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Tay-Sachs disease(TSD)

MedGen UID:
11713
Concept ID:
C0039373
Disease or Syndrome
Synonyms: GM2 gangliosidosis, type 1; HexA deficiency; Hexosaminidase A Deficiency; Hexosaminidase alpha-subunit deficiency (variant B); Sphingolipidosis, Tay-Sachs; TSD
SNOMED CT: Tay-Sachs disease (111385000); Severe hexosaminidase A deficiency (111385000); TSD (111385000); GM>2< gangliosidosis, type 1 (111385000); Hexosaminidase A deficiency (111385000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): HEXA (15q23)
 
Monarch Initiative: MONDO:0010100
OMIM®: 272800
Orphanet: ORPHA845

Disease characteristics

Excerpted from the GeneReview: HEXA Disorders
HEXA disorders are best considered as a disease continuum based on the amount of residual beta-hexosaminidase A (HEX A) enzyme activity. This, in turn, depends on the molecular characteristics and biological impact of the HEXA pathogenic variants. HEX A is necessary for degradation of GM2 ganglioside; without well-functioning enzymes, GM2 ganglioside builds up in the lysosomes of brain and nerve cells. The classic clinical phenotype is known as Tay-Sachs disease (TSD), characterized by progressive weakness, loss of motor skills beginning between ages three and six months, decreased visual attentiveness, and increased or exaggerated startle response with a cherry-red spot observable on the retina followed by developmental plateau and loss of skills after eight to ten months. Seizures are common by 12 months with further deterioration in the second year of life and death occurring between ages two and three years with some survival to five to seven years. Subacute juvenile TSD is associated with normal developmental milestones until age two years, when the emergence of abnormal gait or dysarthria is noted followed by loss of previously acquired skills and cognitive decline. Spasticity, dysphagia, and seizures are present by the end of the first decade of life, with death within the second decade of life, usually by aspiration. Late-onset TSD presents in older teens or young adults with a slowly progressive spectrum of neurologic symptoms including lower-extremity weakness with muscle atrophy, dysarthria, incoordination, tremor, mild spasticity and/or dystonia, and psychiatric manifestations including acute psychosis. Clinical variability even among affected members of the same family is observed in both the subacute juvenile and the late-onset TSD phenotypes. [from GeneReviews]
Authors:
Camilo Toro  |  Leila Shirvan  |  Cynthia Tifft   view full author information

Additional descriptions

From OMIM
Tay-Sachs disease is an autosomal recessive, progressive neurodegenerative disorder which, in the classic infantile form, is usually fatal by age 2 or 3 years.  http://www.omim.org/entry/272800
From MedlinePlus Genetics
Tay-Sachs disease is a rare, inherited disorder that is characterized by neurological problems caused by  the death of nerve cells (neurons) in the brain and spinal cord (central nervous system).\n\nThe most common form of Tay-Sachs disease, known as infantile Tay-Sachs disease, becomes apparent early in life. Infants with this disorder typically develop normally until they are 3 to 6 months old. During this time, their development slows and muscles used for movement weaken. Affected infants stop achieving normal developmental milestones and begin to lose previously acquired skills such as turning over, sitting, and crawling. Infants with this condition develop an exaggerated startle reaction to loud noises. As the disease progresses, children with Tay-Sachs disease experience involuntary muscle twitches(myoclonic jerks), seizures, difficulty swallowing (dysphagia),vision and hearing loss, and intellectual disability. An eye abnormality called a cherry-red spot, which is identified by eye examination, is characteristic of this disorder. Children with infantile  Tay-Sachs disease usually live only into early childhood.\n\nTwo other forms of Tay-Sachs disease, known as juvenile and late-onset, are rare. Signs and symptoms of the juvenile form can appear between the ages of 5 years and late adolescence. Features of late-onset Tay-Sachs disease typically appear in adulthood. People with either of these forms of the condition usually have milder and more variable signs and symptoms than those with the infantile form. Characteristic features of juvenile or late-onset Tay-Saches disease include muscle weakness, loss of muscle coordination (ataxia), speech problems, and psychiatric symptoms. These signs and symptoms vary widely among people with late-onset forms of Tay-Sachs disease.  https://medlineplus.gov/genetics/condition/tay-sachs-disease

