Related Diseases
What is Sandhoff Disease

History

Cause

Treatment

Support

Testing

Additional Information Links

Sandhoff disease is a progressive neurological genetic disorder that appears in three forms:
Classic Infantile, Juvenile and Late Onset or Chronic Sandhoff.

History

Sandhoff disease is named for Konrad Sandhoff, a German chemist who first described Sandhoff in Life Science in 1968. Sandhoff, like its near twin Tay-Sachs, is a progressive neurological autosomal recessive genetic disorder that appears in three forms: Classic Infantile, Juvenile and Late Onset or Chronic Sandhoff. It is important to note that Sandhoff ‘breeds true in a family,’ which means if a family has a child affected by Classic Infantile Sandhoff their other children will only be at risk for having Classic Infantile Sandhoff. One set of parents could not have a child affected by Classic Infantile and Juvenile or Late Onset Sandhoff.

Cause

The fatty material (GM2 gangliosides) which accumulates in the child's brain cells is the same in Sandhoff and Tay-Sachs diseases. However, the enzyme deficiency in Sandhoff Disease arises from mutations in a different gene on a different chromosome: the beta (ß subunit of the hexosaminidase A enzyme (Hex-A) gene on chromosome 5 rather than the alpha (a subunit of the Hex-A gene on chromosome 15 for Tay-Sachs. Since both the alpha and the beta subunits are needed for the Hex-A function, children with Sandhoff are also deficient in Hex-A activity. However the B subunit is also essential for the functioning of another kind of hexosaminidase called Hex-B. As a result, children with Sandhoff disease lack normal levels of both Hex-A and Hex-B while those with Tay-Sachs still have Hex-B activity.

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 special compartments of the cells called lysosomes. Lysosomes contain 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 progressive loss of function that results. Since the accumulation of GM2 gangliosides is at the root of Sandhoff disease, it is classified as a GM2 gangliosidosis – to distinguish it from other lysosomal storage diseases

As with Tay-Sachs disease the severity of Sandhoff disease depends on the amount of residual enzyme that is produced. Children with virtually no hexosaminidase activity will have the infantile (acute onset) form of the disease. Those born with a small amount of hexosaminidase activity will have the juvenile, subacute form and those with still more activity will have a later onset adult (chronic) form of Sandhoff disease. The infantile form is the most severe and, unfortunately, the most common. The juvenile and adult forms of Sandhoff disease occur later and tend to be much more variable in their clinical features. The amount of residual enzyme, and therefore the clinical course, is determined by the specific mutation(s) in the ß-subunit of Hex-A.

Fact:
Sandhoff Disease is also inherited as an autosomal recessive disorder. But, unlike Tay-Sachs occurs more commonly in the non-Jewish population.

Treatment

To date, there is no cure or effective treatment for Sandhoff disease. However, there is active research being done in many investigative laboratories in the U.S. and around the world exploring a range of therapeutic approaches– primarily in a Sandhoff mouse model, an animal model for Sandhoff disease. For the first time in the history of the disease there currently are clinical trials testing the potential of a substrate reduction drug (miglustat) in all three forms of Sandhoff and Tay-Sachs, with the Late Onset trial having started in 2002. The uses of enzyme replacement therapy to provide the Hex-A and Hex B that is missing in babies with classic infantile or significantly reduced in children and adults with Sandhoff disease has been explored but presents serious obstacles. Because the disease affects brain cells that are protected by the blood-brain barrier, enzymes such as Hex-A and Hex B are blocked from entering the brain by the blood. Stem cell transplantation using umbilical cord blood is an investigational procedure attempted with a small number of very young children, but to date there is not enough information for specific results about reversing or slowing damage to the central nervous system in this group with Sandhoff disease. Gene therapy, molecular or pharmacological chaperone therapy and neural stem cell therapy are among those potential treatments being researched.

Support

Although a cure for Sandhoff disease does not exist at the present time, specific support, programs and services for affected individuals and their families are available through organizations such as National Tay-Sachs & Allied Diseases Association, Inc. (NTSAD).

Testing

Since Sandhoff is a recessive genetic disorder, both parents must be carriers for Sandhoff disease in order to have a child with Sandhoff disease. Genes come in pairs, and a carrier of Sandhoff disease has one ß subunit for Hex-A and Hex-B that works and one that does not. This means carriers have about half the normal amount of Hex-A and Hex-B activity, but that’s still enough for them to be completely healthy. However, if each parent passes the non-working copy of the ß subunit gene to his/her child, the child will develop Sandhoff disease. Statistically speaking, if both parents are carriers, they have a 25 percent chance of having a child with Sandhoff disease with each pregnancy.

Because of the nearly total absence of hexosaminidase activity in affected individuals, laboratory diagnosis of an affected child as well as prenatal diagnosis is accurate and reliable. However, enzyme assay for the adult carrier requires special care and careful standardization of the laboratory test. DNA analysis are also available for families in which the specific beta-subunit mutations have been identified; when these are known, the DNA-based tests provide the highest level of specificity and accuracy for both carrier testing in relatives and for prenatal diagnosis. Assistive reproduction technologies such as pre-implantation genetic diagnosis are available to at-risk couples with known DNA mutations who wish to have children but for whom termination is not an option.

NTSAD has current information available on where to obtain the tests that are critical to the diagnosis and management of Sandhoff disease within families.

Sandhoff disease, like Tay-Sachs, is an autosomal recessive disorder but, unlike Tay-Sachs, occurs more commonly in the non-Jewish population. In fact, given the higher incidence of Sandhoff in non-Jews and the clinical similarity of the two diseases, it is probable that some of the non-Jewish children diagnosed before the availability of the laboratory tests actually had Sandhoff disease.

Additional Informational Links

The following online resources may be helpful in learning more about Sandhoff disease: