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Sandhoff disease

 
Neurological Disorder:

Sandhoff disease

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Definition

Sandhoff disease is a relatively rare, genetically inherited disease that results in the progressive deterioration of the central nervous system. In Sandhoff disease, abnormal lipid (fat) accumulation due to a storage defect causes damage to the brain as well as other organs of the body.

Description

Sandhoff disease is an autosomal recessive disorder, meaning that having an affected offspring requires both unaffected parents to be carriers. Parents who carry the disorder will have a 25% risk of having an affected offspring in subsequent pregnancies. This disease is similar to a related disorder known as Tay-Sachs disease, although Sandhoff disease is more severe.

Demographics

As Sandhoff disease is a recessive disorder, males and females are affected with equal frequency. This disorder is more common in people with non-Jewish descent, unlike Tay-Sachs disease, which is prevalent mainly in individuals with Jewish ancestry.

Causes and symptoms

Sandhoff disease is caused by mutations in two different genes that encode subunits that make up a protein called hexosaminidase. Hexosaminidase is an enzyme that breaks down certain fats in the brain. This enzyme is either composed of an alpha and a beta subunit (HexA) or two beta subunits (HexB). Sandhoff disease is caused by a mutation in a gene that is distinct from the gene that causes Tay-Sachs disease. In Tay-Sachs disease, a mutation that affects the alpha subunit of the enzyme causes a deficiency in HexA. Sandhoff disease is caused by mutations that affect the beta subunit, rendering both the HexA and HexB enzymes deficient. A deficiency of this enzyme leads to the accumulation of GM2 ganglioside, a fatty material found in the brain.

The beta subunit is encoded by a gene localized to chromosome 5, while the alpha subunit is encoded by a gene on chromosome 13. There is also another gene on chromosome 5 that encodes an activator that is required for either enzyme to be functional. Similar symptoms are observed in diseases arising from mutations that affect any of these three genes. Only biochemical genetic analysis of enzyme activity can pinpoint the cause and specify the disorder. However, Sandhoff disease can be distinguished from Tay-Sachs disease clinically by virtue of skeletal system or abdominal organ involvement (if present) in the later disease.

At birth, infants tend to be without symptoms and usually do not develop them until approximately six months of age. The symptoms begin with motor deficits (lack of normal movement) and a characteristic startle reaction to various sounds. Babies with Sandhoff disease progressively deteriorate in terms of motor function, and they often have seizures and myoclonus. Myoclonus is abnormal, exaggerated muscle contractions. Blindness can also be part of the symptoms. The loss of motor function includes the ability to swallow, and the affected infant has an increased risk for inhaling feedings into the lungs, frequently leading to pneumonia.

A typical physical feature of Sandhoff disease is the presence of cherry-red spots in the back of the eyes. Additionally, affected children have an abnormally enlarged head and appear to have a doll-like appearance.

Diagnosis

Because Sandhoff disease and Tay-Sachs disease have similar clinical symptoms, distinguishing them requires biochemical analysis. This involves a test to measure enzyme activity of the two hexosaminidase enzymes. If the enzyme activity results indicate that there is no hexosaminidase activity, it means that the patient has Sandhoff disease. If, however, there is still B subunit activity, then this indicates that the patient might have Tay-Sachs disease.

Treatment

There is no cure for Sandhoff disease, and treatment is based on lessening the symptoms once they begin. Medication is usually given to reduce seizures, for example, and a feeding tube may be inserted to prevent aspiration of feedings into the lungs.

Recovery and rehabilitation

Emphasis is placed on comfort rather than recovery, due to the progressive nature of Sandhoff disease. Because of the nature of the disorder, rehabilitation is not usually applicable to help with improving the motor deficits that develop. Physical therapy may be helpful to maintain muscle tone and skeletal alignment for as long as possible, while positional strategies and devices provided by an occupational therapist may increase comfort as symptoms progress.

