Tay-Sachs Disease

Introduction 

Tay-Sachs disease is a hereditary neurodegenerative disease, resulting from a build-up of the fatty substance GM2-ganglioside in the neuronal cell lysosomes due to an inability of the enzyme hexosaminidase to hydrolyse the GM2. This accumulation becomes toxic to the cells, resulting in cell death. This can cause a variety of symptoms in patients, with only mild symptoms presenting at first, as simple as muscle weakness, progressing as the disease worsens, ultimately leading to death.

Incidence

Tay-Sachs is an autosomal recessive disorder, meaning the patient must have two copies of the defective gene for the disease to manifest. If both parents have one copy of the mutated gene, there is a 1:4 chance they will have a child affected by the disease, and a 1:2 chance their child will be a carrier. The mutation responsible is in a gene named the HEXA gene on the long arm of chromosome 15. A mutation in this gene is common in the Ashkenazi-Jewish population, although a number of other population groups also present a high incidence of the disorder. These include Pennsylvanian Dutch, Cajuns in South Louisiana, French Canadians in Eastern Quebec (Chen 2006). In the Jewish population, approximately 1:3600 births were affected, with a carrier frequency of 1:30 (Young 2005) and a higher incidence among a number of other population groups. Advances in genetic screening have resulted in a dramatic decrease in the number of affected births.

Genetics

The HEXA gene (15q23-q24) has been identified to have over 100 mutations to date (Chen 2006) in relation to Tay-Sachs. There are certain mutations associated with particular populations. Chen et al had identified that there is 'a four base-pair insertion into exon 11 of the HEXA gene accounting for 75-80% of all mutations, and a splice site mutation in intron 12, accounting for 15%' specific to the Ashkenazi-Jewish population.

Mahuran et el stated that there are a number of different mutations identified within the Ashkenazi-Jewish population. The first mutation identified was a G to C transversion at the 5' end of intron 12 (Mahuran 1990) This change in base resulted in abnormally processed RNA being produced. The second mutation identified was a 4 base pair insertion of TATC at exon 11, in agreeance with Chen et al. This insertion caused a stop codon to appear 9 base pairs along the chain. This also destabilises the mRNA. Mutation 3 is a single base substitution (G to A), causing the substitution of Ser for Gly at position 269 at the 3' end of exon 7. This mutation resulted in decreased mRNA levels as the mutated chains are unable to form a stable enough configuration to exit the endoplasmic reticulum and be effective (Mahuran 1990). This last mutation has been identified in both Ashkenazi and non-Ashkenazi patients. 

Table 1                 HEXA Gene Mutations Associated with the Ashkenazi Population

(Mahuran 1990 p. 411)

Pathology 

The HEXA gene is comprised of 14 exons and 13 introns, and spanning approximately 40 kb, encodes for β-Hexosaminidase A (Mahuran 1990). This is an enzyme responsible for the breakdown of the fatty substance ganglioside GM2 which is found in the brain (Young 2005). The mutations of the HEXA gene causes an insufficiency in the concentration of this enzyme in the body of the affected person. This deficiency prevents the complete hydrolysis of GM2 ganglioside, and the release of digested products from the neural cells. The top process in Figure 1 shows the normal process of GM2 digestion, without the HEXA mutation. The lower diagram demonstrates the deviation from the normal process brought about by the defective enzyme. 

                                   Figure 1

<http://www.erin.utoronto.ca/~w3bio315/picts/lectures/lecture15/LysosomeTaySachs1.jpg>

The inability of the hexosaminidase to digest the GM2 and the products to be exocytosed results in GM2 accumulation in excessive amounts in the lysosomes of these cells.This accumulation can cause neuronal cell body distention and neuronal cell death, resulting in neuro-degeneration manifesting in a range of progressive symptoms. There are 4 types of Tay-Sachs; infant, juvenile and chronic, and adult-onset, with infant being most prevalent. Generally, the earlier the onset of symptoms, the more severe the case of disease will be.  

