Natural History of Glycosphingolipid and Glycoprotein Lysosomal Storage Disorders
Study Details
Study Description
Brief 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:
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Medical history
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Physical, neurologic, and eye examinations
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Developmental evaluations by a physical therapist, nutritionist and psychologist
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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.
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Urinalysis to check urine sugar levels and kidney function
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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.
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Genetic analysis of DNA to screen for mutations responsible for the patient s GSL storage disorder
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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.)
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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.
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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.
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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.
| Condition or Disease | Intervention/Treatment | Phase |
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Detailed Description
The GM1 and GM2 gangliosidoses are rare 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 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, sialidosis and galactosialidosis in affected individuals of all ages, races and genders using medical technologies including MRI/MRS, hearing evaluation and auditory evoked response testing, EEG, sleep study, EMG/NCV, echocardiogram and abdominal ultrasound as well as subspecialty evaluations in rehabilitative medicine (including gait analysis), ophthalmology, speech language pathology, neurology, and psychology. Biomarkers of disease progression may be explored in CSF, blood, and urine 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 learned from prenatal diagnosis that they were carrying a fetus with infantile disease and had decided to terminate the pregnancy, we accepted samples of fetal tissue prior to June 5, 2019 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Galactosialidosis Galactosialidosis |
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| GM1 gangliosidosis GM1 gangliosidosis |
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| GM2 gangliosidosis GM2 gangliosidosis |
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| Sialidosis Sialidosis |
Outcome Measures
Primary Outcome Measures
- MRI/MRS [Every 12-24 months; depending on age of subject]
Patients may undergo magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in the 3T scanner.
- Neuropsych testing [Every 6-24 months; depending on age of subject]
Developmental testing tools are used to measure disease progression over time.
- Motor function testing [Every 6-24 months; depending on age of subject]
Motor assessments are done by Physiatry, PT, OT, Neurology, and the PI.
Secondary Outcome Measures
- Ophthalmology assessments [Every 6-24 months; depending on age of subject]
Evaluating change over time in eye findings.
- Audiology testing [Every 6-24 months; depending on age of subject]
Evaluating change over time in auditory testing
- Laboratory testing [Every 6-24 months; depending on age of subject]
Evaluating disease biomarkers over time.
- Neurology assessments [Every 6-24 months; depending on age of subject]
Neurology assessments are done to measure change over time.
Eligibility Criteria
Criteria
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INCLUSION CRITERIA:
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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:
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Individuals who in the opinion of the principal investigator are too medically fragile to travel safely to the NIH for evaluation
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Individuals unable to comply with the protocol
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
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| 1 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Human Genome Research Institute (NHGRI)
Investigators
- Principal Investigator: Cynthia J Tifft, M.D., National Human Genome Research Institute (NHGRI)
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Cantor RM, Roy C, Lim JS, Kaback MM. Sandhoff disease heterozygote detection: a component of population screening for Tay-Sachs disease carriers. II. Sandhoff disease gene frequencies in American Jewish and non-Jewish populations. Am J Hum Genet. 1987 Jul;41(1):16-26.
- Myerowitz R, Hogikyan ND. Different mutations in Ashkenazi Jewish and non-Jewish French Canadians with Tay-Sachs disease. Science. 1986 Jun 27;232(4758):1646-8.
- Wada R, Tifft CJ, Proia RL. Microglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation. Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10954-9.
- 020107
- 02-HG-0107