Sandhoff disease
Sandhoff disease, also known as Sandhoff-Jatzkewitz disease, variant 0 of GM2-Gangliosidosis or Hexosaminidase A and B deficiency, is a lysosomal genetic, lipid storage disorder
Lipid storage disorder
Lipid storage disorders are a group of inherited metabolic disorders in which harmful amounts of lipids accumulate in some of the body’s cells and tissues. People with these disorders either do not produce enough of one of the enzymes needed to metabolize lipids or they produce enzymes that do...

 caused by the inherited deficiency to create functional beta-hexosaminidases A and B. These catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2, its derivative GA2, the glycolipid globoside in visceral tissues, and some oligosaccharides. Acccumulation of these metabolites leads to a progressive destruction of the central nervous system and eventually to death. The rare autosomal recessive neurodegenerative disorder is clinically almost indistinguishable from Tay-Sachs disease
Tay-Sachs disease
Tay–Sachs disease is an autosomal recessive genetic disorder...

, another genetic disorder that disrupts beta-hexosaminidases A and S. There are three subsets of Sandhoff disease based on when first symptoms appear: classic infantile, juvenile and adult late onset.


Sandhoff disease is one of several forms of what was formerly known as amaurotic idiocy. This inherited disease is characterized by the accumulation of lipid-containing cells in the viscera and in the nervous system, mental retardation, and impaired vision or blindness. The chemical and enzymatic analysis of various patients with amaurotic idiocy by Konrad Sandhoff :de:Konrad Sandhoff led to the identification of several biochemically distinct diseases: The first biochemical description of GM1-gangliosidosis in 1963, Sandhoff disease in 1968, Tay-Sachs-Disease, the AB-variant of GM2-Gangliosidosis and the B1-variant of GM2-gangliosidosis.

It came to the discovery of the molecular defect in Sandhoff disease, when Konrad Sandhoff studied the biochemistry of sphingolipids and gangliosides in the laboratory of Prof. Horst Jatzkewitz (Max- Planck-Institute for Psychiatry, Munich). In October 1966, he obtained deep-frozen autopsy material from an infantile case with amaurotic idiocy. The glycolipid analysis soon demonstrated differences from all the cases studied before. Besides the neuronal storage of GM2, the storage of GA2 was much more pronounced, and different from all cases of Tay-Sachs disease studied so far, globoside accumulated in the visceral organs and, most importantly, hexosaminidase activity was almost completely absent. The disease causing catabolic enzyme deficiency of hexosaminidases was demonstrated with four different substrates (p–nitrophenyl-β-D-N-acetylglucosaminide, p-nitrophenyl-β-D-N-acetylgalactosaminide, glycolipid [3H]GA2 and [3H]globoside) in four different organs and published in 1968.


There are three different types of Sandhoff disease, classic infantile, juvenile, and adult late onset. Each form is classified by the severity of the symptoms as well as the age in which the patient shows these symptoms:
  • Classic infantile form of the disease is classified by the development of symptoms anywhere from 2 months to 9 months of age. It is the most severe of all of the forms and will lead to death before the patient reaches the age of three
    • This is the most common and severe form of Sandhoff disease. Infants with this disorder typically appear normal until the age of 3 to 6 months, when development slows and muscle
      Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

      s used for movement weaken. Affected infants lose motor skills such as turning over, sitting, and crawling. As the disease progresses, infants develop seizures, vision and hearing loss, mental retardation
      Mental retardation
      Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...

      , and paralysis
      Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...

      . An eye
      Human eye
      The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...

       abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Some infants with Sandhoff disease may also have enlarged organs (organomegaly
      Organomegaly is the abnormal enlargement of organs. For example, clitoromegaly is the enlargement of the clitoris, hepatomegaly is enlargement of the liver, cardiomegaly is enlargement of the heart, and splenomegaly is enlargement of the spleen....

      ) or bone abnormalities. Children with the severe form of this disorder usually live only into early childhood.
  • Juvenile form of the disease shows symptoms starting at age 3 ranging to age 10 and although the child usually dies by the time they are 15, it is possible for them to live longer if they are under constant care.
  • Adult onset form of the disease is classified by its occurrence in older individuals and has an effect on the motor function of these individuals and it is not yet known if Sandhoff Disease will cause these individuals to have a decrease in their life span.

