Chanses of Having a Baby With Tay Sachs Disease

Tay Sachs Illness

NORD gratefully acknowledges Kathleen Renna, BS, Scientific Program Analyst, Sectionalisation of Genomics and Gild, National Human Genome Inquiry Institute and Camilo Toro, MD, NIH Undiagnosed Diseases Programme, National Human Genome Research Institute, National Institutes of Wellness, for assistance in the preparation of this written report.

Synonyms of Tay Sachs Disease

• HEXA deficiency
• hexosaminidase A deficiency
• TSD
• GM2 gangliosidosis, type 1
• hexoaminidase alpha-subunit deficiency (variant B)
• B variant GM2 gangliosidosis
• sphingolipidosis, Tay-Sachs

Subdivisions of Tay Sachs Disease

• infantile Tay-Sachs disease
• juvenile (subacute) Tay-Sachs disease
• tardily-onset Tay-Sachs disease

General Discussion

Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive aggregating of certain fats (lipids) known as gangliosides in the brain and nerve cells. This abnormal aggregating of gangliosides leads to progressive dysfunction of the central nervous system. Tay-Sachs illness is categorized as a lysosomal storage affliction. Lysosomes are the major digestive units in cells. Enzymes within lysosomes break downwards or "digest" nutrients, including sure circuitous carbohydrates and fats (like glycosphingolipids). When one of these lysosomal enzymes (such every bit hexosaminidase A) is missing or ineffective, glycosphingolipids first to build up in the lysosome. If there is besides much aggregating of these materials in the lysosome, the cells in the nervous system degenerate and die, triggering an inflammatory response that amplifies damage in surrounding tissue.

The most common class of Tay-Sachs disease is the Infantile form, which can nowadays around vi months of age equally reduced vision and an exaggerated startle response and eventually progress to a gradual loss of skills and seizures by age 2 and early death, normally by the age of five. In that location is also a juvenile version of the illness starting time at most the historic period of 5 years of age and adult forms of Tay-Sachs disease also known every bit late-onset Tay Sachs disease (LOTS) beginning in the tardily teens and beyond. All three forms of Tay-Sachs illness are inherited in an autosomal recessive manner and the age of onset is a function of the amount, if whatsoever, of residuum enzyme activity.

Scroll back up to restore default view.

Signs & Symptoms

Infantile Tay-Sachs Affliction
The infantile form of Tay-Sachs affliction is characterized by consummate or virtually consummate lack of hexosaminidase A enzyme activity. The disorder ofttimes progresses rapidly, resulting in significant cerebral and physical deterioration.

Infants may announced completely unaffected at birth. Initial symptoms, which usually develop between 3 and vi months, can include mild muscle weakness, twitching or jerking of muscles (myoclonic jerks) and an exaggerated startle response, such every bit when there is a sudden or unexpected dissonance. The startle response may exist partly due to an increased sensitivity to sound (acoustic hypersensitivity).

Betwixt six and x months, affected infants may fail to proceeds new motor skills. They may no longer make eye contact and there may be unusual middle movements. They may be listlessness and irritable. As affected infants historic period, they may experience ho-hum growth, progressive musculus weakness and diminished muscle tone (hypotonia). Affected infants may also showroom gradual loss of vision, involuntary musculus spasms (myoclonus), slow, stiff movements (spasticity) and the loss of previously caused skills (i.e., psychomotor regression) such as itch or sitting upward.

A feature symptom of Tay-Sachs disease is the development of a macular "cherry ruby-red" spot. This ophthalmological finding emerges from aberrant accumulation of pale undigested cloth in the macula which contrasts to the thin foveal transparent background exposing the normal rich choroidal vasculature. This characteristic finding occurs is approximately 90% of individuals with infantile Tay-Sachs disease.

As afflicted infants age, more serious complications may develop including seizures, difficulty swallowing, loss of vision, paralysis and progressive hearing loss. Additional cerebral deficits may include confusion, disorientation and/or deterioration of intellectual abilities. Eventually, infants may go unresponsive to their environment and surroundings. By three to five years of age, life-threatening complications brainstorm to occur such as aspiration pneumonia leading to respiratory failure.

Juvenile (Subacute) Tay-Sachs Disease
The onset of juvenile Tay-Sachs affliction can be anywhere between 2 and 10 years of age. One of the first signs is frequently clumsiness and incoordination. This occurs because affected children accept bug controlling their body'south movements (clutter). Children tend to experience a progressive loss of spoken language, life skills and intellectual abilities. Afflicted individuals may or may not develop a cherry-red spot in the eyes. Degeneration of the optic nerves (optic atrophy) may occur. Some children may accept retinitis pigmentosa, a progressive loss and degeneration of the cells in the retina where shapes and colors are first encoded. Affected children become less responsive to their environment and surroundings. Life-threatening complications unremarkably occur around xv years of age.

Late-Onset Tay-Sachs Affliction
The presentation and symptoms associated with late-onset Tay-Sachs disease vary greatly. Onset of the disease may vary from the late teens to any time in adulthood. This variability may occur fifty-fifty within affected members of the aforementioned family. For example, in a given family 1 person may accept symptoms in their 20s, while another reaches into their 60s or 70s with relatively milder minor symptoms. The disorder progresses much slower than the infantile or juvenile forms of the disease.

Initial symptoms associated with late-onset Tay-Sachs illness may include progressive muscle weakness and wasting (neurogenic cloudburst), incoordination and clumsiness from cerebellar dysfunction (ataxia) or acute psychiatric presentation. Every bit affected individuals age, muscle twitching (fasciculation), cramps, weakness and musculus wasting progresses affecting preferentially the quadriceps and hip flexor muscles, and subsequently, the triceps muscles. Patients need to lock their knees in hyperextension to be able to stand and support their weight. Failure to practice so results in falls and eventually leads to the need for a device to help with walking. Patients may exhibit tremors and progressive slurred speech (dysarthria). Difficulties swallowing (dysphagia) may emerge belatedly in the disease. Some affected individuals feel astute psychiatric manifestations (mania, acute depression or psychosis) that may require emergency psychiatric intendance. Over time, cerebral difficulties including executive dysfunction and some retentiveness difficulties might sally.

Causes

Tay-Sachs affliction is caused past a change (mutation) in the hexosaminidase subunit alpha (HEXA) gene. Genes provide the instructions for the basic construction of proteins, all of which that play a critical role in many functions and construction of the body. When a mutation occurs in a gene, the protein production may exist faulty, inefficient or absent. Depending upon the functions of the protein, this tin affect many organ systems of the body, including the brain.

The HEXA factor encodes the structure of the protein HEXA which is a subunit of the enzyme hexosaminidase A. More than than fourscore different mutations of the HEXA gene have been identified in individuals with the disease. Inheriting ii mutated copies of the HEXA gene (homozygotes) causes deficiency of the hexosaminidase A enzyme, which is necessary to breakup GM2-ganglioside (a glycosphingolipids) within cells of the trunk. Failure to breakdown GM2-ganglioside results in its abnormal aggregating in brain and nervus cells eventually resulting in the progressive deterioration of the central nervous system.

In infantile Tay-Sachs disease, there is a complete lack of hexosaminidase A. In juvenile and late-onset Tay-Sachs disease, there minimal only still some balance hexosaminidase A enzyme activity which explains why these disorders might be less severe and progress at a slower pace than infantile Tay-Sachs illness.

Tay-Sachs disease is inherited every bit an autosomal recessive disease. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene, one from each parent. If an individual inherits ane normal copy of the gene from one parent and an abnormal (mutated) copy of the gene from the other parent, that person will exist a carrier for the disease just will not develop the affliction. The adventure for ii carrier parents to both pass the altered gene and accept an afflicted child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is fifty% with each pregnancy. The run a risk for a kid to receive the normal genes from each parent is 25%. The take chances is the aforementioned for males and females.

Affected Populations

Tay-Sachs disease affects males and females in equal numbers. Tay-Sachs illness used to be considered a prototypical disease of Jewish people of Ashkenazi descent. Community counselling and carrier screening efforts in these communities have succeeded in reducing disease prevalence to figures roughly equivalent to those of not-Jewish populations. Increased prevalence of Tay Sachs disease is also reported in other ethnic groups including those living in the Cajun community of Louisiana and southeastern Quebec. In the general population, the carrier rate for Tay-Sacks disease is approximately 1 in 250-300 people.

Diagnosis

The diagnosis of Tay-Sachs illness may exist confirmed by a thorough clinical evaluation and specialized tests such every bit blood tests that measure the enzyme activity levels of hexosaminidase A. Molecular genetic testing for mutations in the HEXA factor can confirm a diagnosis of Tay-Sachs disease. With the advent of more widely bachelor cistron panels and exome and whole genome sequencing, more patients are initially diagnosed by molecular testing followed by enzymatic confirmation.

It is possible that a diagnosis of Tay-Sachs disease may exist suspected before birth (prenatally) based upon specialized tests, such as amniocentesis and chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed, while CVS involves the removal of tissue samples from a portion of the placenta. These samples are studied to determine hexosaminidase A action. Absence or greatly reduced activity suggests a diagnosis. Prenatal diagnosis is likewise possible through molecular genetic testing of tissue samples obtained through CVS or amniocentesis, particularly if the disease-causing mutation(due south) in the HEXA gene are known in the family.

Carrier testing for Tay-Sachs disease can be accomplished from a blood sample and determines whether an individual carries i disease-causing re-create of the HEXA factor. Relatives of individuals with Tay-Sachs disease can be tested to decide whether they are carriers. Couples who are planning to take a child and take any Jewish ancestry (not only Ashkenazi) are encouraged to undergo carrier screening before proceeding with a pregnancy.

For couples that find that they are carriers, there are several options bachelor for starting a family. These options include assisted reproductive technologies (ART) such as in vitro fertilization (IVF) and adoption. Couples are encouraged to consult with a genetic advisor to hash out these options.

Genetic counseling is bachelor to assist families in testing decisions, interpreting test results and understanding wellness insurance coverage. Families are strongly encouraged to seek out a genetic counselor, particularly before carrier screening, to exist almost informed when making genetics healthcare decisions. For assistance finding a genetic counselor, visit: https://findageneticcounselor.nsgc.org/?reload=timezone

Standard Therapies

Treatment

There is no approved treatment for Tay-Sachs disease. Treatment is directed toward the individual symptom management. Handling may crave the coordinated efforts of a team of specialists. Pediatricians, neurologists, speech pathologists, specialists who assess and treat hearing problems (audiologists), heart specialists and other health care professionals may need to interact to develop a programme for an affected child's treatment.

Because of the potential for feeding difficulties, infants should be monitored for nutritional condition and proper hydration. Nutritional support and supplementation may be necessary. Occasionally, the insertion of a feeding tube may exist required to assist forestall nutrient, liquid or other foreign fabric from accidently going into the lungs (aspiration).

Anticonvulsants may be used to treat seizures in some people with Tay-Sachs disease, just may non be constructive in all people. The types and frequency of seizures can modify over time in some individuals which will require a change in medication type or dosage.

Genetic counseling is recommended for affected individuals and their families. Psychosocial back up is recommended for the unabridged family unit.

Investigational Therapies

Enzyme replacement therapy (ERT) has been considered and adult for lysosomal storage disorders. In Tay-Sachs illness, enzyme replacement therapy involves replacing a missing or deficient hexosaminidate A. An inability to discover a way for the deliver the replacement enzyme (a big molecule) to cantankerous the blood-encephalon barrier limits this strategy.

Chaperone therapy is besides existence studied for the therapy of Tay-Sachs disease. This type of therapy involves very modest molecules called chaperones that attach to newly synthetized hexosaminidase A enzymes. This arroyo seeks to protect degradation of the abnormal hexosaminidase A inside the cells earlier it is degraded, thus allowing the hexosaminidase A, albeit deficient, to exert its activity for a longer time-menstruation. A chaperone called pyrimethamine has been studied every bit a treatment for Tay-Sachs illness. Affected individuals who took the medication showed increased activity of hexosaminidase A. However, increased activeness did non pb to any noticeable improvement in symptoms and was accompanied past undesirable side effects.

Substrate reduction therapy for Tay-Sachs disease seeks to decrease the overall burden of substrate (ganglioside) that needs degradation by reducing its synthesis. In the case Tay-Sachs, substrate reduction requires some caste of penetration into the central nervous system beyond the blood-brain bulwark as the burden of affliction is in the brain and spinal cord. Such strategy is currently under clinical investigation. [ClinicalTrials.gov Identifier: NCT04221451]

Gene therapy is also being studied as another possible approach to therapy for some lysosomal storage disorders. In gene therapy, the defective gene nowadays in a patient is replaced with a normal factor to enable the production of active enzyme and preclude the development and progression of the affliction. Given the permanent transfer of the normal gene, which can produce active enzyme at all sites of disease, this class of therapy is theoretically most likely to pb to a "cure." The Tay-Sachs Factor Therapy (TSGT) Consortium is a collaborative group of scientists seeking to translate information from animal model studies into clinical trials.

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

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, Dr., contact the NIH Patient Recruitment Function:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/

For information most clinical trials sponsored by individual sources, contact: www.centerwatch.com

For more than information about clinical trials conducted in Europe, contact: https://world wide web.clinicaltrialsregister.eu/

Resources

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.

NORD Member Organizations

• National Tay-Sachs and Allied Diseases Clan, Inc.
  • 2001 Beacon Street
  • Suite 204
  • Boston, MA 02135 USA
  • Phone: (617) 277-4463
  • Toll-free: (800) 906-8723
  • Email: [electronic mail protected]
  • Website: http://www.NTSAD.org

Other Organizations

• Genetic and Rare Diseases (GARD) Data Middle
  • PO Box 8126
  • Gaithersburg, MD 20898-8126
  • Phone: (301) 251-4925
  • Price-free: (888) 205-2311
  • Website: http://rarediseases.info.nih.gov/GARD/
• Let Them Hear Foundation
  • 1900 University Avenue, Suite 101
  • Due east Palo Alto, CA 94303
  • Phone: (650) 462-3174
  • Electronic mail: [electronic mail protected]
  • Website: http://www.letthemhear.org
• Metabolic Support UK
  • Unit 11-12 Gwenfro
  • Technology Park, Croesnewydd Rd
  • Wrexham, Wales LL13 7YP U.k.
  • Telephone: 0124420758108452412173
  • E-mail: [email protected]
  • Website: https://www.metabolicsupportuk.org/
• The Arc
  • 1825 One thousand Street NW, Suite 1200
  • Washington, DC 20006
  • Phone: (202) 534-3700
  • Toll-free: (800) 433-5255
  • Electronic mail: [e-mail protected]
  • Website: http://www.thearc.org
• Vaincre Les Maladies Lysosomales
  • two Ter Avenue
  • Massy, 91300 France
  • Phone: 169754030
  • Email: [email protected]
  • Website: http://www.vml-asso.org

References

JOURNAL Manufactures
Liguori Chiliad, Tagarelli Grand, Romeo Northward, Bagala A, Spadafora P. Identification of a patient affected past "juvenile chronic" Tay Sachs disease in Southward Italy. Neurol Sci. 2016;37:1883-1885. https://www.ncbi.nlm.nih.gov/pubmed/27351546

Steiner KM, Brenck J, Goericke Due south, Timmann D. Cerebellar atrophy and muscle weakness: belatedly-onset Tay-Sachs disease exterior Jewish populations. BMJ Case Rep. 2016;2016. https://www.ncbi.nlm.nih.gov/pubmed/27033294

Osher E, Fattal-Valevski A, Sagie Fifty, et al. Upshot of circadian, depression dose pyrimethamine treatment in patients with late onset Tay Sachs: an open up lab el, extended pilot written report. Orphanet J Rare Dis. 2015;10:45. https://world wide web.ncbi.nlm.nih.gov/pmc/articles/PMC4404274/

Hall P, Minnich S, Teigen C, Raymond Thou. Diagnosing lysosomal storage disorders: the GM2 gangliosidoses. Curr Protoc Hum Genet. 2014;83:17.161-eight. https://www.ncbi.nlm.nih.gov/pubmed/25271840

Smith NJ, Winstone AM, Stellitano Fifty, Cox TM, Verity CM. GM2 gangliosidosis in a UK written report of children with progressive neurodegeneration: 73 cases reviewed. Dev Med Kid Neurol. 2012;54:176-182. https://www.ncbi.nlm.nih.gov/pubmed/22115551

Osher Eastward, Fattal-Valevski A, Sagie L, et al. Pyrimethamine increases Beta-hexosaminidase A activity in patients with late onset Tay Sachs. Mol Genet Metab. 2011;102:356-363. https://www.ncbi.nlm.nih.gov/pubmed/21185210

Bley AE, Giannikopoulos OA, Hayden D, et al. Natural history of infantile M(M2) gangliosidosis. Pediatrics. 2011;128:e1233-1241. https://www.ncbi.nlm.nih.gov/pubmed/22025593

Clarke JT, Mahuran DJ, Sathe S, et al. An open-label phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants). Mol Genet Metab. 2011;102:6-12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019177/

Schneider A, Nakagawa S, Go on R, et al. Population-based Tay-Sachs screening amid Ashkenazi Jewish young adults in the 21st century: hexosaminidase A enzyme assay is essential for accurate testing. Am J Med Genet A. 2009;149A:2444-2447. https://www.ncbi.nlm.nih.gov/pubmed/19876898

