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The Myelin Disorders Biorepository Project (MDBP)

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ClinicalTrials.gov Identifier: NCT03047369
Recruitment Status : Recruiting
First Posted : February 9, 2017
Last Update Posted : March 20, 2018
Sponsor:
Collaborators:
Massachusetts General Hospital
University of Wisconsin, Madison
Alfred I. duPont Hospital for Children
Information provided by (Responsible Party):
Children's Hospital of Philadelphia

Brief Summary:

This is an observational designed to:

  • Aim 1: Define novel homogeneous groups of patients with unclassified leukodystrophy and work toward finding the cause of these disorders;
  • Aim 2: Assess the validity and utility of next-generation sequencing in the diagnosis of leukodystrophies;
  • Aim 3: Establish disease mechanisms in selected known leukodystrophies;
  • Aim 4: Track current care and natural history of these patients to define the longitudinal course and determinants of outcomes in these disorders.

These objectives will be achieved by collecting, and subsequently analyzing, data and samples in a longitudinal fashion across leukodystrophies.


Condition or disease
Leukodystrophy White Matter Disease Leukoencephalopathies

Detailed Description:

Genetic white matter disorders (leukodystrophies) are estimated to have an incidence of approximately 1:7000 live births. In the past, patients with white matter disease of unknown cause evaluated by the investigator achieved a diagnosis in fewer than 46% of cases after extensive conventional clinical testing. Even when a diagnosis is achieved, the diagnosis takes an average of eight years and this "odyssey" results in testing charges to patients and insurers in excess of $8,000 on average per patient, including the patients who never achieve a diagnosis at all. With next generation approaches such as whole exome sequencing, the diagnostic efficacy is closer to 70%, but approximately a third of individuals do not achieve a specific etiologic diagnosis. This remaining group of patients (unclassified leukodystrophy) offers the opportunity to describe novel disorders and provide improved diagnostic tools. These diagnostic challenges represent an urgent and unresolved gap in knowledge and disease characterization, as obtaining a definitive diagnosis is of paramount importance for leukodystrophy patients.

Moreover, the mechanisms of disease in many leukodystrophies of known cause are very poorly understood: many are systemic abnormalities that manifest only testing white matter. Finally, little is known about the best symptomatic management of the many leukodystrophies without an etiologic cure and thus limited standards of care are available for the management of these patients.

The purpose of this study is to: (Aim 1) define novel homogeneous groups of patients with unclassified leukodystrophy and work toward finding the cause of these disorders; (Aim 2) assess the validity and utility of next-generation sequencing in the diagnosis of leukodystrophies; (Aim 3) establish disease mechanisms in selected known leukodystrophies; and (Aim 4) track current care and natural history of these patients to define the longitudinal course and determinants of outcomes in these disorders.

It is hoped that the present study will help clarify the nosology of the leukodystrophies and significantly advance our understanding of the pathogenesis of these diseases, the best diagnostic testing tools, and the best symptomatic management of these conditions. Due to the breadth of this approach, and the rarity of these conditions, these approaches will be carried out at multiple clinical centers with specialized expertise in the leukodystrophies.


Study Type : Observational [Patient Registry]
Estimated Enrollment : 12000 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 10 Years
Official Title: New Diagnostic Approaches in Leukodystrophy: The Myelin Disorders Biorepository and Natural History Project
Actual Study Start Date : December 8, 2016
Estimated Primary Completion Date : December 8, 2026
Estimated Study Completion Date : December 8, 2026

Resource links provided by the National Library of Medicine





Primary Outcome Measures :
  1. Define Novel Homogeneous Groups of Patients with Unclassified Leukodystrophy [ Time Frame: 01/08/2016 - 01/08/2026 ]
    In patients with an unclassified leukodystrophy, the study team will collect as much information as available from existing medical records including existing clinical evaluations, neuropsychological/rehabilitation evaluations, and results from blood, urine, spinal fluid, radiological, and peripheral tissue pathological tests. This data will be evaluated to create nosologic groups amongst patients with unclassified leukodystrophy. Additionally, this aim includes the collection and long-term banking of biological samples in subjects with classified and unclassified leukodystrophies to develop a biorepository. These samples will be compared to samples collected from control subjects, either collected directly from enrolled subjects or through existing banked biological samples.