Clinical trials

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is sponsoring, as of February 2004, a study to evaluate children with glycosphingolipid (GSL) storage disorders (such as Sandhoff disease) to investigate changes that occur in the brain that are responsible for nervous system degeneration. In this study, patients will receive medical treatment for their disorder. Contact the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), located at 9000 Rockville Pike, Bethesda, Maryland, 20892, Recruiting: Patient Recruitment and Public Liaison Office, (800) 411-1222 or prpl@mail.cc.nih.gov.

Prognosis

The prognosis for Sandhoff disease is poor. Affected babies usually do not survive past the age of three and typically, death occurs due to complications associated with respiratory infections.

Special concerns

Children who are affected with Sandhoff disease will require full time supervision and caretaking responsibilities. Psychological counseling for family members is often helpful. Genetic counseling for reproductive risks is recommended. There are also several support groups operated and comprised of other families nationwide with Sandhoff disease.

Resources

BOOKS

Icon Health Publications. The Official Parent's Sourcebook on Sandhoff Disease: A Revised and Updated Directory for the Internet Age. New York: Icon Group International, 2002.

Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard. Genetics in Medicine. Philadelphia : Saunders, 2001.

PERIODICALS

Gilbert, F., R. S. Kucherlapati, R. P. Creagan, M. J. Murnane, G. J. Darlington, and F. H. Ruddle. "Tay-Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes." Proc. Nat. Acad. Sci. 72 (1975): 263–267, 1975.

Neufeld, E. F. "Natural history and inherited disorders of a lysosomal enzyme, beta-hexosaminidase." J. Biol. Chem. 264 (1989): 10927–10930.

OTHER

"What every family should know: Sandhoff disease." The National Tay-Sachs & Allied Diseases Association. (February1, 2004). http://www.ntsad.org/pages/sandhoff.htm.

"NINDS Sandhoff Disease Information Page." National Institute of Neurological Disorders and Stroke. (February 1, 2004). http://www.ninds.nih.gov/health_and_medical/disorders/sandhoff.htm.

ORGANIZATIONS

National Tay-Sachs and Allied Diseases Association. 2001 Beacon Street Suite 204, Brighton, MA 02135. (617) 277-4463. (617) 277-0134. (800) 90-NTSAD (906-8723). info@ntsad.org. http://www.ntsad.org.

National Organization for Rare Disorders (NORD). P.O. Box 1968 (55 Kenosia Avenue), Danbury, CT 06813-1968. (203) 744-0100. (203) 798-2291. (800) 999-NORD (6673). orphan@rarediseases.org. http://www.rarediseases.org.


Bryan Richard Cobb, PhD


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Medical Dictionary: Sand·hoff's disease
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Home > Library > Health > Medical Dictionary
(sănd'hôfs')
n.

A form of GM2 gangliosidosis that resembles Tay-Sachs disease except that it does not affect persons of Jewish descent, characterized by a defect in the production of two forms of hexosaminidase.

Wikipedia: Sandhoff disease
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Home > Library > Miscellaneous > Wikipedia
Sandhoff disease
Classification and external resources
ICD-10 E75.0
ICD-9 330.1
OMIM 268800
DiseasesDB 29469
MeSH [1]

Sandhoff disease, also known as Jatzkewitz-Pilz syndrome and Hexosaminidase A and B deficiency,[1] is a rare autosomal recessive,[2] genetic, lipid storage disorder. An autosomal recessive disease is one passed down from two carrier parents to their offspring. The disease causes a lysosomal storage disorder where the patient has the inability to create the beta-hexosaminidase A and beta-hexosaminidase B, which is an enzyme that leads to a build-up of GM2 gangliosides in tissues of the body. This build-up is toxic at high levels, which leads to a progressive destruction of the central nervous system, damages the tissues and eventually leads to death. There are three subsets of the disease based on when the patient shows symptoms: classic infantile, juvenile and adult late onset. Clinically Sandhoff disease is undeterminable from Tay-Sachs disease[1][3], another genetic disorder that disrupts the beta-hexosaminidase A.

Contents

History

Horst Jatzkewitz, Hartmut Pilz, and Konrad Sandhoff first noticed Sandhoff disease in Germany in 1965. Initially these men were studying the biochemistry of different enzymes and found an exceptional case of Tay-Sachs [4]. These men classified Sandhoff as an abnormal Tay-Sachs disease, and published their findings in the Journal of Neurochemistry under the title, “Quantitative Bestimmungen von Gangliosiden und ihren neuraminsäurefreien Derivaten bei infantilen, juvenilen und adulten Formen der amaurotischen Idiotie und einer spätinfantilen biochemischen Sonderform.” Then, in 1968 Konrad Sandhoff, U. Andreae, and Horst Jatzkewitz further discussed the disease in the journal Life Sciences in 1968[5]. Konrad Sandhoff is given the most credit for the discovery of the disease and is currently researching biochemical and enzymatic aspects of the gangliosidoses and other lysosomal storage diseases.

Types

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[6]:

  • 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[7]
    • 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 muscles 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, and paralysis. An eye 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) 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[8].
  • 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[9].

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) 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.

Symptoms

Sandhoff disease symptoms are clinically indeterminable from Tay-Sachs Disease. The classic infantile form of the disease has the most severe symptoms and is incredibly hard to diagnose at this early age[9]. 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 build up of GM2 gangliosides. Since the body is unable to create the enzymes it needs within the central nervous system it is unable to attach to these gangliosides to break them apart and make them non-toxic . With this build-up 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), pneumonia, or bronchopneumonia[10]. 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 of the disease [11]. They experience loss of muscle coordination (ataxia), which affects their ability to walk, mental retardation, cherry red spots in the retina, and eventually losing the ability to walk altogether. In the adult form of the disease it may only lead to muscle weakness affecting their ability to walk or to get out of bed[12].

Pathophysiology

Sandhoff disease has an autosomal recessive pattern of inheritance.

Mutations in the HEXB gene cause Sandhoff disease. The gene provides instructions for making a protein crucial to the enzymes beta-hexosaminidase A and beta-hexosaminidase B,[3] 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.

Causes

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, there is only a 25% chance that they will have a child containing the genetic coding for the disease (see figure right)[13].

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[9]. The difference in the codons has the consequence of inhibiting two enzymes located in the lysosome of the Central Nervous System. Lysosomes are deemed the garbage disposal of any cell because lysosome contain different enzymes to break down carrying toxins to ensure they do not accumulate to deadly levels prohibiting function of the Central Nervous system[10] .

Using restriction enzymes, it was discovered that a mutation on chromosome 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[14]. align=left

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.[15]

Discovery of several mutations in Ashkenazi Jews 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.[15][19]

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.

Diagnosis

Actual test results from Jefferson Lab positive for Sandhoff Disease.

Sandhoff disease can be detected through the following procedures (before it is apparent through physical examination): a biopsy removing a sample of tissue from the liver, genetic testing, molecular analysis of cells and tissues (to determine the presence of a genetic metabolic disorder), enzyme assay, and occasionally a urinalysis 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 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[9] 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[14].

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 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[19].

Treatment

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.[14]

