The disease has many variants:

• Type 1: Classic infantile acute Tay-Sachs disease; the children do not seem to be affected at birth but the symptoms appear around 3 to 5 months of age with muscular weakness. These patients never walk and they have significant neurological signs that worsen over time with microcephaly due to brain gliosis. They usually start having difficulty in breathing and swallowing and usually die by the age of four years.
• Type 2: Sandhoff disease 
• Late infantile variant of Tay-Sachs disease; neurodegeneration is slower but the patients usually die with 4 to 5 years of symptom onset. 
• Type 3: Juvenile Tay-Sachs disease; there is some enzyme activity, and the children usually get diagnosed at the age of three to ten years. There may be deterioration of acquired milestones such as speech and skills and onset of dementia. The patients usually progress into a vegetative rigid state and die by the age of 15.
• Chronic asymptomatic variant [5]

• Developmental Delay

  Differential diagnosis Any other cause of developmental delay: Dementia. Seizures. Upper motor neurone disorder. [patient.info]

  The clinical manifestations of Tay-Sachs disease include progressive developmental delay, seizures, deafness, blindness, spasticity, and dystonia, which are caused by the accumulation of gangliosides in the central nervous system. [ncbi.nlm.nih.gov]

  As a result, symptoms begin to develop that may include deafness or blindness, decreased muscle tone, paralysis, seizures, developmental delays, and a cherry-red spot visible on the eyes. [diseaseinfosearch.org]

• Progressive Intellectual Disability 

  Children with this disease start missing developmental milestones after 6 months of age and become progressively intellectually disabled, meaning that intellectual disability gets worse throughout the life of the child, and appear to have floppy muscle [msdmanuals.com]

• Progressive Dementia

  Other symptoms can include ataxia, progressive dementia, psychosis, a vegetative state in some cases, muscular atrophy, and muscular denervation. [molecularbasisdisease.pbworks.com]

  The condition appears soon after birth and features blindness, deafness, progressive dementia, seizures, paralysis and death, usually before the age of 3. [medical-dictionary.thefreedictionary.com]

• Death in Childhood

  The classic type causes death in childhood, but some forms do not appear until adulthood and do not lead to early death. [snpedia.com]

• Failure to Thrive

  This report describes a case report of a postmortem performed on a 5-year old patient of Tay-Sachs disease, presenting with failure to thrive, muscular flaccidity, and cherry-red spots on macula on fundoscopy. [ncbi.nlm.nih.gov]

• Hypertension

  American Journal of Hypertension is now published by Oxford Journals. [nature.com]

  In the future, genetic links to common diseases (eg, diabetes, hypertension, cardiovascular diseases, endometriosis, cancers) may be identified, and PGD will become available to control the transmission of these diseases to future generations. [web.archive.org]

• Muscular Atrophy

  This patient highlights the emergence of different clinical features over many years and emphasizes the need to consider LOTS in the differential diagnosis of progressive muscular atrophy. [ncbi.nlm.nih.gov]

  Other symptoms can include ataxia, progressive dementia, psychosis, a vegetative state in some cases, muscular atrophy, and muscular denervation. [molecularbasisdisease.pbworks.com]

  Clinical genetics, 2005, 68, 4, p. 287-301 Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene Navon R, Khosravi R, Melki J, et al. [myobase.org]

• Muscle Hypotonia

  At 6 to 10 months limp and floppy muscles (hypotonia). decreased alertness and playfulness. difficulty sitting up or rolling over loss of motor skills. decreased hearing and eventual deafness. gradual loss of vision. an abnormal increase in head size [radiopaedia.org]

  At 6 to 10 months: •Limp and floppy muscles (hypotonia). •Decreased alertness and playfulness. •Difficulty sitting up or rolling over •Loss of motor skills. •Decreased hearing and eventual deafness. •Gradual loss of vision. [flipper.diff.org]

• Hunger

  By JEN GUNTER Well Photo Credit Illustration by Celia Jacobs Outrunning Hunger Intense exercise may change the way certain neurons influence our appetite and metabolism. [nytimes.com]

• Seizure

  Go to the emergency room or call the local emergency number (such as 911) if: Your child has a seizure of unknown cause The seizure is different from previous seizures The child has difficulty breathing The seizure lasts longer than 2 to 3 minutes Call [medlineplus.gov]

  When to Contact a Medical Professional Go to the emergency room or call the local emergency number (such as 911) if: Your child has a seizure of unknown cause The seizure is different from previous seizures The child has difficulty breathing The seizure [mountsinai.org]

