Sandhoff disease
Sandhoff disease is a rare, inherited genetic disorder characterized by the accumulation of specific fats within nerve cells, leading to their gradual degeneration and progressive nervous system deterioration. It is classified as an autosomal recessive condition caused by mutations in the HexB gene located on chromosome 5. Individuals are at risk if both biological parents carry mutations in this gene, and the disease affects both males and females, with higher prevalence noted in certain populations, including those from northern Argentina, Saskatchewan, and Cyprus.
Symptoms typically manifest by six months in infants, presenting as loss of muscle tone, exaggerated startle responses, seizures, and eventual paralysis. Juvenile and adult-onset forms of the disease present differently, with symptoms ranging from muscle weakness to cognitive decline. Diagnosis relies on biochemical tests to measure enzyme activity associated with HexB and genetic testing for mutations. While no cure exists, symptomatic treatments can help manage certain aspects of the disease, and ongoing research is exploring potential experimental therapies. Genetic screening for parents can aid in prevention efforts. Unfortunately, the prognosis is often poor, with many affected individuals succumbing to the disease in early childhood or adolescence.
Sandhoff disease
ALSO KNOWN AS: Beta-hexosaminidase-beta-subunit deficiency; GM2 gangliosidosis, Type II; hexosaminidase A and B deficiency disease; Sandhoff-Jatzkewitz-Pilz disease; total hexosaminidase deficiency
DEFINITION Sandhoff disease is a rare, inherited disorder that causes abnormal accumulation of particular types of fats inside nerve cells, which eventually kills them. This disease culminates in a gradual and progressive deterioration of the nervous system.
Risk Factors
Anyone whose biological parents both carry mutations in the HexB gene is at risk for Sandhoff disease. This genetic disease equally affects males and females but more commonly occurs in the Creole population of northern Argentina; Metis Indians in Saskatchewan, Canada; and Christian Marionite communities from Cyprus.
Etiology and Genetics
Sandhoff disease is an autosomal recessive hereditary disease caused by mutations in the HexB gene. The HexB gene is located on the long arm of chromosome 5, in band region 13. People must inherit two copies of a mutant form of the HexB gene in order to have Sandhoff disease. Children whose parents both carry a mutant copy of the HexB gene have a 25 percent chance of being born with Sandhoff disease. The HexB gene encodes the information for the synthesis of a protein called hexosaminidase B.
Cells are bordered by the plasma membrane, which is composed of phosphate-containing lipids, proteins, and another groups of lipids called sphingolipids. Many sphingolipids have chains of sugars attached to them and are collectively called glycolipids. Glycolipids are very common in the membranes of nerve cells, but cells must constantly produce new glycolipids and degrade old ones in order to keep their plasma membranes in good working condition.
Once made, membrane lipids are loaded into spherical vesicles that fuse with the membrane. Membrane lipids are removed from the membrane by being loaded into vesicles that pinch off the membrane and fuse with a waiting vesicle called a lysosome. Lysosomes serve as the garbage disposal of cells, and they contain a cadre of enzymes called acid hydrolases that degrade the components brought to the lysosome. Hexosaminidase B is one of the lysosomal acid hydrolases that degrade glycolipids.
Hexosaminidase B is part of two different acid hydrolases. It forms a complex with another protein called hexosaminidase A to form an acid hydrolase called β-hexosaminidase A. Hexosaminidase A is encoded by the HexA gene, and mutations in HexA cause Tay-Sachs disease, which is clinically very similar to Sandhoff disease. β-hexosaminidase A degrades a glycolipid called the GM ganglioside. Hexosaminidase B also forms a complex with itself to make an acid hydrolase called β-hexosaminidase B, which degrades so called “neutral glycolipids.”
Mutations in the HexB gene that inactivate hexosaminidase B abrogate the enzymatic activities of β-hexosaminidase A and B. Cells accumulate GM gangliosides and neutral glycolipids, which kills the cells. Because nerve cells make such extensive use of complex glycolipids, they are among the most sensitive to an inability to degrade them. Gradual death of nerve cells causes an inexorable and progressive deterioration of nerve functions.
Sandhoff disease belongs to a larger group of genetic diseases called lysosomal storage diseases, in which the activity of lysosomal acid hydrolases is compromised.
Symptoms
With the classical infantile form of Sandhoff disease, infants begin showing symptoms by six months. They lose muscle tone and movement (motor control) and show an exaggerated startle response to loud noises. As the nervous system deteriorates, babies suffer from seizures; loss of sight, hearing, and the ability to swallow; and paralysis.
In the juvenile form, symptoms start between three to ten years of age and include muscle weakness, loss of coordination (ataxia) and speech, and mental problems.
The adult-onset form occurs in older people, and the symptoms (muscle weakness) are milder and vary.
Screening and Diagnosis
Biochemical tests on blood or biopsied tissues are required to distinguish Sandhoff disease from Tay-Sachs disease. The absence of β-hexosaminidase A and B activity is diagnostic for Sandhoff disease.
Genetic tests for prenatal or preimplantation diagnoses are available for Sandhoff disease. Prenatal diagnoses use tissue derived from amniocentesis, chorionic villus sampling, placental biopsy, umbilical cord blood sampling, or fetal skin biopsy to screen unborn babies. Preimplantation genetic diagnosis screens individual blastomeres from embryos formed by in vitro fertilization.
Treatment and Therapy
No cure exists for Sandhoff disease. Antiseizure medication can mitigate seizures, and feeding tubes can prevent food aspiration into the lungs. Experimental treatments with stem cells and gene therapy are ongoing.
Prevention and Outcomes
Genetic screening of prospective parents can reduce the rates of Sandhoff disease.
The infantile form of Sandhoff disease usually causes death before the age of four, while the juvenile-onset form causes death by age fifteen. Adult-onset patients experience severe lifestyle restrictions.
Bibliography
Mehta, Atul B., and Bryan Winchester. Lysosomal Storage Disorders: A Practical Guide. Chichester: Wiley, 2013. Print.
Milunsky, Aubrey, and Jeff M. Milunsky. Genetic Disorders and the Fetus: Diagnosis, Prevention, and Treatment. 6th ed. Chichester: Wiley, 2010. Print.
Nelson, David L., and Michael M. Cox. Lehninger Principles of Biochemistry. 5th ed. New York: Freeman, 2008. Print.
Noggle, Chad A., Raymond S. Dean, and Arthur MacNeill Horton. The Encyclopedia of Neuropsychological Disorders. New York: Springer, 2012. Print.
Parker, James N., and Philip M. Parker. The Official Parent’s Sourcebook on Sandhoff Disease: A Revised and Updated Directory for the Internet Age. San Diego: Icon Health, 2002. Print.
Sahyouni, Jamal Khaled, et al. "Infantile Sandoff Disease with Ventricular Septal Defect: A Case Report." Journal of Medical Case Reports, vol. 16, no. 317, 25 Aug. 2022, doi.org/10.1186/s13256-022-03550-0. Accessed 5 Sept. 2024.