See also

Additional images

Sphingolipidoses

References

  1. ^ a b Online 'Mendelian Inheritance in Man' (OMIM) 268800
  2. ^ Huang JQ, Trasler JM, Igdoura S, Michaud J, Hanal N, Gravel RA (October 1997). "Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases" (Free full text). Human molecular genetics 6 (11): 1879–1885. doi:10.1093/hmg/6.11.1879. PMID 9302266. http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9302266. 
  3. ^ a b Chamoles NA, Blanco M, Gaggioli D, Casentini C (April 2002). "Tay-Sachs and Sandhoff diseases: enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn-screening cards". Clinica chimica acta; international journal of clinical chemistry 318 (1-2): 133–137. doi:10.1016/S0009-8981(02)00002-5. PMID 11880123. 
  4. ^ synd/3695 at Who Named It?
  5. ^ Sandhoff K, Andreae U, Jatzkewitz H (1968). "Deficient hexozaminidase activity in an exceptional case of Tay-Sachs disease with additional storage of kidney globoside in visceral organs". Life Sci. 7 (6): 283–288. doi:10.1016/0024-3205(68)90024-6. PMID 5651108. 
  6. ^ Zhang, Zhi-Xin, Nobuaki Wakamatsu, Emilie H.Mulesi, George H.Thomasi and Roy A.Gravel (1994). "Impact of premature stop codons on mRNA levels in infantile Sandhoff disease". Human Molecular Genetics 3 (1): 139-145. 
  7. ^ "What is Sandhoff Disease from a medical perspective". Parents of Children whom are living or whom have lived with Sandhoff Disease. http://sandhoffdisease.webs.com/parentsperspective.htm. Retrieved 2009-05-03. 
  8. ^ Hendriksz, C.J., P.C. Corry, J.E. Wraith, G.T.N. Besley, A. Cooper, and C.D. Ferrie (2004). "Juvenile Sandhoff disease-Nine New Cases and a review of the literature". Journal of Inherited Metabolic Disease 27 (2): 241-249. 
  9. ^ a b c d Gomez-Lira, Macarena,Antonella Sangalli, Monica Mottes, Chiara Perusi, Pier Franco Pignatti, Nicol6 Rizzuto, and Alessandro Salviati (1995). "A common β hexosaminidase gene mutation in adult Sandhoff disease patients". Human Genetics 96 (4): 417-422. 
  10. ^ a b "Introduction to Sandhoff Disease". The Medical Biochemistry Page. http://themedicalbiochemistrypage.org/sandhoffdisease.html. Retrieved 2009-05-03. 
  11. ^ "Sandhoff Disease". Genetics Home Reference. http://ghr.nlm.nih.gov/condition=sandhoffdisease. Retrieved 2009-05-03. 
  12. ^ Medical Books Excerpts. Lippincott Williams & Wilkin. 2008. 
  13. ^ a b Lowden JA et. al. (1978). "Carrier detection in Sandhoff disease". American Journal of Human Genetics 30 (1): 338-345. PMID 414620. 
  14. ^ a b c "Lysosomal Diseases Testing Laboratory". Department of Neurology Jefferson Hospital. http://www.jeffersonhospital.org/neurology/article4360.html. Retrieved 2009-05-03. 
  15. ^ a b "Online Mendelian Inheritance in Man". United States National Institute of Health. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=268800. Retrieved 2009-04-22. 
  16. ^ "Carrier Testing". National Tay-Sachs & Allied Disease Association, Inc. http://www.ntsad.org/. Retrieved 2009-05-03. 
  17. ^ Kleiman FE et. al (1994). "Sandhoff disease in Argentina: high frequency of a splice site mutation in the HEXB gene and correlation between enzyme and DNA-based tests for heterozygote detection". Human Genetics 94 (3). PMID 8076944. 
  18. ^ Drousiotou A et. al.. "Sandhoff disease in Cyprus: population screening by biochemical and DNA analysis indicates a high frequency of carriers in the Maronite community". Human Genetics 107 (1): 12-17 PMID=10982028. 
  19. ^ a b Cantor RM, Kaback MM (1985). "Sandhoff disease (SHD) heterozygote frequencies (HF) in North American (NA) Jewish (J) and non-Jewish (NJ) populations: implications for carrier (C) screening". American Journal of Human Genetics 37: A48. 

External links

This article incorporates some public domain text from The U.S. National Library of Medicine

v • d • e
(LSD) Inborn error of lipid metabolism: lipid storage disorders (E75, 272.7-272.8)
Sphingolipidoses
(to ceramide)
NCL
Other

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