Secondary Outcome Measures :
  1. Assess Validity of Next-Generation Sequencing in the Diagnosis of Leukodystrophies [ Time Frame: 01/08/2016 - 01/08/2026 ]
    Unclassified leukodystrophy patients enrolled in this study may undergo next generation sequencing approaches, including research whole exome sequencing (WES), whole genome sequencing (WGS), RNA sequencing and high throughput genomics analysis in parallel to standard clinical testing to achieve novel molecular classifications.

  2. Assess Utility of Next-Generation Sequencing in the Diagnosis of Leukodystrophies [ Time Frame: 01/08/2016 - 01/08/2026 ]
    Clinical utility defined as changes in care and clinical state, included changes in medical morbidities, surgeries, pharmacologic management of complications and implementation of disease specific therapies.

  3. Track Current Care of Leukodystrophy Patients [ Time Frame: 01/08/2016 - 01/08/2026 ]
    Includes a longitudinal collection of clinical data on diagnostic and therapeutic interventions in leukodystrophy patients and related controls.

  4. Track Natural History of Leukodystrophy Patients [ Time Frame: 01/08/2016 - 01/08/2026 ]
    Includes longitudinal collection of clinical data on disease presentation, progression and morbidities.

  5. Establish Disease Mechanisms in Leukodystrophies [ Time Frame: 01/08/2016 - 01/08/2026 ]
    Specific leukodystrophies will be selected for further mechanistic study, using clinical and laboratory tools to establish increased understanding of the underlying pathophysiology. The over-riding hypothesis of this aim is that integrated biochemical, genomic, metabolic, histologic and immunologic profiles of patients with leukodystrophy will define downstream pathway changes consistent with primary defects causing white matter disease. Appropriate controls will be used for comparison to disease related samples.


Biospecimen Retention:   Samples With DNA
Enrolled participants (and immediate relatives) will submit blood samples to be processed and stored in a secure biorepository.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
All case subjects will be known or suspected to have a leukodystrophy or genetic leukoencephalopathy. Control subjects will be enrolled through non-affected relatives of case subjects.
Criteria

Inclusion Criteria:

  • Suspected or confirmed diagnosis of leukodystrophy based primarily on the finding of central nervous system neuroimaging consistent with this diagnosis or on an existing diagnosis of a leukodystrophy or genetic leukoencephalopathy as defined in existing classification systems;
  • Males or females of any age;
  • Parental/guardian permission (informed consent) and if appropriate, child assent or patient consent;
  • Willingness to provide clinical data, participate in standardized assessment and provide biologic samples.

Exclusion Criteria:

  • Identification of a diagnosis not consistent with a genetic disorder of the white matter such as an acquired demyelinating condition (e.g. Multiple Sclerosis) or an infectious etiology prior to enrollment, with the exception of sequelae of congenital infections such as cytomegalovirus (CMV);
  • Inability to provide consent;
  • Weight below safe range for biological sample collection (typically <3kg).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03047369


Contacts
Contact: Omar Sherbini, MPH (215) 590-3068 sherbinio@email.chop.edu

Locations
United States, Pennsylvania
The Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Omar Sherbini, MPH    215-590-3068    sherbinio@email.chop.edu   
Principal Investigator: Adeline Vanderver, MD         
Sponsors and Collaborators
Children's Hospital of Philadelphia
Massachusetts General Hospital
University of Wisconsin, Madison
Alfred I. duPont Hospital for Children
Investigators
Principal Investigator: Adeline Vanderver, MD Children's Hospital of Philadelphia

Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT03047369     History of Changes
Other Study ID Numbers: 14-011236
First Posted: February 9, 2017    Key Record Dates
Last Update Posted: March 20, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Fully de-identified data may be shared with collaborating scientists, clinicians, and data management services.

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Children's Hospital of Philadelphia:
leukodystrophy
white matter disease
leukoencephalopathy
myelin
demyelinating
mdbp

Additional relevant MeSH terms:
Leukoencephalopathies
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases