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Disclaimer: This article is for informational purposes only and is not intended for diagnostic use. LifeDNA does not provide diagnostic reports on any traits discussed. Genetics is just one piece of the puzzle; please consult a healthcare professional for comprehensive guidance on any health condition.
Tay-Sachs disease (TSD) is a rare, inherited neurodegenerative disorder that primarily affects infants, leading to progressive deterioration of the nervous system. It is caused by mutations in the HEXA gene, which encodes the enzyme β-hexosaminidase A (Hex A). The genetic basis of Tay-Sachs disease is well understood, and advances in genetic testing have made early diagnosis and carrier screening possible.
β-Hexosaminidase A (Hex A) is an enzyme that acts like a cellular cleanup crew. It helps to break down a fatty substance called GM2 ganglioside inside our brain and in nerve cells. GM2 ganglioside is a fatty substance (glycolipid) found in nerve cell membranes, especially in the brain. It plays a role in cell signaling and communication, but it must be broken down. If not properly degraded, GM2 gangliosides accumulate in nerve cells, leading to neurodegeneration and severe brain dysfunction.
Tay-Sachs disease is an autosomal recessive disorder, meaning that an affected individual must inherit two defective copies of the HEXA gene—one from each parent. The HEXA gene is located on chromosome 15q23-q24 and encodes the α-subunit of β-hexosaminidase A, an enzyme found in lysosomes.
Mutations in HEXA disrupt Hex A activity, leading to the accumulation of GM2 gangliosides in neurons. Over time, this accumulation causes progressive neurodegeneration, which manifests in severe developmental regression, loss of motor and sensory function, and early death in most cases.
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There are over 100 known mutations in the HEXA gene that can cause Tay-Sachs, including:
A 2021 study investigated the genetic causes of Tay-Sachs in three unrelated consanguineous families from Pakistan and Morocco, identifying novel and known HEXA gene mutations. Using whole exome sequencing and targeted gene sequencing, researchers discovered two novel homozygous variants (p.Asp386Alafs13 and p.Trp266Gly) and a previously reported Ashkenazi-associated mutation (p.Tyr427Ilefs5) in a Pakistani patient, marking its first report in this population.
Based on enzyme activity and disease progression, Tay-Sachs disease is classified into three forms:
3. Late-Onset (Adult) Tay-Sachs Disease (LOTS)
Since Tay-Sachs is an autosomal recessive disorder, an individual must inherit two mutated copies of HEXA to develop the disease. Carriers, who have one normal and one mutated allele, do not show symptoms but can pass the mutation to their children.
While relatively rare in general population (~1 in 250–300 carriers), Tay-Sachs has a high carrier frequency in specific populations:
The high frequency of recessive mutations in some populations have been attributed to a phenomenon called the ‘founder effect’.
The founder effect is a type of genetic drift that occurs when a small group of individuals becomes isolated from a larger population, leading to a reduced genetic diversity and an increased frequency of certain genetic traits or mutations. This happens because the new population is derived from a limited number of ancestors, and their genetic variations are passed down, sometimes leading to a higher prevalence of specific inherited conditions.
This effect is seen in isolated or historically endogamous communities, such as the Ashkenazi Jewish population, French Canadians, Amish communities, and certain Finnish and Icelandic groups. Other examples of conditions attributed to the founder effect are Gaucher disease, as well as BRCA1/BRCA2-related cancers which occur at higher rates.
Read our in-depth analysis of Gaucher Disease
Carrier screening through genetic testing is widely available, especially in high-risk populations, allowing for reproductive counseling and prenatal diagnosis.
With advances in molecular genetics, preimplantation genetic diagnosis (PGD) allows couples carrying HEXA mutations to select unaffected embryos during in vitro fertilization (IVF).
Currently, there is no cure for Tay-Sachs disease, and treatment is primarily supportive care aimed at managing symptoms. However, gene therapy and substrate reduction therapy are being actively researched:
In 2020 a novel approach to treating Tay Sachs was introduced. Researchers used AAV-delivered CRISPR gene editing to integrate a modified HEXM gene into liver cells of neonatal Sandhoff mice, enabling enzyme production and secretion. After four months, enzyme activity in the blood and brain significantly increased, leading to reduced GM2 ganglioside levels in most tissues, improved motor function, and reduced brain and liver cellular abnormalities.
A 2022 study reported a gene therapy trial for infantile Tay-Sachs disease, focusing on safety as the primary endpoint. Two patients received AAVrh8-HEXA and AAVrh8-HEXB gene therapy. In this therapy a modified virus (AAVrh8) is used to deliver working copies of the HEXA and HEXB genes into nerve cells. These genes help produce functional HexA, the missing enzyme in Tay-Sachs disease, allowing cells to break down GM2 gangliosides (see intro section). Both tolerated the procedure well, with no vector-related adverse events. HexA enzyme activity increased and remained stable in cerebrospinal fluid. One patient showed temporary disease stabilization but later progressed. The other patient remains seizure-free at age 5 on the same anticonvulsant therapy.
Also read about other autosomal recessive disorders:
Tay-Sachs disease is a devastating neurodegenerative disorder caused by mutations in the HEXA gene. Its autosomal recessive inheritance pattern and high carrier frequency in certain populations have led to robust genetic screening programs. While no cure currently exists, advances in gene therapy and enzyme replacement therapy offer hope for future treatments. Early diagnosis and genetic counseling remain essential tools in managing this condition and preventing its transmission.