Shapiro Exist, Pastores GM, Gianutsos J, Luzy C, Kolodny Eh. Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment. Genet Med. 2009;xi:425-533. https://www.ncbi.nlm.nih.gov/pubmed/19346952

Shapiro Be, Logigian EL, Kolodny EH, Pastores GM. Belatedly-onset Tay-Sachs disease: the spectrum of peripheral neuropathy in 30 affected patients. Muscle Nerve. 2008;38:1012-1015. https://www.ncbi.nlm.nih.gov/pubmed/18642377

Maegawa GH, Stockley T, Tropak One thousand, et al. The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. Pediatrics. 2006;118:el550-562. https://www.ncbi.nlm.nih.gov/pubmed/17015493

Bach G, Tomczak J, Risch N, Ekstein J. Tay-Sachs screening in the Jewish Ashkenazi population: DNA testing is the preferred procedure. Am J Med Genet. 2001;99:70-75. https://www.ncbi.nlm.nih.gov/pubmed/11170098

Hill LW, Schorr SJ. Prenatal screening for Tay-Sachs disease by Louisiana obstetricians: a survey report. Due south Med J. 2001;94:910-12. https://world wide web.ncbi.nlm.nih.gov/pubmed/11592753

Guidotti JE, Mignon A, Haase Chiliad, et al. Adenoviral cistron therapy of the Tay-Sachs disease in hexosaminidase A-deficient knock-out mice. Hum Mol Genet. 1999;8:831-38. https://www.ncbi.nlm.nih.gov/pubmed/10196372

Platt FM, Butters TD. New therapeutic prospects for the glycosphingolipid lysosomal storage diseases. Biochem Pharmacol. 1998;56:421-30. https://www.ncbi.nlm.nih.gov/pubmed/9763217

De Gasperi R, Gama Sosa A, Battistini S, et al. Belatedly-onset GM2 gangliosidosis: Ashkenazi Jewish family with an exon 5 mutation (Tyr– >His) in the Hex A alpha-chain gene. Neurology. 1996;47:547-52. http://www.neurology.org/content/47/2/547.short

Nakai H, Byers MG, Nowak SJ, Shows TB. Assignment of beta-hexosaminidase A alpha-subunit to human chromosomal region 15q23 – q24. Cytogenet Cell Genet. 1991;56:164. https://www.ncbi.nlm.nih.gov/pubmed/1829032

Navon R, Kolodny EH, Mitsumoto H, Thomas GH, Proia RL. Ashkenazi-Jewish and non-Jewish developed GM2 gangliosidosis patients share a common genetic defect. Am J Med Genet. 1990;46:817-21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1683663/

Navon R, Proia RL. The mutations in Ashkenazi Jews with adult GM2 gangliosidosis, the developed form of Tay-Sachs disease. Science. 1989;243:1471-74. https://www.ncbi.nlm.nih.gov/pubmed/2522679

Internet
Assisted Reproductive Technologies. Society for Assisted Reproductive Technology (SART) website. Available at: https://www.sart.org/patients/a-patients-guide-to-assisted-reproductive-technology/general-information/assisted-reproductive-technologies/ Accessed: March 30, 2021

Toro C, Shirvan L, Tifft C. HEXA Disorders. 1999 Mar 11 [Updated 2020 Oct ane]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://world wide web.ncbi.nlm.nih.gov/books/NBK1218/ Accessed March 30, 2021.

Tay-Sachs Illness. MedlinePlus. Reviewed October 2012. Bachelor at: https://ghr.nlm.nih.gov/condition/tay-sachs-disease Accessed March 30, 2021.

Tay-Sachs Disease. National Tay-Sachs and Centrolineal Diseases, Inc. website. Reviewed March 2021. Bachelor at: https://world wide web.ntsad.org/index.php/the-diseases/tay-sachs Accessed: March 30, 2021

Tay-Sachs Disease. Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number:272800; Updated: 07/05/2017. Available at: http://omim.org/entry/272800 Accessed March 30, 2021.

Tay-Sachs Gene Therapy Consortium website. Available at: http://www.tsgtconsortium.com/alphabetize.html Accessed March 30, 2021

Years Published

1984, 1985, 1986, 1987, 1988, 1989, 1992, 1997, 1998, 1999, 2000, 2001, 2002, 2017, 2021

The information in NORD's Rare Disease Database is for educational purposes only and is not intended to supervene upon the advice of a dr. or other qualified medical professional.

The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may impress one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD'due south copyright.

National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100

powellparpur.blogspot.com

Source: https://rarediseases.org/rare-diseases/tay-sachs-disease/

Share this post