Both Juvenile and Adult onset forms of Sandhoff disease are very rare. Signs and symptoms can begin in childhood, adolescence, or adulthood and are usually milder than those seen with the infantile form of Sandhoff disease. As in the infantile form, mental abilities and coordination are affected. Characteristic features include muscle weakness, loss of muscle coordination (ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...

) 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.


Sandhoff disease symptoms are clinically indeterminable from Tay-Sachs Disease
Tay-Sachs disease
Tay–Sachs disease is an autosomal recessive genetic disorder...

. The classic infantile form of the disease has the most severe symptoms and is incredibly hard to diagnose at this early age. The first signs of symptoms begin before 6 months of age and the parents’ notice when the child begins digressing in their development. If the children had the ability to sit up by themselves or crawl they will lose this ability. This is caused by a slow deterioration of the muscles in the child’s body from the buildup of GM2 gangliosides. Since the body is unable to create the enzymes it needs within the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 it is unable to attach to these gangliosides to break them apart and make them non-toxic. With this buildup there are several symptoms that begin to appear such as muscle/motor weakness, sharp reaction to loud noises, blindness, deafness, inability to react to stimulants, respiratory problems and infections, mental retardation, seizures, cherry red spots in the retina, enlarged liver and spleen (hepatosplenomegaly
Hepatosplenomegaly is the simultaneous enlargement of both the liver and the spleen . Hepatosplenomegaly can occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of a serious and life threatening lysosomal storage disease...

), pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

, or bronchopneumonia
Bronchopneumonia or bronchial pneumonia or "Bronchogenic pneumonia" is the acute inflammation of the walls of the bronchioles...


The other two forms of Sandhoff disease have similar symptoms but to a lesser extent. Adult and juvenile forms of Sandhoff disease are more rare then the infantile form. In these cases victims suffer cognitive impairment (retardation) and a loss of muscle coordination that impairs and eventually destroys their ability to walk; the characteristic red spots in the retina also develop. The adult form of the disease, however, is sometimes milder, and may only lead to muscle weakness that impairs walking or the ability to get out of bed.


Mutations in the HEXB
Beta-hexosaminidase subunit beta is an enzyme that in humans is encoded by the HEXB gene.-Further reading:...

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 cause Sandhoff disease. The gene provides instructions for making a protein crucial to the enzymes beta-hexosaminidase A and beta-hexosaminidase B, which function in nerve cells to break down fatty substances, complex sugars, and molecules that are linked to sugars. In particular, beta-hexosaminidase A breaks down a fatty compound called GM2 ganglioside. Mutations in the HEXB gene disrupt the activity of these enzymes, preventing the breakdown of GM2 ganglioside and other molecules.

As a result, progressive damage caused by the resulting buildup of GM2 ganglioside leads to the destruction of nerve cells, causing the signs and symptoms associated with Sandhoff disease.


Two parents carrying a mutated gene and passing it on to their offspring cause the disease. Even with both parents carrying the disease in their genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....

, there is only a 25% chance that they will have a child containing the genetic coding for the disease (see figure right).

Each form of the disease is caused by the differences in the various mutations of the genome, in particular the codons on the 14 exons in the HEX B gene located within chromosome 5 (see figure bottom), leading to the differences in severities of the symptoms. The difference in the codons has the consequence of inhibiting two enzymes located in the lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...

s of the neurons of the central nervous system. Lysosomes contain various enzymes to break down byproducts and toxins to ensure they do not accumulate enough to interfere with the function of the central nervous system.

Using restriction enzymes, it was discovered that a mutation on chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

 5 particularly within the C1214T allele caused the adult onset form of Sandhoff Disease. For the patient showing symptoms of the infantile or juvenile form they have a mutation on exon I207V from their father, and a 16 base pair deletion from their mother which can be located on as many as 5 exons, exons 1-5.

Mutations and polymorphism

All articles regarding Sandhoff Disease frequencies among distinct groups of people contain discrepancies from one another. More than 25 mutations have been reported other than novel mutations.
  • One article says that Sandhoff Disease is found commonly in individuals with a non-Jewish decent.
  • While others say that it is more commonly in:
    • the Creole population of northern Argentina
      Argentina , officially the Argentine Republic , is the second largest country in South America by land area, after Brazil. It is constituted as a federation of 23 provinces and an autonomous city, Buenos Aires...

    • the indigenous Métis
      Métis people (Canada)
      The Métis are one of the Aboriginal peoples in Canada who trace their descent to mixed First Nations parentage. The term was historically a catch-all describing the offspring of any such union, but within generations the culture syncretised into what is today a distinct aboriginal group, with...

       in Saskatchewan
      Saskatchewan is a prairie province in Canada, which has an area of . Saskatchewan is bordered on the west by Alberta, on the north by the Northwest Territories, on the east by Manitoba, and on the south by the U.S. states of Montana and North Dakota....

