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Tay-Sachs Disease, Genetic Testing

Tay-Sachs disease is a rare and fatal genetic disorder that primarily affects the nervous system. It falls into a group of disorders known as lysosomal storage diseases. Tay-Sachs disease is characterized by the absence or insufficient activity of the hexosaminidase A (Hex-A) enzyme. Without this enzyme, a fatty substance called GM2 ganglioside accumulates in the nerve cells, leading to progressive damage. The prevalence of gangliosidosis is 1 in 3.900 births among Ashkenazi Jews and 1 in 1.000.000 births in the general population. Although the incidence of the disease is very low, it is estimated that one in 250 people carry a Tay-Sachs-related variant.

Tay-Sachs disease genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

The key features and aspects of Tay-Sachs disease are:

  • Genetic Basis: Tay-Sachs is an autosomal recessive disorder, meaning an individual must inherit two copies of the mutated gene (HEXA) — one from each parent — to develop the condition. The HEXA gene provides instructions for producing the Hex-A enzyme.
  • Onset and Progression: Symptoms of Tay-Sachs disease typically appear in the first few months of life. The disease progresses rapidly, leading to severe neurological impairment. Sometimes, a later-onset form known as Late-Onset Tay-Sachs Disease (LOTS) may occur, with symptoms appearing in adolescence or adulthood. However, the infantile form is more common and more severe.
  • Neurological Symptoms: The most characteristic symptoms of Tay-Sachs disease involve the nervous system. Infants with the condition may experience developmental regression, loss of motor skills, muscle weakness, increased startle response to sounds, and an exaggerated startle reflex. Seizures are also common.
  • Cherry-Red Spot: An eye abnormality called a cherry-red spot may be present on eye examination. This occurs due to the accumulation of lipids in the cells of the retina.
  • Prognosis: Unfortunately, Tay-Sachs disease has an inferior prognosis. The majority of affected individuals do not survive beyond early childhood, and death typically occurs by the age of 4 or 5 years. The later-onset forms may have a more variable course but are also associated with significant neurological decline.
  • Carrier Screening: Carrier screening for Tay-Sachs disease is available and is particularly relevant for individuals of Ashkenazi Jewish descent, as the carrier frequency is higher in this population. Prenatal testing and genetic counseling are also options for at-risk couples.
  • No Cure: There is no cure for Tay-Sachs disease. Treatment is primarily supportive and aimed at managing symptoms and providing quality-of-life care.

Three variants of the disease have been described depending on the age of disease onset:

  • The early-onset or infantile form (enzyme activity 0-5%) is the most severe and has as its main symptoms gray matter degeneration beginning between 3 and 6 months of age, muscle weakness, irritability, and increased sensitivity to sensory stimuli such as auditory stimuli. The appearance of a cherry-red spot on the ocular macula may indicate the disease.
  • In the juvenile form (enzyme activity 10-15%), the onset of the disease is between 2 and 6 years of age, with ataxia, behavioral disorders, and a progressive loss of intellectual abilities that eventually compromise the survival of the patients.
  • The chronic adult form (enzyme activity 10-15%) may begin around the age of 10, although the disorder is often not diagnosed until adulthood. It presents with muscle weakness in the lower extremities, atrophy, incoordination, tremor, dystonia, and psychiatric manifestations with cognitive impairment.
More Information

The HEXA gene encodes the alpha subunit of the lysosomal enzyme hexosaminidase-A, a deficiency that causes toxic accumulation of GM2 gangliosides and leads to progressive neurodegeneration. Many Tay-Sachs disease-causing mutations have been described, which may be present in homozygosis or compound heterozygosis.

The c.805G>A mutation (p.Gly269Ser) affects the enzyme's dimerization capacity, significantly altering its catalytic capacity. This variant is associated with late-onset Tay-Sachs and is one of the most common disease-causing variants in adult patients of Ashkenazi Jewish descent. However, it has also been found in people from Eastern Europe.

Other relatively frequent variants in patients with infantile-type Tay-Sachs are c.1073+1G>A, c.1421+1G>C, and c.1274_1277dupTATC. The c.1073+1G>A variant causes an alteration of the exon 9 cleavage and splice site, resulting in a truncated protein. The c.1421+1G>C mutation causes an alteration of the mRNA cleavage and splicing site, resulting in an incomplete protein. The c.1274_1277dupTATC mutation results in the appearance of an early stop codon and, as a consequence, an afunctional truncated protein. The variants c.1421+1G>C and c.1274_1277dupTATC are frequent in Ashkenazi Jews.

The pathogenic variant c.1510C>T results in a change of an arginine amino acid to a cysteine amino acid, decreasing the enzyme's catalytic capacity. It is associated with the infantile form of the disease and has been found mainly in Caucasian patients.

On the other hand, the most common variant in French Canadians is c.571-1G>T, a 7.6 kb deletion that includes exon 1 and the promoter of the HEXA gene and is present in 80% of Japanese patients.

Tay-Sachs disease genetic testing analyzes the 22 most frequent pathogenic mutations of the HEXA gene.

The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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