Tay-Sachs disease (TSD) is an inherited rare autosomal recessive lysosomal disease caused by mutations in the Hexosaminidase A(Hex-A) gene, causing deficiency of Hex-A enzyme. This shortage leads an accumulation of GM2 gangliosides in the nervous system. TSD can be categorized into three types: Infantile, Juvenile, or Late Onset. Infantile and Juvenile forms cannot be treated and are deadly.
Clinical Description, classification and symptoms
| Classification Level | Disorder |
| Prevalence | Unknown |
| Age of Onset | All ages |
| Inheritance | Autosomal recessive |
The early infantile form begins between 3 and 6 months and the late infantile form between 12 and 24 months.
Early symptoms include being startled by loud noises and eventually losing vision. Psychomotor regression with hypotonia, amaurosis, quickly pharmaco-resistant epilepsy, and progressive macrocephaly occurs in the second semester. A bright red spot in the center of the eye is common but doesn’t indicate a problem. Worsening muscle weakness can cause paralysis. The disorder worsens to brain dysfunction and can kill children. In juveniles, progressive cerebellar ataxia causes dystonia, behavioral abnormalities, intellectual decline, and death in the second decade. Late onset begins at 10 or later and is usually diagnosed in adulthood.
Diagnosis and Treatment Management
The causative gene HEXA encodes the alpha subunit of hexosaminidase A and is found on chromosome 15(15q23). The diagnosis is usually first indicated by identifying harmful changes in certain genes from a panel, exome, or genome test. HEX A gene analysis is usually performed to confirm diagnosis. In the pediatric version of Tay-Sachs, in infancy, it gets worse quickly and often leads to death around ages 2 to 4. If TSD starts later in childhood, during the juvenile stage, death usually happens in the teenage years. All patients show pharmaco-resistant seizures in the advanced stages of the disease. For the adult form, the disease is generally very slow progressive and may last decades. Patients may gradually become disabled, losing the ability to walk and having problems using their arms, speaking, eating, and sometimes experiencing issues with thinking.
Tay-Sachs disease has no known cure, and there are currently no proven treatments to reduce the disease’s course. Certain therapies can aid in symptom management and the avoidance of problems. Comfort and support are the main objectives of treatment.
Among the supportive therapies are:
Respiratory treatment: Mucus buildup in the lungs is frequent and increases the risk of lung infections, which impair breathing. Exercise, chest physical therapy (CPT), and other methods can aid in clearing the lungs of mucus.
Physical treatment: Physical therapy may be beneficial as the illness worsens to maintain range of motion and keep joints flexible.
Occupational therapy: To assist with day-to-day functioning, therapists can suggest activities and assistive technology.
Therapy for speech and language: Speech-language pathologists can help with issues related to swallowing.
Some therapeutic interventions include:
Enzyme replacement therapy involving administering synthetic or recombinant enzymes to replace the deficient hexosaminidase A. However, this approach has limitations for Tay-Sachs, as the enzyme does not easily cross the blood-brain barrier, meaning it cannot directly target the central nervous system (CNS), where the damage occurs.
Gene therapy aims to correct the underlying genetic mutation that causes Tay-Sachs by delivering a functional copy of the HEXA gene. This could potentially allow the body to produce the enzyme in the necessary amounts to break down the GM2 ganglioside.
Substrate Reduction Therapy aims to reduce the accumulation of GM2 ganglioside by inhibiting the production of its precursors.
Neuroprotective Therapy aim to slow down or halt the neurodegenerative process in Tay-Sachs disease. These approaches focus on protecting the brain cells from further damage rather than directly addressing the enzyme deficiency.
Image: Pathogenesis, Symptoms, Diagnosis of Tay Sach’s Disease, Key players involved in the treatment of TSD; Image Source: Malini Gupta
While none of these therapies currently offer a definitive cure, they hold promise for slowing disease progression or alleviating symptoms. Much of the research is in the preclinical or early clinical stages, and it may take years before effective treatments become widely available. Data Bridge Market Research reports that the global market for Tay-Sachs disease treatments, valued at USD 2.34 billion in 2023, is projected to grow to USD 3.63 billion by 2031, with a compound annual growth rate (CAGR) of 5.6% from 2024 to 2031.
For more on rare diseases, stay tuned for next instalment of Care for Rare. Meanwhile, click here for more available resources and support groups for TSD.
Malini Gupta, Ph.D,
Sources
- https://rarediseases.org/rare-diseases/sickle-cell-disease/
- https://www.orpha.net/en/disease/detail/845
- https://ntsad.org/
- https://www.curetay-sachs.org/
- https://cats-foundation.org/
- https://www.databridgemarketresearch.com/reports/global-tay-sachs-disease-treatment-market
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