Natural History of Glycosphingolipid and Glycoprotein Lysosomal Storage Disorders

  • STATUS
    Recruiting
  • participants needed
    200
  • sponsor
    National Human Genome Research Institute (NHGRI)
Updated on 19 September 2021
deficiency
MRI

Summary

This study will evaluate children with glycosphingolipid (GSL) storage disorders to investigate brain changes that cause nervous system degeneration. No experimental treatments are offered in this study; participants will receive standard medical care for their disease. The information from this study may help researchers develop new therapies for these disorders and monitor the effects of treatment.

Patients of any age with Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, or type 2 Gaucher disease may be eligible for this study.

Participants will be admitted to the NIH Clinical Center for 4 to 5 days every 6 months for a clinical evaluation involving the following tests and procedures:

  • Medical history
  • Physical, neurologic, and eye examinations
  • Developmental evaluations by a physical therapist, nutritionist and psychologist
  • Blood tests to check nutritional status, liver and kidney function, and, in patients treated for seizures, level of anti-seizure drugs. Some blood will also be used for research purposes.
  • Urinalysis to check urine sugar levels and kidney function
  • Skin biopsy to obtain cells to grow in culture. The biopsy area is numbed with an anesthetic cream and a 1/8-inch piece of skin is removed with a circular punch and scissors.
  • Genetic analysis of DNA to screen for mutations responsible for the patient s GSL storage disorder
  • Magnetic resonance imaging (MRI) brain scans. Children with type 2 Gaucher disease, Sandhoff disease and GM1 gangliosidosis will also have liver and spleen scans. Brain scans will be done every 6 months the first year. After that, they may be done less often, depending on the results. For the MRI, the child lies still in a narrow cylinder (the scanner). A magnetic field and radio waves are used to produce pictures of the organs under study. (Children will be sedated for MRI. Children who cannot be sedated will not have this test.)
  • Electroencephalogram (EEG) to measure electrical activity of the brain and detect possible seizures. For this test, electrodes (small metal discs attached to wires) are attached to the child s head with a paste and the brain waves (electrical activity) are recorded while the child rests quietly.
  • Brainstem auditory evoked response (BAER) to measure hearing. Electrodes are attached to the child s head (similar to the EEG procedure) and the brain waves are recorded when a sound stimulation is given.
  • Lumbar puncture (spinal tap) to study proteins in the cerebrospinal fluid, which bathes the brain and spinal cord. A needle is inserted in the space between the bones (vertebrae) in the lower back. About 2 tablespoons of fluid is collected through the needle. This test is done under anesthetic at the same time the MRI is done. If the child cannot be sedated, a local anesthetic will be used.

Description

The GM1 and GM2 gangliosidoses are lysosomal storage disorders that primarily affect the brain and are uniformly fatal. The glycoproteinoses sialidosis and galactosialidosis are ultra-rare disorders involving predominantly the skeletal and central nervous systems that are likewise fatal or severely debilitating. No effective therapy for patients with these diseases has yet been demonstrated. Historically, since these disorders are fatal very little natural history information or disease characterization using modern medical techniques has been collected. This information is vital in order to establish the pattern of disease progression and to identify clinical, biochemical and biophysical markers that can be used as endpoints in future therapeutic trials.

This protocol aims to study the natural history of the GM1 and GM2 gangliosidoses in affected individuals of all ages, races and genders using medical technologies including MRI/MRS, hearing evaluation and auditory evoked response testing, and EEG, as well as subspecialty evaluations in rehabilitative medicine, ophthalmology, speech language pathology, neurology, and psychology. Biomarkers of disease progression will be explored in CSF and blood samples for correlation with disease staging. Fibroblast cultures will be established for testing potential therapeutic agents. Some fibroblast lines will be used to create induced pluripotent stem cells (iPSC) for differentiation into neural tissues, more relevant for the study of these disorders that primarily affect the central nervous system (CNS).We hypothesize that relevant biomarkers will correlate with disease progression and will shed light on the pathophysiology of disease progression in these devastating disorders.

As a means of acquiring additional information, subjects or their parents may also be asked to complete a questionnaire regarding their medical and developmental history, initial clinical presentation of the disease and steps toward diagnosis. At their request, the same questionnaire may be sent to families who do not wish to undergo clinical evaluation at the NIH, who are medically fragile and unable to travel, or whose affected member(s) are already deceased.

We know that children with infantile GM2 gangliosidosis develop increasing macrocephaly as part of their disease. No normal curves for head circumference vs. age currently exist for this disorder. In an attempt to provide such curves to the clinical community parents may also be asked to provide head circumference data on their children whether they are being seen at NIH or whether a clinical questionnaire is being completed for children too medically fragile to travel or already deceased.

We know that for infantile onset disease the storage of ganglioside in neurons begins during the second trimester of pregnancy. In rare situations where carrier couples learn from prenatal diagnosis that they are carrying a fetus with infantile disease and have decided to terminate the pregnancy, we will accept samples of fetal tissue for analysis of biomarkers including gene expression analysis that may lend clues as to the underlying pathogenesis of disease. This may lead to increased understanding of the early events in disease pathogenesis and suggest possible therapies.

We anticipate that information obtained from the small population of patients with glycosphingolipid and glycoprotein disorders evaluated in this study will have a broader impact on patients with other neurodegenerative lysosomal storage disorders and perhaps more common disorders of neurodegeneration.

Details
Condition Gaucher Disease, Gangliosidosis, Myoclonus, Cerebral Atrophy, Brain Atrophy, Neurological Regression, Cherry Red Spot, cortical atrophy, myoclonic jerks
Clinical Study IdentifierNCT00029965
SponsorNational Human Genome Research Institute (NHGRI)
Last Modified on19 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Individuals greater than 6 months of age with GM1 or GM2 gangliosidosis documented by enzyme deficiency and/or mutation analysis in a CLIA-approved laboratory

Exclusion Criteria

Individuals who in the opinion of the principal investigator are too medically fragile to travel safely to the NIH for evaluation
Individuals unable to comply with the protocol
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