Nervous System Degeneration in Glycosphingolipid Storage Disorders

2014-08-27 03:56:21 | BioPortfolio


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.


Inherited defects in the lysosomal degradation pathway of glycosphingolipids (GSLs) result in a group of autosomal recessive disorders predominantly characterized by severe neurodegeneration 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 pathogenesis 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.

Study Design





National Institutes of Health Clinical Center, 9000 Rockville Pike
United States




National Institutes of Health Clinical Center (CC)

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:56:21-0400

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Medical and Biotech [MESH] Definitions

A group of autosomal recessive lysosomal storage disorders marked by the accumulation of GANGLIOSIDES. They are caused by impaired enzymes or defective cofactors required for normal ganglioside degradation in the LYSOSOMES. Gangliosidoses are classified by the specific ganglioside accumulated in the defective degradation pathway.

A glycosphingolipid that accumulates due to a deficiency of hexosaminidase A or B (BETA-N-ACETYLHEXOSAMINIDASES), or GM2 activator protein, resulting in GANGLIOSIDOSES, heredity metabolic disorders that include TAY-SACHS DISEASE and SANDHOFF DISEASE.

A group of recessively inherited diseases characterized by the intralysosomal accumulation of G(M2) GANGLIOSIDE in the neuronal cells. Subtypes include mutations of enzymes in the BETA-N-ACETYLHEXOSAMINIDASES system or G(M2) ACTIVATOR PROTEIN leading to disruption of normal degradation of GANGLIOSIDES, a subclass of ACIDIC GLYCOSPHINGOLIPIDS.

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