Juvenile Sandhoff Disease

Sandhoff is caused by the absence of a vital enzyme called Hexosaminidase A (Hex-A) and Hexosaminidase B (Hex-B). While Hex-A and Hex-B differ in the kinds of subunits they contain, both play a role in the degradation of GM2 gangliosides, specific substances containing fat and sugar that are made predominantly in the neurons of the brain. Individuals with Sandhoff are unable to degrade these GM2 gangliosides, and the gangliosides accumulate in lysosomes, containing many enzymes that degrade different kinds of molecules and can be thought of as the recycling centers of the cell. If one of the lysosomal enzymes is deficient, then the molecule it degrades accumulates in the cell, eventually resulting in cell death. Since GM2 is found mainly in neurons, its accumulation leads to the progressive loss of neurons in the brains of children with Sandhoff disease and the results in progressive loss of function.

Individuals who have low levels of Hex-A and Hex-B, have a slower onset of symptoms and progression of disease, compared to those with Classic Infantile Sandhoff. It is important to note that within each form of Sandhoff disease, there is a range of severity and each person’s experience with the disease is distinctive. In children with Juvenile Sandhoff, Hex-A enzyme activity is extremely low but not as low as in children with Classical Infantile Sandhoff. Therefore, children with the Juvenile form of the disease usually develop symptoms between before 5 years of age more closely resembles the symptoms of the Classic Infantile form. Though the course of the disease is slower, end stages generally occur in late adolescence.

If starting after age 5, symptoms may be milder than those that characterize earlier onset forms. Cognition may decline although normal mental and hearing abilities have also been reported. Affected individuals develop ataxia (lack of coordination), dysarthria (slurred speech), muscle atrophy (weakness), muscle cramps, tremors, unsteady gait and sometimes mental illness. Vision may also remain intact or decline late, and seizures may occur. Although individuals with Juvenile Sandhoff may survive into late childhood or adolescence, death usually occurs within the first 15 years due to other complications, such as respiratory infection.

Again, the differences in age of onset and severity of symptoms shows the broad range of this disease and why it continues to be a mystery to even many seasoned medical professionals.