    • Christian Maronite communities from Cyprus
      Cyprus , officially the Republic of Cyprus , is a Eurasian island country, member of the European Union, in the Eastern Mediterranean, east of Greece, south of Turkey, west of Syria and north of Egypt. It is the third largest island in the Mediterranean Sea.The earliest known human activity on the...

Discovery of several mutations in Ashkenazi Jews
Ashkenazi Jews
Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim , are the Jews descended from the medieval Jewish communities along the Rhine in Germany from Alsace in the south to the Rhineland in the north. Ashkenaz is the medieval Hebrew name for this region and thus for Germany...

 may reflect ascertainment bias rather than a high population frequency, because Ashkenazi Jews were the targeted population in a mass screening program for Tay-Sachs disease. Several rare SD mutations were discovered as researchers resolved cases of enzyme deficiency among suspected TSD carriers, but no cases of the disease itself have been reported.

However, since it is an autosomal recessive disease it is likely found in any ethnic group passing from generation to generation through carriers without being expressed in their offspring. Even though the family may not have a history of Sandhoff Disease, it is possible for two individuals to have a child with the disease. Since Sandhoff Disease was only discovered in 1968, there are years the disease has gone undetected because of misdiagnoses.


Sandhoff disease can be detected through the following procedures (before it is apparent through physical examination): a biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...

 removing a sample of tissue from the liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...

, molecular analysis of cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

s and tissues (to determine the presence of a genetic metabolic disorder), enzyme assay
Enzyme assay
Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition.-Enzyme units:...

, and occasionally a urinalysis
A urinalysis , also known as Routine and Microscopy , is an array of tests performed on urine, and one of the most common methods of medical diagnosis...

 to determine if the above-noted compounds are abnormally stored within the body. For a child to suffer from this disease, both parents must be carriers, and both must transmit the mutation to the child. Thus, even in the case where both parents have the mutation, there is only a 25 percent chance their child will inherit the condition. Frequently, parents are given the opportunity to have a DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 screening if they are at high risk, to determine their carrier status before they have children. However, it is also highly recommended to undergo testing even for those parents who do not have a family history of Sandhoff disease. Over 95% of the families that have children with Sandhoff disease had no known prior family history of the condition, as the mutation in the HEXB gene is "silent," or recessive, and often passed undetected from one generation to the next Naturally, if an individual carries the mutation, he or she has a risk of transmitting it to the unborn child. Genetic counseling is recommended for those who have the mutation.

The most well known laboratory to perform the blood tests is through Lysosomal Diseases Testing Laboratory, Jefferson University with Dr. Wenger. Dr. Wenger’s laboratory does testing for all lysosomal diseases including Sandhoff and Tay-Sachs. They test for build-up of certain toxins in the body as well as a low count of enzymes.

It is possible for parents who are about to have a child or had a child with Sandhoff Disease can have a PGD or PEGD. PEGD is pre-embryonic genetic diagnosis for the parents that would not benefit from a pre-implantation genetic diagnosis because of their religion or negative attitude for the discarding of embryos. PEGD sequences the genome of the embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...

 to be produced by two parents if they were to conceive a child. If the family has a history of Sandhoff disease it is recommended they have their genome sequenced to ensure they are not carriers or to sequence the genome of their child.


Currently Sandhoff disease does not have any standard treatment and does not have a cure. However, a person suffering from the disease needs proper nutrition, hydration, and maintenance of clear airways. To reduce some symptoms that may occur with Sandhoff disease, the patient may take anticonvulsants to manage seizures or medications to treat respiratory infections, and consume a precise diet consisting of puree foods due to difficulties swallowing. Infants with the disease usually die by the age of 3 due to respiratory infections. The patient must be under constant surveillance because they can suffer from aspiration or lack the ability to change from the passage way to their lungs versus their stomach and their spit travels to the lungs causing bronchopneumonia. The patient also lacks the ability to cough and therefore must undergo a treatment to shake up their body to remove the mucus from the lining of their lungs. Medication is also given to patients to lessen their symptoms including seizures.

Currently the government is testing several treatments including N-butyldeoxynojirimycin in mice, as well as stem cell treatment in humans and other medical treatments recruiting test patients.

External links

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