Clinical features

From HPO
Cherry red spot of the macula
MedGen UID:
786046
Concept ID:
C2216370
Finding
Pallor of the perifoveal macula of the retina with appearance of a small circular reddish choroid shape as seen through the fovea centralis due to relative transparancy of the macula.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Apathy
MedGen UID:
39083
Concept ID:
C0085632
Mental or Behavioral Dysfunction
An emotional state of indifference characterized by a lack of interest or concern.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Exaggerated startle response
MedGen UID:
329357
Concept ID:
C1740801
Finding
An exaggerated startle reaction in response to a sudden unexpected visual or acoustic stimulus, or a quick movement near the face.
Psychomotor deterioration
MedGen UID:
373191
Concept ID:
C1836842
Finding
Loss of previously present mental and motor abilities.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Aspiration
MedGen UID:
751786
Concept ID:
C2712334
Finding
Inspiration of a foreign object into the airway.
GM2-ganglioside accumulation
MedGen UID:
341335
Concept ID:
C1848920
Finding
Cellular accumulation of GM2 gangliosides.
Cherry red spot of the macula
MedGen UID:
786046
Concept ID:
C2216370
Finding
Pallor of the perifoveal macula of the retina with appearance of a small circular reddish choroid shape as seen through the fovea centralis due to relative transparancy of the macula.
Pallor
MedGen UID:
10547
Concept ID:
C0030232
Finding
Abnormally pale skin.
Blindness
MedGen UID:
99138
Concept ID:
C0456909
Disease or Syndrome
Blindness is the condition of lacking visual perception defined as visual perception below 3/60 and/or a visual field of no greater than 10 degrees in radius around central fixation.
Cherry red spot of the macula
MedGen UID:
786046
Concept ID:
C2216370
Finding
Pallor of the perifoveal macula of the retina with appearance of a small circular reddish choroid shape as seen through the fovea centralis due to relative transparancy of the macula.

Professional guidelines

PubMed

Obstet Gynecol 2009 Oct;114(4):950. doi: 10.1097/AOG.0b013e3181bd12f4. PMID: 19888064
Gross SJ, Pletcher BA, Monaghan KG; Professional Practice and Guidelines Committee.
Genet Med 2008 Jan;10(1):54-6. doi: 10.1097/GIM.0b013e31815f247c. PMID: 18197057Free PMC Article

Recent clinical studies

Etiology

Hussein N, Henneman L, Kai J, Qureshi N
Cochrane Database Syst Rev 2021 Oct 11;10:CD010849. doi: 10.1002/14651858.CD010849.pub4. PMID: 34634131Free PMC Article
Kot S, Karumuthil-Melethil S, Woodley E, Zaric V, Thompson P, Chen Z, Lykken E, Keimel JG, Kaemmerer WF, Gray SJ, Walia JS
Int J Mol Sci 2021 Jun 23;22(13) doi: 10.3390/ijms22136751. PMID: 34201771Free PMC Article
Sillon G, Allard P, Drury S, Rivière JB, De Bie I
J Genet Couns 2020 Dec;29(6):1173-1185. Epub 2020 Apr 17 doi: 10.1002/jgc4.1284. PMID: 32302469
Cecchi AC, Vengoechea ES, Kaseniit KE, Hardy MW, Kiger LA, Mehta N, Haque IS, Moyer K, Page PZ, Muzzey D, Grinzaid KA
Mol Genet Genomic Med 2019 Aug;7(8):e836. Epub 2019 Jul 10 doi: 10.1002/mgg3.836. PMID: 31293106Free PMC Article
Jahnová H, Poupětová H, Jirečková J, Vlášková H, Košťálová E, Mazanec R, Zumrová A, Mečíř P, Mušová Z, Magner M
J Neurol 2019 Aug;266(8):1953-1959. Epub 2019 May 10 doi: 10.1007/s00415-019-09364-3. PMID: 31076878