Clinical Features 

Infant onset is the most prevalent form of Tay Sachs disease. The other forms have similar features, although sometimes to a lower severity and not always resulting in death.

In infantile Tay-Sachs, symptoms first appear around the age 2-6 months, with normal development up until then. As it is a neurodegenerative disorder, the first symptoms are a decline in general motor skills and muscle weakness. It becomes difficult for the child to hold their head up, with many other problems presenting. These include blindness, poor feeding, lethargy, hypotonia (low pressure in the intraocular fluid), hyperreflexia (increased activity of the physiological reflexes), opisthotonos (a spasm of the muscles in which the head and lower limbs are thrust forward, and the spine is arched), hyperacusis (exceptional hearing), deafness, spasticity, myoclonic seizures. Other symptoms can include ataxia, progressive dementia, psychosis, a vegetative state in some cases, muscular atrophy, and muscular denervation.

A major indicator of Tay-Scahs is a cherry red spot on the fovea centralis of the macula in the eye (Chen 2006) as shown in Figure 2. The spot indicates the destruction of ganglion cells in the foveal area, with the remaining cells filled with ganglioside (Chen 2006). 

                    Figure 2 

                    Cherry Red Spot

                             (The International Pathology Laboratory for Medical Education 2009)

Diagnosis 

A simple blood test is available to detect levels of hexosaminidase activity in suspected cases. More intensive testing may also include CT scan or MRI of the brain. Figure 3 shows MRI scans from a child with Tay-Sachs, progressing from 14 months to 35 months of age, from (A) to (F). Note the progressive distension resulting from the GM2 accumulation in the cells of one area of the brain. 

                         Figure 3

(Hayase 2009)

Prenatal diagnosis is also possible. Either a DNA analysis or an enzyme analysis to check for an absence of hexoasminidase activity in cultured amniocytes or chorionic villus cells (Chen 2006). As is it a genetic disorder, there are no treatments available. If a positive case is identified in-utero, there is the option of termination of the pregnancy. If the disease is identified after birth, the only option is to manage the condition as best as possible, to make the child comfortable for the remaining time.

If both parents are found to be carriers of the mutation, the risk of giving birth to an affected child is 25%. Options available to couples who find themselves in this situation include egg/sperm donation, preimplantation genetic diagnosis, and adoption. 

References:

Chen, H 2006, Atlas of Genetic Diagnosis and Counseling,1st edn, Humana Press Inc. New Jersey.

Filho, J Shapiro, B 2004, 'History of Neurology: Seminal Citation', Tay-Sachs Disease, vol 61 pp. 1466-1468

Myerowitz, R Costigan, C 1988, 'The Journal of Biological Chemistry', The major defect in Ashkenazi Jews with Tay-Sachs Disease is an insertion in the gene for the a-chain of B-Hexosaminidase, vol. 263, no. 35, pp. 18587-18589

Pierce, B 1990, The Family Genetic Sourcebook, Wiley, New York.

Emery, A Mueller, R 1992, Elements of Medical Genetics, 8th edn, Churchill Livingstone, Edinburgh, New York.

Young, I 2005, Medical Genetics, Oxford University Press, Oxford.

The Internation Pathology Laboratory for Medical Education, viewed 2 September 2009 <library.med.utah.edu/WebPath/COW/COW158.html>

Mahuran, D Triggs-Raine, B Feinenbaum, A Gravel, R 1990, 'The Molecular Basis of Tay Sachs Disease: Mutation Identification and Diagnosis', Clinical Biochemistry, vol 23, pp. 409-415

Hayase, T Shimizu, J Goto, T Nozaki, Y Mori, M Takahashi, N Namba, E Yamagata, T Momoi, M 2009, 'Unilaterally and rapidly progressing white matter lesion and elevated cytokines in a patient with Tay-Sachs disease', Brain and Development, doi:10.1016/j.braindev.2009.01.007