  Seizures. Upper motor neurone disorder. [patient.info]

  Her seizures and right hemisphere lesion improved with glycerol and dexamethasone treatment. When dexamethasone was discontinued, her symptoms worsened and lesions later appeared in the left hemisphere. [ncbi.nlm.nih.gov]

• Stroke

  Supported in part by grants (NB 08682) from the National Institute of Neurological Disease and Stroke and a grant (430D) from the National Multiple Sclerosis Society. We are indebted to Drs. [doi.org]

  NIH: National Institute of Neurological Disorders and Stroke [medlineplus.gov]

  National Institute of Neurological Disorders and Stroke. “NINDS Tay-Sachs Disease Information Page.” http://www.ninds.nih.gov/disorders/taysachs/taysachs.htm (Accessed January 30, 2010). National Tay-Sachs and Allied Diseases Association. [embryo.asu.edu]

  National Institute of Neurological Disorders and Stroke website. Available at: ...(Click grey area to select URL) Accessed July 6, 2018. Last reviewed May 2018 by Kari Kassir, MD Last Updated: 7/6/2018 [health.cvs.com]

  National Tay-Sachs & Allied Diseases Assocation – USA www.ntsad.org National Institute of Neurological Disorders and Stroke – USA www.ninds.nih.gov/Disorders/All-Disorders/Tay-Sachs-Disease-Information-Page National Institute of Health – USA www.nlm.nih.gov [brainfoundation.org.au]

• Apathy

  Other features include apathy, uncontrollable seizures, spasticity and dementia. Death follows in the second or third year of life. Juvenile form At 3-10 years patient starts to lose motor and verbal skills. [patient.info]

  Most patients never walk and exhibit increasing apathy and inattention. Hyperacusis (ie, persistent extension response to sound, startle reaction) can aid in early diagnosis. [emedicine.medscape.com]

• Clonus

  Progressive weakness and loss of motor skills beginning between 3-6 months Decreased attentiveness Increased startle response A cherry red spot of the fovea centralis of the macula of the retina can be seen in >90% of cases Hyperreflexia with sustained ankle clonus [en.wikibooks.org]

  Evaluate for hyperreflexia with sustained ankle clonus during the physical examination. Histologic studies: In infantile cases, MCBs stain strongly with periodic acid-Schiff (PAS) stain on frozen sections but not on paraffin sections. [emedicine.medscape.com]

• Mental Deterioration

  In infants, it is characterized by progressive mental deterioration, blindness, paralysis, epileptic seizures, and death, usually between ages three and five. [infoplease.com]

  In infants, it is characterized by progressive mental deterioration, blindness, paralysis, epileptic seizures, and death by age four. [elsevier.com]

  The disorder often progresses rapidly, resulting in significant mental and physical deterioration. Infants may appear completely unaffected at birth. [rarediseases.org]

Laboratory diagnosis

Genetic testing is advised in populations with a high incidence. Current tests identify up to 99% of carriers with low false negative rates. The activity of the enzyme can be determined suing enzyme analysis techniques. The test are very accurate but there may be limitations in pregnant women or women on contraceptives. Prenatal diagnosis may be done if both parents are known to be carriers via amniocentesis and the cell tested for the enzyme activity [6].

Imaging

Imaging such as magnetic resonance imaging (MRI) of the brain may show generalised atrophy and cerebellar atrophy.

There is no treatment currently with a few trails of enzyme replacement but they have been unsuccessful. Treatment is supportive and includes nutrition and treatment of infections. Treatment of seizures and mental problems is difficult. Occupational and physical therapy may be useful. Counselling of the parents is essential due to the grave prognosis. Support groups are helpful for the family [7].

The prognosis is ultimately poor for all but the asymptomatic variant. Type 1 having the worst, with death early on in life (infantile). The only difference is the time to death in the patients.

The accumulation of the GM2 ganglioside glycolipid is caused by a defect or absence of beta-hexosaminidase A, which is required for the degradation of the glycolipid. It is a single gene mutation and its mode of inheritance is autosomal recessive. The gene is found on chromosome 15. A lack of hexosaminidase A leads to accumulation of GM2 ganglioside which leads to the neurodegeneration. The enzyme activity can vary giving different variants of the disease. The worst having 0.1% normal activity [2].

The incidence in the normal population is 1 in every 360,000 as compared to Ashkenazi Jewish population where the incidence is 1 in every 3600, with carrier rates as high as 1 in 25. There is also a higher incidence in French Canadians and the Cajuns of Louisiana. Prenatal diagnosis has increased the rates of detection with carriers being identified, especially in these high risk groups [3].

