Longitudinal Study of Neurodegenerative Disorders

Brief Title

The Natural History of Metachromatic Leukodystrophy

Official Title

The Natural History of Metachromatic Leukodystrophy

Brief Summary

      There have not been longitudinal studies which track patients' neurologically or
      developmentally in a systematic manner. By simultaneously tracking patients' neurodevelopment
      along with neuroimaging and neurophysiologic studies it becomes much easier to draw
      conclusions on the differential effects of the disease process and any available treatments
      that patients might receive. In addition, many of the gene mutations, which cause MLD have
      not been linked to the age of onset or the expected disease course.

Detailed Description

      Metachromatic leukodystrophy (MLD), an autosomal recessively inherited lysosomal storage
      disorder, causes a deficiency of arylsulfatase A. This results in accumulation of sulfated
      glycolipids (sulphatide) within lysosomes of myelin forming cells in the central and
      peripheral nervous system and to a lesser extent in lysosomes of cells comprising the liver,
      kidneys, and gallbladder. The disease is characterized by progressive demyelination with wide
      variability in clinical onset and severity. Depending upon the age at onset and disease
      progression, MLD may be classified as late infantile (6 months to 4 years), early juvenile (4
      to 6 years), late juvenile (6 to 16 years), and adult (>16 years). In the late infantile and
      early juvenile forms, blindness, gait disturbances, loss of speech, loss of hearing, and
      quadriparesis are common signs. In older children and adults the disease may present with
      gait disturbances, mental regression, and behavioral abnormalities. Disease progression, also
      variable, results in death within a few years to several decades; however, disease
      progression among affected siblings seems to follow a similar course, unlike many other

      Bone marrow transplantation (BMT) has been the only partially effective treatment reported
      for MLD. BMT has been shown to halt disease progression when asymptomatic patients achieve
      engraftment prior to the age at which symptoms occurred in an affected, symptomatic sibling.
      Despite stabilization of the clinical course when receiving BMT before symptoms, patients'
      neurophysiologic test abnormalities persist. The clinical implication of this finding has not
      been further researched. Patients who show mild to moderate progression of their disease
      prior to transplantation continue to exhibit disease progression to severe impairment.
      However, specific degrees of clinical impairment in neurodevelopmental function have not been
      monitored to determine what level of cognitive and motor impairment can be present and still
      allow the patient to confer benefits from treatment. Patients with late infantile MLD appear
      to benefit the least from the transplantation process based on preliminary unpublished data.
      Several case report studies for patients with late infantile MLD indicate delayed, but
      continued progression of the disease despite BMT, while others suggest initial deterioration
      followed by stabilization.

      Transplantation with allogenic hematopoietic stem cells has been shown to positively
      influence the disease progression of other lysosomal storage diseases such as Hurler Syndrome
      and Krabbe Disease and testing for enzyme replacement for MLD is already underway. For future
      researchers to be able compare the benefits of children with MLD who receive treatment to
      those who remained untreated, a better understanding of the natural progression of late
      infantile MLD is necessary. The current literature contains studies of individual or small
      groups of MLD patients that tracked intelligence quotients and neurophysiologic function, but
      did not correlate this with patients' neurodevelopment. A longitudinal study of a larger
      population of patients with late infantile MLD has yet to be performed. This protocol is a
      longitudinal observational study to capture natural history data in patients with late
      infantile MLD. This data will provide baseline neurobehavioral, neuroimaging, and
      neurophysiological information that can in the future be used to evaluate treatment effects.

Study Type


Primary Outcome

Results of cognitive and motor testing

Secondary Outcome



Metachromatic Leukodystrophy


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

January 2012

Completion Date

January 2030

Primary Completion Date

January 2030

Eligibility Criteria

        Inclusion Criteria:

          1. The patient must have a confirmed diagnosis of MLD as defined by:

             ASA activity < 10 nmol/h/mg in leukocytes

             Presence of elevated sulfatide in urine

          2. The patient must have voluntary function (as judged by the investigator), including
             cognitive and motor function that is no more than 3 standard deviations below normal
             at the time of enrollment.

          3. The patient must have an age at the time of screening birth to < 6 years

          4. The patient must have had onset of symptoms before the age of 4 years

          5. The subject and his/her guardian(s) must have the ability to comply with the clinical

        Exclusion Criteria:

          1. Known multiple sulfatase deficiency

          2. Presence of major congenital abnormality

          3. Presence of known chromosomal abnormality and other neurological conditions unrelated
             to MLD that can affect psychomotor development

          4. History of hematopoietic stem cell transplantation

          5. Presence of known clinically significant cardiovascular, hepatic, pulmonary or renal
             disease or other medical condition

          6. Any other medical condition or serious intercurrent illness, or extenuating
             circumstance that, in the opinion of the principal investigator, would preclude
             participation in the trial

          7. Use of any investigational product within 30 days prior to study enrollment or
             currently enrolled in another study which involves clinical investigations.

          8. The patient's parent(s) and/or legal guardian is unable to understand the nature,
             scope, and possible consequences of the study.

          9. Patient is unable to comply with the protocol, i.e. inability to return for follow-up
             evaluations or otherwise unlikely to complete the study as determined by the principal




N/A - 6 Years

Accepts Healthy Volunteers



Maria L Escolar, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

University of Pittsburgh

Study Sponsor

Maria L Escolar, MD, Principal Investigator, University of Pittsburgh, Children's Hospital of Pittsburgh-UPMC

Verification Date

June 2022