Understanding Tay-Sachs disease

Tay-Sachs disease is a rare neurological disorder that mainly affects children reaching six months of age but may manifest in juvenile and adulthood years. The inheritance pattern of Tay-Sachs disease is autosomal recessive, with high genetic susceptibility among Eastern European and Ashkenazi Jewish populations.¹ Mutations in the enzyme hexosaminidase-A (HEXA) gene located on chromosome 15 lead to a HEXA deficiency in Tay-Sachs affected individuals. This hinders the lysosomal degradation of GM2 gangliosides and results in the toxic accumulation of GM2 gangliosides in nerve cells.² Although gangliosides have crucial functions in signal transduction, inflammation and neuronal differentiation, an increase in GM2 ganglioside load in neurons may induce neuronal cell death and lead to progressive loss of neurological ability.³ 

As mentioned previously, different forms of the disorder occur throughout infantile, juvenile and adult-hood stages, all with varying displays of neurological symptoms. Infantile Tay-Sachs disease clinical manifestations may begin as early as one week after birth; ² non-immunological hydrops fetalis (NIHF) presentation is often the first indication of Tay-Sachs disease in infants.⁴ Initial diagnosis of infantile Tay-Sachs disease relies on the observance of the ‘classical’ clinical manifestations, namely heightened startle reflex to auditory stimuli (noise) and weakened motor abilities.² Macula “cherry red spot” is a common clinical manifestation of infantile Tay-Sach disease. The absence of ganglion cells in the foveal pit leads to the retention of the red, or in other cases a brown or black spot. ⁵ As the disease progresses, affected individuals continue to lose their motor and sensory functions, such as the development of dysphasia and blindness.⁶ The life expectancy of infants with Tay-Sachs disease ranges from 3 to 5 years of age ⁷, with respiratory infections commonly reported as the main cause of death.² 

The progression of infantile Tay-Sachs is the most severe compared to the juvenile and adult-onset forms of the disorder. As infantile Tay-Sachs disease-affected individuals completely lack the HEXA enzyme, whilst minimal HEXA enzyme activity is observed in juvenile and adult-onset Tay-Sachs disease, which could explain the differences in the period and severity of disease progression.6 Although juvenile and adult-onset Tay-Sachs disease often share similar clinical features with the infantile Tay-Sachs disease there are noticeable differences, such as the absence of a macula cherry red spot. Moreover, since adult-onset Tay-Sachs disease progression is comparably less aggressive, there is often a delay in diagnosing the disorder.² 

Current prevention strategies

As of the writing of this article there is no curative treatment for slowing down Tay-Sachs disease development and no known postpartum preventative strategies, instead there are multidisciplinary approaches that prioritise management of the clinical manifestations.² The following are current preventative strategies that aid Tay-Sachs disease diagnosis:

• Genetic counselling:
  • Education on the diagnosis, disease progression and the implications of carrier status 
• Carrier screening:
  • Individuals with a family history of Tay-Sachs disease and those from populations with high carrier frequencies are screened for the Tay-Sachs gene⁸
• Prenatal testing:
  • Amniocentesis and Chorionic Villus Sampling (CVS) methods determine if the foetus possesses the Tay-Sachs gene²
• Preimplantation Genetic Diagnosis (PGD)-
  • PGD is used in conjunction with in vitro fertilisation (IVF) to select for embryos lacking the Tay-Sachs gene before implantation⁹ 

Other forms of diagnostic tests for postpartum diagnosis of Tay-Sachs disease:

• Blood test:
  • Initial testing to examine the amount of HEXA enzyme activity¹⁰
• Molecular genetic testing:
  •  The sequencing of genes to screen for genetic variation of the HEXA enzyme, including deletion and duplication mutations²
• Eye exam:
  • Examination of the back of the eye may reveal the cherry red spot clinical feature

