NORD gratefully acknowledges Katherine E. Bruder, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
Sandhoff disease is a rare lysosomal storage disease. It causes the destruction of nerve cells (neurodegeneration). This leads to problems with thinking and moving. Sandhoff disease is caused by harmful changes in the HEXB gene. Harmful changes in this gene cause decreased amounts of two enzymes in the recycling centers (lysosomes) of the cell. Without these enzymes, certain fats (lipids) build up in large amounts in the nerve cells. This damages the brain and spinal cord (central nervous system). Sandhoff disease is very similar to Tay Sachs disease.
Lysosomal storage diseases affect the enzymes in the recycling centers (lysosomes) of the cell. Lysosomes use enzymes to break down or “digest” molecules in our cells. When these enzymes are not working properly, the molecules accumulate in harmful amounts. This causes damage to different organs in the body.
Infantile Sandhoff Disease
The most common type of Sandhoff disease causes rapidly progressing mental and motor decline in infancy. Within the first six months of life, infants with Sandhoff disease will experience weakness. They lose skills like turning over, sitting, and crawling. They can also have trouble with feeding, overreaction to loud sudden noises, delayed speech, early blindness, seizures, heart murmur, and continuously tight muscles (spasticity). A doctor may notice red spots in the back of the eye (cherry-red spots of the macula) and an abnormal reflex of the foot that indicates damage to the nervous system (the Babinski reflex). Other signs of Sandhoff disease can include a large head (macrocephaly) and unique facial features. Infants with this form of Sandhoff disease usually do not live past 2-5 years.
Juvenile and Adult Sandhoff Disease
Sandhoff disease can also happen in older children and adults. These individuals will experience a slower mental and motor decline than in infantile Sandhoff disease. The onset and severity of symptoms can vary. A specific symptom of later-onset Sandhoff disease is muscle weakness affecting the muscles of the arms, legs, and hips. Other symptoms include muscle loss (muscle atrophy), balance problems, uncontrollable muscle contraction (dystonia), damage to nerves controlling involuntary bodily functions (autonomic neuropathy), a loss of intellectual function (cognitive dysfunction), psychiatric illness and dementia.
Sandhoff disease is caused by harmful mutations in a gene called HEXB. These gene mutations cause decreased amounts of two important enzymes: beta-hexosaminidase A and beta-hexosaminidase B. These enzymes are found in the recycling centers (lysosomes) of the cell and their job is to break down fatty substances called GM2 gangliosides and globosides. The symptoms of Sandhoff disease happen because these fats (lipids) accumulate in harmful amounts in the brain and nerve cells. This damages the brain and spinal cord (central nervous system).
Sandhoff disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Sandhoff disease is a rare disorder that is estimated to affect 1 in 1,000,000 individuals. It affects males and females in equal numbers. Sandhoff disease occurs in multiple populations but may be most common in the Creole population of Argentina, Metis citizens of Saskatchewan, Canada and people with Lebanese ancestry.
Sandhoff disease is commonly diagnosed by testing the activity of the beta-hexosaminidase A and beta-hexosaminidase B enzymes (enzyme assays). People with Sandoff disease have reduced or absent activity of both enzymes. Genetic testing is used to confirm the diagnosis.
There is currently no cure for Sandhoff disease. Management is based on the symptoms and is mostly supportive. Supportive treatment includes ensuring proper nutrition and hydration, keeping the airway open, and seizure control with anticonvulsants.
Genetic counseling is recommended for affected individuals and their families.
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