Sandhoff Disease

Disease Overview

Summary

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.

Introduction

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.

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Synonyms

• GM2 gangliosidosis, type 2
• hexosaminidases A and B deficiency
• beta-hexosaminidase-beta-subunit deficiency
• total hexosaminidase deficiency
• Sandhoff-Jatzkewitz-Pilz disease

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Signs & Symptoms

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.

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Causes

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.

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Affected populations

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.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Sandhoff disease. Comparisons may be useful for a differential diagnosis.

Tay-Sachs disease is a rare, inherited lysosomal storage disease. It causes the destruction of nerve cells (neurodegeneration), leading to problems with thinking and moving. Tay-Sachs disease happens because of a lack of an enzyme called beta-hexosaminidase A. This causes a buildup of certain fats (lipids) called GM2 gangliosides in the brain and nerve cells which damages the brain and spinal cord (central nervous system). Common symptoms include an overreaction to sudden noises, listlessness, loss of previously acquired skills, severely diminished muscle tone (hypotonia), cherry-red spots within the middle layer of the eyes, gradual loss of vision, hearing loss, increasing muscle stiffness, restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). Most commonly, Tay-Sachs happens in infancy, but there are juvenile and adult forms of the disease. (For more information on this disorder, choose “Tay-Sachs” as your search term in the Rare Disease Database.)

Gaucher disease is a rare, inherited lysosomal storage disease. It is caused by a lack of an enzyme called glucocerebrosidase. This causes a buildup of a certain sugar-containing fat (glycolipid) called glucocerebroside. Buildup of glucocerebroside can lead to a variety of symptoms including an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of red blood cells (anemia) and platelets (thrombocytopenia), skeletal abnormalities, neurological complications. There are different forms of Gaucher disease that affect which symptoms occur and when. The severity of symptoms can differ between affected people. (For more information on this disorder, choose “Gaucher” as your search term in the Rare Disease Database.)

Niemann-Pick disease refers to a group of rare disorders that affect how fats (lipids) are broken down. There is a harmful buildup of these fats (lipids) in the spleen, liver, lungs, bone marrow, and brain. Symptoms may include lack of muscle coordination, brain decline, learning problems, loss of muscle tone (hypotonia), increased sensitivity to touch, spasticity, feeding and swallowing difficulties, slurred speech, and an enlarged liver and spleen (hepatosplenomegaly). The different types of disorders include Niemann-Pick type A, type B, type C1, and type C2. Symptoms and onset of disease differ depending on the type of Niemann-Pick disorder. (For more information on this disorder, choose “Niemann-Pick” as your search term in the Rare Disease Database.)

Juvenile CLN3 disease (formerly called Batten disease) is a rare lysosomal storage disease that belongs to a group of disorders known as neuronal ceroid lipofuscinoses. These disorders are caused by the harmful buildup of fatty, granular molecules in nerve cells and other parts of the body. Symptoms of Juvenile CLN3 disease begin between 5 and 15 years of age and include loss of vision, seizures, and neurological degeneration causing clumsiness, balance problems, and changes in behavior and personality. (For more information on this disorder, choose “Juvenile CLN3” as your search term in the Rare Disease Database.)

Adult neuronal ceroid lipofuscinosis (ANCL) (also known as Kufs disease) refers to several rare disorders known as neuronal ceroid lipofuscinoses. These disorders are caused by the harmful buildup of fatty, granular molecules in nerve cells and other parts of the body. Symptoms of ANCL typically begin around age 30, but it is possible for symptoms to occur in the teen years and in people over the age of 50. There are two forms of ANCL. In ANCL type A, symptoms include muscle contraction (myoclonus), seizures, difficulty coordinating voluntary movements (ataxia), and difficulty speaking (dysarthria). Symptoms of ANCL type B include difficulty coordinating voluntary movements (ataxia), tics or tremors, dementia, and behavioral or psychiatric changes. (For more information on this disorder, choose “Adult Neuronal Ceroid Lipofuscinosis” as your search term in the Rare Disease Database.)

Leigh syndrome is a rare disorder causing decline of the central nervous system. Leigh syndrome is caused by an error in enzymes that help produce energy in the mitochondria of the cells. Symptoms usually begin between two months and two years of age. They include loss of motor skills, loss of appetite, vomiting, seizures, irritability, weakness, poor muscle tone (hypotonia), and high levels of lactic acid in the blood (lactic acidosis). (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)

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Diagnosis

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.

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Standard Therapies

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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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Cachon-Gonzalez MB, Zaccariotto E, Cox TM. Genetics and therapies for GM2 gangliosidosis. Curr Gene Ther. 2018;18(2):68–89.

Ferreira CR, Gahl WA. Lysosomal storage diseases. Transl Sci Rare Dis. 2017;2(1-2):1-71.

Frey, LC, Ringel SP and Filley CM. The natural history of cognitive dysfunction in late-onset GM2 gangliosidosis. Arch Neurol 2005;62:989-994.

MacLeod PM, Wood S, Jan JE, et al. Progressive cerebral ataxia, spasticity, psychomotor retardation, and hexosaminidase deficiency in a 10 year-old child: juvenile Sandhoff disease. Neurology 1977;27:571-573.

Rubin M, Karpati G, Wolfe LS, et al. Adult onset motor neuropathy in the juvenile type of hexosaminidase A and B deficiency. J Neurol 1988:87:103-119.

Tavasoli AR, Parvaneh N, Ashrafi MR, Rezaei Z, Zschocke J, Rostami P. Clinical presentation and outcome in infantile Sandhoff disease: a case series of 25 patients from Iranian neurometabolic bioregistry with five novel mutations. Orphanet J Rare Dis. 2018;13(1):130.

INTERNET
Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. Part 16: Lysosomal Disorders. In: Valle D, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Mitchell G, Brunetti-Pierri N, Scriver CR, Sly WS, Beaudet AL, Bunz F. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw Hill Education; 2019. https://ommbid.mhmedical.com/book.aspx?bookID=2709#225069419 Accessed July 6, 2020.

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Programs & Resources

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