Diagnosis

Bibi F, Ullah A, Bourinaris T, Efthymiou S, Kriouile Y, Sultan T, Haider S, Salpietro V, Houlden H, Kaukab Raja G
Klin Padiatr 2021 Sep;233(5):226-230. Epub 2021 Apr 8 doi: 10.1055/a-1371-1561. PMID: 33831955
Sillon G, Allard P, Drury S, Rivière JB, De Bie I
J Genet Couns 2020 Dec;29(6):1173-1185. Epub 2020 Apr 17 doi: 10.1002/jgc4.1284. PMID: 32302469
Cecchi AC, Vengoechea ES, Kaseniit KE, Hardy MW, Kiger LA, Mehta N, Haque IS, Moyer K, Page PZ, Muzzey D, Grinzaid KA
Mol Genet Genomic Med 2019 Aug;7(8):e836. Epub 2019 Jul 10 doi: 10.1002/mgg3.836. PMID: 31293106Free PMC Article
Jahnová H, Poupětová H, Jirečková J, Vlášková H, Košťálová E, Mazanec R, Zumrová A, Mečíř P, Mušová Z, Magner M
J Neurol 2019 Aug;266(8):1953-1959. Epub 2019 May 10 doi: 10.1007/s00415-019-09364-3. PMID: 31076878
Zhang J, Chen H, Kornreich R, Yu C
Methods Mol Biol 2019;1885:233-250. doi: 10.1007/978-1-4939-8889-1_16. PMID: 30506202

Therapy

Hussein N, Henneman L, Kai J, Qureshi N
Cochrane Database Syst Rev 2021 Oct 11;10:CD010849. doi: 10.1002/14651858.CD010849.pub4. PMID: 34634131Free PMC Article
Kot S, Karumuthil-Melethil S, Woodley E, Zaric V, Thompson P, Chen Z, Lykken E, Keimel JG, Kaemmerer WF, Gray SJ, Walia JS
Int J Mol Sci 2021 Jun 23;22(13) doi: 10.3390/ijms22136751. PMID: 34201771Free PMC Article
Colussi DJ, Jacobson MA
SLAS Discov 2019 Mar;24(3):295-303. Epub 2019 Jan 7 doi: 10.1177/2472555218814538. PMID: 30616450Free PMC Article
Vu M, Li R, Baskfield A, Lu B, Farkhondeh A, Gorshkov K, Motabar O, Beers J, Chen G, Zou J, Espejo-Mojica AJ, Rodríguez-López A, Alméciga-Díaz CJ, Barrera LA, Jiang X, Ory DS, Marugan JJ, Zheng W
Orphanet J Rare Dis 2018 Sep 17;13(1):152. doi: 10.1186/s13023-018-0886-3. PMID: 30220252Free PMC Article
Hussein N, Weng SF, Kai J, Kleijnen J, Qureshi N
Cochrane Database Syst Rev 2018 Mar 14;3:CD010849. doi: 10.1002/14651858.CD010849.pub3. PMID: 29537064Free PMC Article

