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Tay-Sachs Disease

Hexosaminidase A Deficiency

Genetic disease tend to be higher in certain communities, many because they tend to procreate among themselves. This leads to persistence of the genetic aberration and increase in frequency. Tay-Sachs disease was described by Warren Tay and Bernard Sachs in the late 1800s.


Presentation

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]
Progressive Dementia
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]
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]
  • Some patients may present with symptoms suggesting spinocerebellar degeneration, Friedreich ataxia, amyotrophic lateral sclerosis, or spinal muscular atrophy. The patient's intellect may be either mildly impaired or within normal limits.[emedicine.com]
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]
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[nlm.nih.gov]
  • 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]
  • Seizures. Upper motor neurone disorder.[patient.info]
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.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.com]
Decerebrate Posturing
  • Psycho-motor deterioration increases by the second year and invariably leads to decerebrate posturing (typical of patients in persistent vegetative states), difficulty in swallowing and increased seizure activity.[themedicalbiochemistrypage.org]
  • Further deterioration in the second year of life results in decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state.[flipper.diff.org]
  • Further deterioration in the second year of life results in: decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state.[web.archive.org]
Neurologic Manifestation
  • ., 1996 , vol. 2 (pg. 424 - 429 ) 23 Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoffdisease mice, J. Clin.[doi.org]
  • Recent experimental and clinical attempts to develop icv and intrathecal ERTs for LSDs with neurological manifestations 14, 15, 16 are expected to lead to central nervous system–directed ERTs using the CI-M6PR expressed on neural cells as a delivery target[web.archive.org]

Workup

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.

Ischemic Changes
  • The change of brain observed in this case were interpreted as a combined result of (i) essential change to classical Tay-Sachs disease, (ii) ischemic change due to frequently repeated seizures, (iii) chronic toxicity by long-term anticonvulsant administration[ncbi.nlm.nih.gov]

Treatment

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].

Prognosis

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.

Etiology

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].

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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].

Prevention

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].

Summary

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].

Patient Information

  • 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. 

References

Article

  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.

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Last updated: 2019-07-11 21:35