitivity and specificity. In a pilotstudy glycosylsphingosin-sulfatid has been determined as a sensitive and specific biomarker. This is a metabolic product likely to be involved in the pathophysiology of the disease. Therefore it is the goal of the study to validate this new biochemical marker from the blood (plasma) of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment. Examining blood samples will allow to determine whether measurement of the identified marker lyso-Gb1-Sulfatid is feasible in blood samples and will further promote early detection of MLD.

Though MLD 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 MLD, while approximately every 2000th newborn in a non-Arabian country may be eligible.

• Study Type: Observational

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt, 55131
    • 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: 1 day and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with Metachromatic Leukodystrophy disease or profound suspicion for Metachromatic Leukodystrophy disease

Description

INCLUSION CRITERIA:

• Informed consent will be obtained from the patient or the parents before any study related procedures
• Patients from one day
• The patient has a diagnosis of Metachromatic Leukodystrophy disease or profound suspicion for Metachromatic Leukodystro-phy disease
• High-grade suspicion present, if one or more criteria are valid:

Positive family anamnesis for MLD

Neurologic symptoms of unknown origin: peripheral neuropathy, clumsiness, choreatiform movements, spastic quadriplegia, loss of ambulation, bulbar dysfunction/paresis, dysphagia, seizure disorders

Psychiatric symptoms of unknown origin: mental regression, emotional la-bility, disorganized thinking or hallucinations/delusions

Muscle symptoms of unknown origin: muscle weakness

EXCLUSION CRITERIA:

• No Informed consent from the patient or the parents before any study related procedures
• No diagnosis of MLD or no valid criteria for high-grade suspicion of MLD

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Observation; Patients with Metachromatic Leukodystrophy disease or profound suspicion for Metachromatic Leukodystrophy 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 metachromatic leukodystrophy disease from the blood	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 month

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: February 21, 2012
• First Submitted That Met QC Criteria: February 21, 2012
• First Posted (ESTIMATE): February 22, 2012

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: leukodystrophies; Metachromatic Leukodystrophy Disease
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Demyelinating Diseases; Neurologic Manifestations; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neuromuscular Manifestations; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Leukoencephalopathies; Hereditary Central Nervous System Demyelinating Diseases; Sulfatidosis; Muscle Weakness; Peripheral Nervous System Diseases; Leukodystrophy, Metachromatic
• Other Study ID Numbers: BMLD 06-2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO