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.

Condition
Gangliosidoses Gaucher Disease

Further Study Details: 

Expected Total Enrollment:  20

Inherited defects in the lysosomal degradation pathway of glycosphingolipids (GSLs) result in a group of autosomal recessive disorders predominantly characterized by severe eurodegeneration and death in infancy or childhood. In both Tay-Sachs (MIM#272800) and Sandhoff (MIM#268800) disease massive accumulation of GM2 ganglioside is seen in cells--particularly neurons--where its rate of synthesis is the highest. GM1 gangliosidosis (MIM#230500) and Gaucher disease type 2 (MIM#230900) result in GM1 ganglioside and glucosylceramide storage respectively. Despite our understanding of the enzyme deficiencies in each of the GSL storage disorders, very little is understood about the molecular athogenesis of neurodegeneration. No effective therapies have emerged that can successfully preserve CNS function.

Our recent work, using a mouse model of Sandhoff disease, suggests that as GSL storage increases in the CNS, gene expression is altered leading to the expression of inflammatory markers including TGF-alpha and IL-1beta that precede the onset of neuronal apoptosis and clinical decline. Here, we propose a longitudinal natural history study to investigate the expression of inflammatory proteins in the CNS of children with GSL storage disorders, and to correlate them with neurodegenerative changes as assessed by magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and clinical disease progression.

The objectives of this study are as follows:

To develop sensitive clinical tools including MRI and MRS to monitor the central nervous system changes seen in children with GSL storage disorders.

To correlate the expression of inflammatory proteins in the CNS with the clinical decline seen as a result of neurodegeneration.

To identify molecular markers of disease progression that can be used to monitor therapeutic interventions in GSL storage disorders.

To understand the mechanism of neurodegeneration in GSL storage disorders.

Genders Eligible for Study:  Both

Criteria

INCLUSION/EXCLUSION CRITERIA:
Subject Selection: Any patient with biochemically confirmed infantile or juvenile Tay-Sachs, Sandhoff, or GM1 gangliosidosis or type 2 Gaucher disease will be accepted into this study.
No exclusions will be based on race or gender. Both sexes will be recruited.
Patients will be recruited without regard to ethnic group, however the gene frequency of Tay-Sachs is higher in individuals of Ashkenazi Jewish descent and Sandhoff disease may be higher in the Hispanic population.
Patients will be excluded if they cannot travel to the NIH because of their medical condition.
Patients will be excluded if they are unable to undergo MRI/MRS imaging for the following reasons:
-Implanted cardiac pacemaker or autodefibrillator
-Implanted neural pacemaker
-Cochlear implants
-Metallic foreign bodies in the eye or central nervous system (such as an aneurysmal clip)
-Any form of implanted wire or metal device that may concentrate radio frequency fields
-History of an adverse reaction to sedation or anesthesia
-Determination by the anesthesiologist that they are too medically fragile to undergo sedation or anesthesia for the MRI.

Maryland
      National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  020107; 02-DK-0107
Record last reviewed:  March 2, 2004
Last Updated:  November 23, 2004
Record first received:  January 27, 2002
ClinicalTrials.gov Identifier:  NCT00029965
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08