Although there are a range of diagnostic tools to screen for the Tay-Sachs gene, unfortunately not all are made available to the general public. Since Tay-Sachs disease was long assumed to be a prototypical disease of Ashkenazi Jewish descents, and more recently other non-Jewish populations,⁶ this limited the reach of diagnostic possibility to others beyond the Tay-Sachs disease-established populations. Additionally, procedures such as PGD and IVF are expensive which makes it inaccessible for many couples to have a child free of Tay-Sachs disease.² Early diagnosis of Tay-Sachs disease is particularly difficult for juvenile and adult-onset cases, which is dependent upon the rate of disease progression and whether the patient is part of a high-risk population.²

Current and future treatment

There is currently no cure for Tay-Sachs disease and most modern treatment options aim to alleviate clinical manifestations, including:

• Multiple anticonvulsant medications to control seizures, which is tailored to individual needs²
• Monitoring of nutritional status as affected individuals are prone to developing dysphasia, and if necessary, a feeding tube may be inserted into the stomach⁶
• Physical therapy to maintain flexibility and mobility as long as possible¹⁰ 

Treatment opportunities that target the HEXA enzyme and substrate levels to directly raise HEXA enzyme activity:

• Enzyme replacement therapy (ERT):
  • Injections of functional HEXA into blood with highly reduced levels or complete absence of HEXA 
  • Whilst promising, clinical trials conducted on patients in the advanced stage and early stage of the disease resulted in no improvement in disease improvement in either cohort¹¹

• Enzyme enhancement therapy:
  • This therapy targets the mutations that increase stability to HEXA; pharmacological chaperones (PC) bind to the protein and stabilise the native conformation 
  • Pyrimethamine (PYR) is a PC that increases the HEXA activity in fibroblasts of Tay-Sachs disease affected individuals but fails to delay disease progression³ 
• Gene therapy:
  • The delivery of functional HEXA gene into Tay-Sachs disease impacted cells via a viral vector
  • Clinical trials reported that after administration of the gene therapy treatment, there were significant improvements in disease progression, including stronger muscle control and reduced seizures¹²
• Bone marrow transplantation:
  • Multipotent neural stem cells, expressing the HEXA gene, are transplanted into the patient. There is subsequent substrate reduction therapy to maintain a low level of GM2 gangliosides¹³

The above therapeutic strategies do not prevent Tay-Sachs disease but rather aim to correct the neural dysfunctionalities associated with the disorder. Most, if not all, therapeutic strategies are still in their clinical stages but remain potential breakthrough approaches with future research. 

FAQ’s

How does Tay-Sachs disease impact the families of those affected?

Multidisciplinary treatment options pose a financial burden to those affected with Tay-Sachs disease and their families. The cost of healthcare, including diagnostic tests, medical equipment and medications, makes treatment difficult to access to all Tay-Sachs affected individuals.² Additionally, families often experience serious emotional distress upon Tay-Sachs diagnosis, as this disorder is a progressive and fatal disease with limited specific treatment. Tay-Sachs disease carriers are subject to genetic implications as they are at risk of having children with the disorder, which broadens the emotional burden to extended family members who may also be carriers.

What are the challenges in developing a cure for Tay-Sachs disease?

Tay-Sachs disease is a complex disease, which makes it difficult to develop therapies that can adequately address the underlying genetic and biochemical issues.The effectiveness of therapeutic approaches are also limited by their inability to cross the blood-brain barrier to reach the affected neurons.² Since Tay-Sachs is a rare disease, this makes it difficult to secure sufficient funding for research for new treatment opportunities. Furthermore, pharmaceutical companies are less incentivised to research Tay-Sachs disease and other rare lysosomal storage diseases.¹⁴ 

Summary

Tay-Sachs disease is an autosomal dominant neurological disease resulting from HEXA deficiency and accumulation of GM2 gangliosides. The symptoms of Tay-Sachs vary between the three main forms of Tay-Sachs disease: infantile, juvenile and adult-onset. All categories of Tay-Sachs disease share commonality of neurological impairment manifestations and shortened life spans. The rate of disease progression differs based on the age of onset and effectiveness of treatment that target the clinical features. While symptom management and supportive care aim to delay disease progression as long as possible, Tay-Sachs disease is still a fatal condition which poses an emotional burden for affected individuals and their families. Although there is ongoing research for new therapeutic approaches, overcoming the substantial challenge of funding and collaboration are required to develop effective treatments.