Introduction

Tay Sachs disease is a rare genetic disease which causes progressive damage to all body cells, but symptoms are specifically due to the damage to the neurons which are the cells in the brain and also the cells of the spinal cord.¹ Despite its rarity only occurring in 1 in every 320,000 live births, its effect is usually fatal. 

Certain populations are at higher risk of Tay Sachs including Ashkenazi Jews. There are three forms of Tay Sachs, infantile, juvenile affecting older children and late-onset which occurs in early adulthood.² Out of these three types, infantile is the most common and manifests with specific symptoms which typically emerge between 3 to 6 months and worsen as the nervous system continues to deteriorate.³

What is tay sachs disease? 

The pathology behind its effects is due to a mutation in the HEXA gene which is found on the alpha subunit locus on chromosome 15.⁴ An individual with Tay-Sachs disease will present with symptoms when they have a copy of the mutated HEXA gene from both parents, this is why the disease is known as autosomal recessive.³ 

The HEXA gene mutation can cause a deficiency of the lysosomal enzyme beta-hexosaminidase A (HexA). The normal function of HexA is to break down and recycle fatty substances called gangliosides and in particular the GM2-type ganglioside which are the lipids found in the nervous system. GM2-type ganglioside’s normal function is to form the structure of neuron cell membranes, help cell communication and differentiation and nervous system regulation.⁵ However, in Tay-Sach disease, there is a deficiency of the beta-hexosaminidase A and an accumulation of the gangliosides within cells which triggers an inflammatory response and progressive damage to cells of the brain and spinal cord.⁶

Early symptoms (the first 3-6 months)

An infant who inherits both copies of the mutant gene will usually appear unaffected at birth and symptom presentation will occur between 3 to 6 months of life. It is the most common type of Tay-Sachs disease and the nervous system is mainly affected due to the reduced levels or complete absence of the hexosaminidase A enzyme. 

The initial symptoms include: 

• Developmental delays: This is shown when infants are delayed in reaching normal developmental milestones. Developmental milestones include learning to sit up independently, crawl or walk as expected for their age. This is caused by the GM2 ganglioside accumulation in critical areas of the brain involved in development including the cerebral cortex, basal ganglia, and brainstem⁷
• An exaggerated startle response: This is another symptom which is seen in the earliest part of the disease. In normal infants, the startle reflex is a normal automatic muscle response to an unexpected stimulus such as a loud noise, this response is protective and controlled by a portion of the brainstem known as the nucleus reticularis caudalis pontis

But in Tay-Sach disease, the brain stem is damaged so the infant may show an increased startle response to loud noises as they are more sensitive to sound; this is called acoustic hypersensitivity. 

Over time in normal individuals, the startle response is reduced when continuously exposed to stimuli; this is known as habituation but in Tay-Sachs, the cerebral regulation of this is disrupted so habituation does not occur.⁸

Progressive symptoms (6-12 months)

• Regression of achieved developmental milestones: After 6 months, infants may fail to gain any new motor skills and may lose the skills previously learnt which is known as regression.⁷
• Muscle weakness: Infants initially experience mild muscle weakness and reduced muscle tone (hypotonia) which progressively becomes more severe. This can be exhibited by infants who are unable to hold their heads up or sit.¹ 
• Cognitive decline: Infants become more confused and disorientated, they show signs of dementia and intellectual disability. Their behaviour may be more irritable and their lack of interest presented as a lack of eye contact.¹
• Cherry-red spots in their eye: This is a characteristic symptom of Tay-Sachs disease and is seen in around 90% of affected individuals. It is used to describe the appearance of a red circular shape in the eye specifically centrally of an area called the macula which is located on the retina. It is seen through a microscope and using dilating eye drops. It is a result of the accumulation of gangliosides in the neurons of the eye called the retinal ganglion cells. The cherry red spot is a normal finding of the retina, but in Tay-Sachs disease its appearance is accentuated as the gangliosides push the surrounding retinal ganglion cells aside so the circulation in the retina (cherry-red spots) can be seen easily. The build-up of gangliosides in the eye will eventually cause loss of vision for the infant. This is not a specific sign of Tay-Sach disease as it can be seen in other lipid storage diseases.⁹

Advanced and severe symptoms (after 12 months)

• Muscle stiffness and spasms: During the first year, symptoms begin to become more sudden and severe. The muscle spasms they experience are involuntary (myoclonus) and their motor function is uncoordinated and movement is stiff and slow (spasticity).⁶
• Hearing problems: Not only does Tay-Sachs disease cause progressive blindness but also deafness as gangliosides accumulate in both of these systems.⁵
• Neurological decline: This continues and eventually the infant becomes completely unresponsive to their environment.
• Seizures: By the age of 2, an infant may experience seizures. A seizure is a sudden change in behaviour, consciousness or movement caused by an uncontrolled electrical activity in the brain. Symptoms vary depending on what region of the brain is affected, for example, an infant may experience severe twitching or shaking of the whole body or may have durations of prolonged staring which can easily go unnoticed. As the child gets older, seizure activity increases.
• Increase in head size: Some infants will experience an increase in head size (macrocephaly) after the age of 2 due to lipid accumulation causing neuronal cell swelling and expansion of the brain.⁶
• Vegetative state and paralysis: The infant continues to experience increased muscle weakness, which will eventually cause paralysis so they are unable to move. The decreased muscle tone will also affect the function of muscles involved in swallowing and breathing. Difficulty swallowing is referred to as dysphagia, it can lead to complications like food entering the lower airways rather than the stomach leading to aspiration pneumonia as well as nutritional deficiencies. Aspiration pneumonia also makes infants more susceptible to other respiratory infections. The function of muscles within the respiratory system is also affected and patients may have difficulty breathing. Both of these can be fatal.¹

Death 

Unfortunately, there is no cure for infantile Tay-Sach disease and by the ages of 3 to 5 early death can occur usually as a result of respiratory complications.

Summary 

Tay-Sachs disease commonly affects infants and is inherited in an autosomal recessive pattern. Although rare in the general population, Ashkenazi Jews have a higher incidence rate of Tay Sach disease. It is caused by a mutation to the HEXA gene in both parents causing a deficiency in the lysosomal enzyme beta-hexosaminidase A (HexA) which breaks down fatty substances called gangliosides. This leads to the buildup of gangliosides in body cells and clinical symptoms are the result of its buildup and cell damage to neurons. 

At birth, infants appear unaffected and the initial symptoms of Tay-Sachs disease occur around three to six months depending on severity, these include developmental delays and an increased startle reflex. 

Progressive symptoms after six months in infants include regression, muscle weakness, cognitive decline, cherry-red spots in the eye and reduced vision. Lastly, the advanced symptoms after 12 months include muscle stiffness and spasms, blindness, deafness, neurological decline, seizures, increase in head size, paralysis, breathing and swallowing problems. 

Eventually, by the ages of 3-5, early death will occur in the infant usually as a result of respiratory failure. 

Although there is no cure for infantile Tay Sach disease, it is important to recognise early symptoms for management and reduction in complications.