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.

• 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.