Tay-Sachs Disease: Causes- Pathology and Treatment


Tay-Sachs disease is a neurodegenerative disorder that occurs when an individual has a mutation within the HEXA gene, hindering the central nervous system’s ability to break down toxins (Vu et al., 2018). These toxins build up within the body and destroy neurons located in the brain and spinal cord. Due to neuronal death within the central nervous system, individual experience a wide range of symptoms including seizures, ataxia and the decay of vision, hearing, speech, and motor skills (DynaMed, 2017). This can occur in infants, children, and adults; the most common form of Tay-Sachs disease is infantile-onset. There are no current treatments available for Tay-Sachs disease, only treatment management. Genetic counseling and prescreening methods for prospective parents is recommended if they are suspected to be a carrier of the disease.


Tay-Sachs disease is a rare neurodegenerative, genetic disorder where toxic waste accumulates within the body and destroys neurons within the central nervous system (Tay Sachs Disease, 2019; DynaMed, 2017).  Tay-Sachs disease occurs on average one in one hundred thousand births (Solovyeva et al., 2018).  Hexosaminidase A (HexA) gene is responsible for creating an enzyme that removes toxins from the body, but individuals with Tay-Sachs disease have a mutation that hinders HexA’s functioning (Vu et al., 2018).  Tay-Sachs disease has over 130 different mutations identified that negatively affects affects the amount of work HexA performs (Tay-Sachs Disease, 2019; Solovyeva et al., 2018).  If symptoms of Tay-Sachs disease appear during infancy or early childhood, the dysfunction is severe (DynaMed, 2017; Solovyeva et al., 2018).  This time period in development signals critical dendritic growth and synaptic communication within the brain as the child begins to interact with the world around them.  The individual will continue to develop normally until the HexA’s dysfunction causes neuronal death.  The death of neurons within the central nervous system causes a variety of symptoms, but most notably, muscle weakness, seizures, vision difficulties, and ataxia (DynaMed, 2017; Solovyeva et al., 2018).  This disorder is fatal in infants and young children, whereas, adults can live longer with symptom management since their HexA’s dysfunction is not as severe (Tay-Sachs Disease, 2019).

Physiological Causes

Tay-Sachs disease starts when an individual’s DNA sequence mutates in the 15th chromosome, which affects the HexA gene that is responsible for helping create an enzyme that breaks down toxins (Tay-Sachs Disease, 2019; Vu et al., 2018).  The toxins that beta-hexosaminidase targets are referred to as GM2 gangliosides (Cachon-Gonzalez, Zaccariotto, & Cox, 2018; Solovyeva et al., 2018). HexA in conjunction with HexB form the enzyme beta-hexosaminidase, designed to break down GM2 gangliosides within the body (Solovyeva et al., 2018).  Beta-hexosaminidase is one of over 50 different enzymes stored within the lysosomes of a cell that removes toxic waste from the body (Cooper, 2000).  If an individual has a mutation within HexA, their ability to produce beta-hexosaminidase for the lysosomes is impaired .  Without the help of  beta-hexosaminidase, the body’s number of GM2 gangliosides will gradually accumulate depending upon the severity of genetic mutation (Solovyeva et al., 2018).  A small number of rare diseases affect the functioning of beta-hexosaminidase enzyme, including Tay-Sachs disease, AB variant, and Sandoff disease.  This group of disorders are referred to in the medical community as GM2-gangliosidosis because they all fail to remove these toxins within the body (Cachon-Gonzalez et al., 2018; Solovyeva, 2018).  Tay-Sachs disease mutates HexA functioning, whereas Sandoff disease has a mutation in both HexA and HexB. AB variant cannot synthesize HexA and HexB into beta-hexosaminidase due to a GM2 activator protein deficiency (Solovyeva, 2018). All of the GM2-gangliosidosis disorders result in a build up of toxins within the brain and the spinal cord and have identical symptomatology (Cachon-Gonzalez et al., 2018). The age of diagnosis informs clinicians on the prognosis; infants and children that develop Tay-Sachs disease have a severe mutation within HexA where the gene only functions 0-5% of the time, whereas adults with the HexA mutation have around 15% functionality (DynaMed, 2017).  The early neuronal development within the brain of infants is crucial for their survival, which makes Tay-Sachs disease for infants and children is fatal. Adults with Tay-Sachs disease have a good prognosis due to a slower accumulation of toxic waste which decreases the chance for neuronal death (Tay-Sachs Disease, 2019).

