Genetic diseases are becoming more prevalent in the population, research, and diagnosis. This occurs partly due to the changing environment and demographics, as well as the increasing availability of medical knowledge about these complex illnesses. Tay-Sachs disease is one of the better-known genetic disorders since it was the first to be screened and identified by researchers. It is a rare neurological disorder, affecting primarily infants and resulting in early death. This report will focus on outlining the history, clinical features, and genetics of Tay-Sachs disease.
The first discovery of the disease is attributed to a British ophthalmologist Warren Tay in 1881 who observed a red spot on the retina of a one-year-old patient with progressive degeneration of the central nervous system (Kelley, 2018). This symptom became characteristic of various metabolic neurological disorders including the Tay-Sachs Disease. A few years later, an American neurologist Bernard Sachs studied the disorder observed by Tay and described its hereditary nature, particularly in individuals of Eastern European Jewish origin. In 1969, Dr. Shintaro Okada and Dr. John S. O’Brien noted the deficiency of the Hexosaminidase A enzyme in patients with Tay-Sachs, and in the early 1990’s the HEXA gene was identified as the cause of the disease and over 100 mutations from various ethnic groups have been identified (Kelley, 2018).
Description of Disease
Tay-Sachs disease is a neurodegenerative rare genetic disorder characterized by mutations in the HEXA gene. This results in the accumulation of gangliosides in the brain and nerve cells leading to the progressive digression of the central nervous system. The most common form of Tay-Sachs disease is infant onset, which becomes apparent early on in life. Up to 3-6 months infants develop normally, until symptoms begin to appear. These include limited motor function and skills, including turning over, sitting, and crawling as well as an abnormal reaction to loud noises. A notable feature is a red spot in the retina which later leads to vision loss in many cases. Additional symptoms include hearing loss, seizures, paralysis, and mental disability. There is no cure for the disorder, with infants usually not surviving longer than the age of 3-4 (Genetics Home Reference, 2019). Other much rarer examples of Tay-Sachs disease include juvenile and late-onset forms with milder symptoms. However, patients with the juvenile form rarely live past late adolescence, while late-onset Tay-Sachs usually occurs before mid-30s adulthood, having much greater chance of survival albeit a severe disability and decreased quality of life.
The disorder is classified as a lysosomal storage disease that can be diagnosed through blood testing of the hexosaminidase A enzyme or complex genetic testing. Many symptoms are shared with other genetic metabolic diseases with an abnormal build-up of a particular element. Therefore, the differential diagnosis for Tay-Sachs includes Leigh syndrome, Sandhoff disease or neuronal ceroid lipofuscinoses. While there is no treatment devised for Tay-Sachs, a comprehensive team consisting of neurologists, pediatricians, and genetic specialists among others can offer therapy to deter neural degeneration and onset of symptoms (National Organization for Rare Disorders, 2017). This is particularly relevant for infants who may experience difficulties with feeding and hydration due to muscle weakness or spasms, requiring proper nutritional support
Inheritance of Disease
Tay-Sachs disease is inherited through autosomal recessive means, indicating that the mutation of the responsible gene must be present in both copies. The autosomal recessive pattern indicates that both parents are carriers of one copy of the mutated gene, which is combined in a child when the condition emerges. Carriers of the autosomal recessive Tay-Sachs do not present any symptoms, nor is it a sex-linked condition. The disease cannot be actively prevented or induced by parents at any time during pregnancy. When both parents have the gene, there is a 25% chance of the child having the disease, 50% chance of being a carrier, and 25% chance of being both unaffected and not a carrier (Genetic and Rare Diseases Information Center, 2015).
Autosomal recessive disorders are not commonly seen in every generation of an affected family. It affects both males and females equally. Tay-Sachs disease remains relatively rare, although 1 in approximately 250-300 people carrying an altered gene. The most commonly affected population is the non-Ashkenazi Jewish population with one in 3,600 live births affected (National Organization for Rare Disorders, 2017). Other populations at risk include some Italian, Irish Catholic, French Canadian, and Cajun (living in Louisiana or southeastern Quebec) communities. The infantile form of the disease occurs most often, but late-onset Tay-Sachs is often misdiagnosed as is the condition in general as a rare genetic disease, making it difficult to track its true frequency within populations or even families.
Tay-Sachs disease occurs as a result of a mutation in the hexosaminidase subunit alpha (HEXA) gene, which is responsible for the creation of the enzyme hexosaminidase A. When the mutation occurs, the production of the protein is disrupted and may be faulty or absent, and since the enzyme is vital to various systemic functions in the body, any such disruption is a disorder. The hexosaminidase A enzyme is directly necessary to breakdown lipids known as GM2-ganglioside within the body. The infantile form of the disorder the level of hexosaminidase A is non-existent, while late-onset Tay-Sachs shows deficiency thus progresses much slower (National Organization for Rare Disorders, 2017). The lack of proper GM2-ganglioside breakdown in the body leads to extensive accumulation in the brain and nerve cells, eventually leading to progressive deterioration of the central nervous system
Gene Locus and Mutations
The affected HEXA gene is located on chromosome 15, specifically on the long (q) arm in positions q23-q24. The mutated HEXA gene could be variously affected with many types of mutations including base insertions, splice phase mutations, and deletions potentially affecting the gene, and thus disrupting the enzyme production patterns described earlier. Over 100 mutations are currently known to researchers. However, despite the mutation or its cause, the HEXA gene is altered and then passed along in an autosomal recessive pattern. The variety of mutations possibly occurring in the HEXA gene has been suggested as the explanation for the variability of the disease, including differing onset forms (Dersh, Iwamoto, & Argon, 2016). The concept that two completely unrelated mutations causing the HEXA gene alteration, individually occurring in each parent, can be combined in the resulting Tay-Sachs disease is known as compound heterozygosity which is rare for single-gene genetic disorders.
In conclusion, Tay-Sachs disease is a rare neurodegenerative genetic disorder occurring in various forms. Due to mutations to the HEXA gene, the enzyme responsible for lipid breakdown is deficient, leading to abnormal accumulation and damage to the brain and nerve cells. Tay-Sachs is an autosomal recessive condition, where both parents must be carriers for any risk to the child. However, the number of known mutations to the HEXA gene exceeding 100 and growing over the years, the prevalence of carriers is 1 in approximately 300 people. Tay-Sachs disease has historically and continues to fascinate researchers as its molecular mechanisms studied for the purpose of finding a cure or potentially learn about other genetic diseases.