The accumulation of the glycolipid leads to neurodegeneration, which can vary in its onset and is proportional to the speed at which the glycolipids accumulate within the neurons. There are no alternate pathways for its degradation thus the cell has no way of stopping its accumulation. The accumulation leads to neuronal cell dysfunction and ultimately cell death [4].

Genetic screening and counselling is essential for high risk communities, and if both parents are found to be carriers then prenatal diagnosis has to be made and decisions about the pregnancy discussed. This may even include termination of the pregnancy, but is dependent on the laws of the country/state [8] [9] [10].

Tay-Sachs disease is a type of GM2 gangliosidoses, a lipid storage disease caused by mutations of the HEXA gene on chromosome 15 that lead to alteration of enzymes. Tay-Sachs disease is a variant and is caused by absence or defects of hexosaminidase A. Tay-Sachs disease is an autosomal recessive disease that causes excess storage of cell membrane glycolipid (GM2 ganglioside) within the lysosomes. This leads to accumulation within neuronal cells with their subsequent degeneration. The overall prognosis is poor, but screening tests have identified the carriers allowing for genetic counselling and prenatal testing [1].

• Definition: Tay-Sachs disease is a genetic disease with a very poor outcome. It is very common in communities that procreate in a small pool, such as Ashkenazi Jews and French Canadians. There several different variants, but the only difference is the speed at which the symptoms progress.
• Cause: It is caused by a genetic mistake. There is a problem in a gene that give instructions for the formation of a certain enzyme that breaks down a substance in cells. This substance GM2 ganglioside accumulates in brain cells killing them. 
• Symptoms: Symptoms include poor development mentally of the child with poor brain growth and this is evident by the small heads. There will be mental problems and difficulty in walking and speech. These deteriorate over time to the point the child cannot swallow or breath and they eventually die of an infection. The rate of decline depends on the variants. 
• Diagnosis: Diagnosis is made when children present with poor development. The doctors will do test to find out the levels of the enzyme. The diagnosis can also be made in the unborn child is the parents are carriers of the disease.
• Treatment: There is currently no treatment for the disease, only supportive care and counselling. This supportive care may include drugs to control symptoms and keep the child comfortable. There are support groups available to help the families and siblings of the patients deal with the condition and overall poor outcome of the disease. There have been a few attempted treatments but the results have been poor up to now. Screening currently is best option. 

1. Gravel RA, Kaback MM, Proia RL, et al. The GM2 Gangliosidoses. In: Scriver CR, Beaudet AL, Sly WS, et al,. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY: McGraw-Hill; 2001:3827-3876
2. Burg J, Conzelmann E, Sandhoff K, Solomon E, Swallow DM. Mapping of the gene coding for the human GM2 activator protein to chromosome 5. Ann Hum Genet. Jan 1985;49
3. Eng, CM, Burgert, TS, Schecter, C, et al. Multiplex genetic testing in the Ashkenazi Jewish population. Am J Hum Genet 1995; 57:A57.
4. Conzelmann E, Sandhoff K. AB variant of infantile GM2 gangliosidosis: deficiency of a factor necessary for stimulation of hexosaminidase A-catalyzed degradation of ganglioside GM2 and glycolipid GA2. Proc Natl Acad Sci U S A. Aug 1978;75(8):3979-83.
5. Matsuoka K, Tamura T, Tsuji D, Dohzono Y, Kitakaze K, Ohno K, et al. Therapeutic potential of intracerebroventricular replacement of modified human ß-hexosaminidase B for GM2 gangliosidosis. Mol Ther. Jun 2011;19(6):1017-24
6. 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.
7. Monaghan KG, Feldman GL, Palomaki GE, et al. Technical standards and guidelines for reproductive screening in the Ashkenazi Jewish population. Genet Med 2008; 10:57.
8. ACOG committee opinion. Number 318, October 2005. Screening for Tay-Sachs disease. Obstet Gynecol. Oct 2005;106(4):893-4
9. Hall P, Minnich S, Teigen C, Raymond K. Diagnosing Lysosomal Storage Disorders: The GM2 Gangliosidoses. Curr Protoc Hum Genet. Oct 1 2014;83:17.16.1-8
10. Kaya N, Al-Owain M, Abudheim N, Al-Zahrani J, Colak D, Al-Sayed M, et al. GM2 gangliosidosis in Saudi Arabia: multiple mutations and considerations for future carrier screening. Am J Med Genet A. Jun 2011;155A(6):1281-4.