Disease Pathology

The most common form of Tay-Sachs disease occurs during infancy (Solovyeva et al., 2018).  At birth, an infant with Tay-Sachs disease will start to develop normally.  The accumulation of GM2 gangliosides within the central nervous system has started, but has not reached significant levels to see neuronal death.  Around age three to six months old, the infant’s neurons begin to degrade and communication across the central nervous system is impacted.  This degradation of neurons causes muscle weakness, an increased startle response, and leads to the loss of motor skills.  If the infant is crawling at this time, they will lose the ability to do so (DynaMed, 2017).   As time progresses, the symptoms become more obstructive until death.  Around six to ten months old, the infant will lose their sight and react to less stimuli.  A common marker of disorders within the GM2-gangliosidosis family is the cherry red spot within the macula of the eye (Tripathy & Patel, 2019).  The cherry red spot forms during this stage of disease development .  Eventually, the entire central nervous system begins to shut down.  Seizures start and become progressively worse (DynaMed, 2017). The child gradually becomes comatose before their body succumbs to Tay-Sachs disease.  Death almost always occurs prior to the age of 4 (Nestrasil et al., 2018).

Juvenile-onset of Tay-Sachs disease appears typically from the ages of three to ten years of age (Solovyeva et al., 2018).  The individuals affected at this age range have some similar symptoms to infantile-onset including weakened muscles, motor skill deficits, seizures, and vision loss (DynaMed, 2017).  However, given the advance in development when compared to infancy, juvenile Tay-Sachs disease has some unique symptoms.  Patients may experience slurred speech and difficulty swallowing due to motor difficulties present in pathology.  Abnormal patterns of walking can be a sign of Tay-Sachs considering the common symptoms of muscle weakness and issues with motor control.  Eventually, similar to infantile-onset, the individual’s body will enter a comatose state and death will typically occur prior to the age of 15 (DynaMed, 2017; Solovyeva et al., 2018).

Adult-onset Tay-Sachs disease is the most rare form of the disorder with the best prognosis.  In most cases, HexA’s dysfunction becomes apparent long before adulthood due to the high levels of GM2-gangliosides causing neuronal death.  However, when Tay-Sachs is diagnosed in adults, clinicians find the individual’s HexA typically has 5 to 20% of it’s normal functionality (Solovyeva et al., 2018).  With this level of function, adults with Tay-Sachs disease can survive and live their life managing the symptoms. Because of the rarity and wide range of mutations in HexA, adults with Tay-Sachs disease can have a variety of symptoms .  Some patients will present with memory loss and dementia like symptoms due to the disruption of synaptic transmission by accumulations of GM2-gangliosides (CITE).  Ataxia is common, around 88% of individuals present with atypical gait which (Solovyeva et al., 2018).  Cerebral atrophy is a revealing marker for Tay-Sachs disease as well.  However, due to the extreme rarity of this disease, other symptoms an adult patient presents with can vary and are considered ‘abnormal’ for the tract of the disorder (CITE). This can make late-onset diagnosis of Tay-Sachs disease difficult for health care professionals.


Tay-Sachs disease is very rare within the medical community and can be difficult to diagnose due to the large variety of mutations that can occur surrounding HexA (Akerman et al., 1997 ;ACOG, 2017).  Often, individuals present first with mobility issues and muscle weakness which can look similar to amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), spinal muscular atrophy, and other neuromuscular diseases (Peters et al., 2008).  Additionally, Tay-Sachs disease outside of infancy is exceptionally uncommon.  Peters et al. (2018) discussed conceptualizing a unique case study of a 23-year-old man who had Tay-Sachs disease.  Prior to diagnosis, the patient reported experiencing symptoms of muscle loss, most notably in the upper legs, beginning at age 18.  He reported no genetic history for neuromuscular disorders. The clinicians initially diagnosed the patient with ALS, but with additional testing, the health care team noticed inconsistencies with the typical pathology.  To investigate this further and rule out ALS, the clinicians ordered a biopsy and MRI.  The biopsy of the patient’s thigh muscle showed significant atrophy, but was missing some physiological traits of  neuromuscular disorders.  The MRI displayed normal functioning except for cerebellar degeneration.  When the patient’s white blood cells were tested, the results showed significantly low levels of the beta-hexosaminidase enzyme and confirmed a diagnosis of Tay-Sachs disease (Peters et al., 2008).  This description of late-onset of Tay-Sachs pathology for a young adult adds to small variety of literature on abnormal manifestations of this disease.

