Sandhoff disease ... (Gangliosidosis GM2) (Sandhoff disease) - Gen HEXB.

Sandhoff disease is a rare hereditary disorder that gradually destroys nerve cells in the brain and spinal cord. The most common and severe form of Sandhoff disease becomes evident in childhood. Affected children usually appear normal until the age of 3 to 6 months, when development slows down and skeletal muscles weaken. These children lose motor skills such as turning, sitting and crawling. Also they develop an exaggerated startle reaction to loud noises. As the disease progresses, children with Sandhoff disease have seizures, loss of vision and hearing, mental retardation and paralysis. An eye abnormality called cherry - red spot is characteristic of this disease. Other signs may include organomegaly or bone abnormalities. Children with severe infantile form of Sandhoff disease usually live only in early childhood.

There are other forms of Sandhoff disease very rare. Signs and symptoms may begin in childhood, adolescence or adulthood and are generally milder than those observed with the infantile form. Characteristic features include muscle weakness, ataxia and other problems with movement, speech problems and mental illness. These signs and symptoms vary widely among people with late - onset forms of Sandhoff disease.

This process is due to mutations in the HEXB gene, located on the long arm of chromosome 5 (5q13). This gene encodes a subunit of two related enzymes, beta-hexosaminidase and beta-hexosaminidase B. Each of these enzymes is composed of two subunits. Beta-hexosaminidase includes an alpha subunit (encoded from HEXA gene) and a beta subunit (encoded from HEXB gene). Beta-hexosaminidase B consists of two beta subunits, which are encoded from HEXB gene. Beta-hexosaminidase beta-hexosaminidase A and B play a critical role in the central nervous system. These enzymes are found in the lysosomes, where they break sphingolipids, oligosaccharides, and molecules linked carbohydrate (as glycoproteins). In particular, beta-hexosaminidase A is part of a complex that breaks down a fatty substance called GM2 ganglioside.

They have identified about 30 HEXB mutations in the gene responsible for Sandhoff disease. These mutations reduce or eliminate the activity of beta-hexosaminidase and beta-hexosaminidase B. absent or malfunctioning enzymes are unable to break GM2 ganglioside and other molecules allowing these compounds to accumulate within cells . High concentrations of ganglioside GM2 are particularly toxic to nerve cells in the central nervous system. GM2 ganglioside excess causes progressive destruction of these cells, which leads to many of the characteristic features of Sandhoff disease. Most known mutations in the HEXB gene cause severe form of Sandhoff disease, which becomes apparent in infancy. These mutations prevent cells encode any beta-hexosaminidase beta-hexosaminidase or B, or result encoding completely nonfunctional versions of these enzymes. The most common mutation suppresses a large segment of DNA near the beginning of the HEXB gene, which results in a complete loss of enzyme activity. Other mutations reduce but not eliminate the activity of enzymes. These genetic changes are responsible for the less severe forms of Sandhoff disease, which appear later in life.

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with Sandhoff disease, by complete PCR amplification of the exons of the HEXB gene, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).