Prognosis

Sillon G, Allard P, Drury S, Rivière JB, De Bie I
J Genet Couns 2020 Dec;29(6):1173-1185. Epub 2020 Apr 17 doi: 10.1002/jgc4.1284. PMID: 32302469
Cecchi AC, Vengoechea ES, Kaseniit KE, Hardy MW, Kiger LA, Mehta N, Haque IS, Moyer K, Page PZ, Muzzey D, Grinzaid KA
Mol Genet Genomic Med 2019 Aug;7(8):e836. Epub 2019 Jul 10 doi: 10.1002/mgg3.836. PMID: 31293106Free PMC Article
Jahnová H, Poupětová H, Jirečková J, Vlášková H, Košťálová E, Mazanec R, Zumrová A, Mečíř P, Mušová Z, Magner M
J Neurol 2019 Aug;266(8):1953-1959. Epub 2019 May 10 doi: 10.1007/s00415-019-09364-3. PMID: 31076878
Lew RM, Burnett L, Proos AL, Barlow-Stewart K, Delatycki MB, Bankier A, Aizenberg H, Field MJ, Berman Y, Fleischer R, Fietz M
J Paediatr Child Health 2015 Mar;51(3):271-9. Epub 2014 Jun 13 doi: 10.1111/jpc.12632. PMID: 24923490
Jamali S, Eskandari N, Aryani O, Salehpour S, Zaman T, Kamalidehghan B, Houshmand M
Iran Biomed J 2014;18(2):114-9. doi: 10.6091/ibj.1137.2013. PMID: 24518553Free PMC Article

Clinical prediction guides

Mistri M, Mehta S, Solanki D, Kamate M, Gupta N, Kabra M, Puri R, Girisha K, Hariharan S, Nampoothiri S, Sheth F, Sheth J
J Hum Genet 2019 Oct;64(10):985-994. Epub 2019 Aug 6 doi: 10.1038/s10038-019-0647-8. PMID: 31388111
Cecchi AC, Vengoechea ES, Kaseniit KE, Hardy MW, Kiger LA, Mehta N, Haque IS, Moyer K, Page PZ, Muzzey D, Grinzaid KA
Mol Genet Genomic Med 2019 Aug;7(8):e836. Epub 2019 Jul 10 doi: 10.1002/mgg3.836. PMID: 31293106Free PMC Article
Vu M, Li R, Baskfield A, Lu B, Farkhondeh A, Gorshkov K, Motabar O, Beers J, Chen G, Zou J, Espejo-Mojica AJ, Rodríguez-López A, Alméciga-Díaz CJ, Barrera LA, Jiang X, Ory DS, Marugan JJ, Zheng W
Orphanet J Rare Dis 2018 Sep 17;13(1):152. doi: 10.1186/s13023-018-0886-3. PMID: 30220252Free PMC Article
Nakamura S, Saito Y, Ishiyama A, Sugai K, Iso T, Inagaki M, Sasaki M
Brain Dev 2015 Jan;37(1):101-6. Epub 2014 Feb 15 doi: 10.1016/j.braindev.2014.01.011. PMID: 24534057
Jamali S, Eskandari N, Aryani O, Salehpour S, Zaman T, Kamalidehghan B, Houshmand M
Iran Biomed J 2014;18(2):114-9. doi: 10.6091/ibj.1137.2013. PMID: 24518553Free PMC Article

Recent systematic reviews

Hussein N, Henneman L, Kai J, Qureshi N
Cochrane Database Syst Rev 2021 Oct 11;10:CD010849. doi: 10.1002/14651858.CD010849.pub4. PMID: 34634131Free PMC Article
Hussein N, Weng SF, Kai J, Kleijnen J, Qureshi N
Cochrane Database Syst Rev 2018 Mar 14;3:CD010849. doi: 10.1002/14651858.CD010849.pub3. PMID: 29537064Free PMC Article
Hussein N, Weng SF, Kai J, Kleijnen J, Qureshi N
Cochrane Database Syst Rev 2015 Aug 12;(8):CD010849. doi: 10.1002/14651858.CD010849.pub2. PMID: 26264938Free PMC Article
Lew RM, Burnett L, Proos AL, Barlow-Stewart K, Delatycki MB, Bankier A, Aizenberg H, Field MJ, Berman Y, Fleischer R, Fietz M
J Paediatr Child Health 2015 Mar;51(3):271-9. Epub 2014 Jun 13 doi: 10.1111/jpc.12632. PMID: 24923490

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