While anyone could have a gene mutation, certain populations are at higher risk for the specific mutation that develops Tay-Sachs disease.  These populations include select French-Canadian villages in Quebec, the Amish community in Pennsylvania, Ashkenazi Jewish individuals hailing from central Europe, and the Cajun population in Louisiana (DynaMed, 2017; Tay Sachs Disease, 2019;).  Specifically, the Ashkenazi Jewish and French-Canadian population are the most at risk for developing Tay-Sachs disease with one in thirty people being a carrier (Hussein, Weng, Kai, Kleijnen, & Quresh, 2018).  Tight-knit communities such as the ones mentioned have less genetic variability and are known to be carriers for the HexA mutation.  A carrier would have the recessive gene for Tay-Sachs disease, but has a dominant gene that suppresses the recessive gene’s expression. If two carriers have children, the chance of their offspring receiving both recessive genes for the mutation is one in four. However, it’s more likely that the child will become a carrier like their parents with a one half chance (American College of Obstetricians and Gynecologists, 2017; Hussein et al., 2018).  Even a handful of individuals ascribing to a certain community carrying this recessive trait would greatly increase the population’s genetic odds of contracting the disease.

Prevention and Treatment Options

Currently, there are no treatment options for Tay-Sachs disease, only symptom management.  The medical community has made attempts to create pharmaceutical options for the disorders in the GM2-gangliosidosis family but with no avail.  Additionally, gene therapy for Tay-Sachs disease would be successful but the blood brain barrier has blocked the therapeutic genes that researchers have tried to deliver to increase HexA functionality (Kyrkanides et al., 2005; Solovyeva et al., 2018).  While testing mice, the researchers discovered they could inject the beneficial genes right into the brain and surpass the blood brain barrier, but this comes with complications for humans.  In order for the genes to be effective, the individual would need a large sum of injections throughout the central nervous system and according to scientists, this option is not realistic or viable (Solovyeva et al., 2018).  Science is making progress on targeting treatments for lysosomal storage disorders (which would include Tay-Sachs disease due to the lack of beta-hexosaminidase) but have not found the appropriate drug to increase HexA functioning (Thomas & Kermode, 2019.; Solovyeva et al., 2018) . One drug called Migulstat, a substrate reduction therapy, was tested in clinical trials on 20 adults with Tay-Sachs disease but there was no clinically significant findings (Solovyeva et al., 2018).

While treatment options for infancy-onset Tay-Sachs disease are extremely limited, prospective parents can take strides to prevent passing unfavorable genetic disorders to their offspring.  The American College of Obstetrics and Gynaecology has specifically stated genetic screening should occur for the Ashkenazi Jewish, French-Canadian, and Cajun population prior to pregnancy to assess for carrier status.  If there is a genetic history of Tay-Sachs disease in the family, clinicians may not see a positive result when testing possible carriers because the screening does not include all of the variety of genetic mutations (ACOG, 2017).  Akerman et al., (1997) pioneered the effort to identify new mutations of HexA outside of the Ashkenazi Jewish population, but additional work needs to be done to explore every possible mutation (Akerman et al., 1997). These screening panels identify 98% of carriers, but rare HexA mutations outside of the identified at-risk populations may not be identified (ACOG, 2017).  If parents are identified to both be carriers of Tay-Sachs disease, options are available to prevent passing the disease onto offspring.  Women can utilize amniocentesis, a test that samples from the amniotic fluid in the womb, to test for possible conditions.  Amniocentesis can give prospective parents an idea of the fetus’s health early in the pregnancy so that they can make educated decisions about their futures.  A test similar to amniocentesis, chorionic villus sampling, can also assess the fetus’s health through the mother’s placenta tissue (Alfirevic, Navaratnam, Mujezinovic, 2017).  Additionally, couples can consider in vitro fertilization to pick viable gametes and avoid passing on genetic conditions like Tay-Sachs disease to offspring (Hussein, 2018).  However, in vitro fertilization is not an option for everyone due to the high cost of the procedure.  Therefore, some couples may abstain from having biological children and adopt.  Prevention of genetic disorders like Tay-Sachs is pivotal due to the fatal nature of the disease.  Due to a lack of treatment options, precautions should be taken by individuals in high-risk communities to receive genetic counseling, assessment, and prenatal testing to avoid the development of Tay-Sachs disease.


Tay-Sachs disease is caused by a mutation in the HexA gene which partially forms the beta-hexosaminidase enzyme which fails to clear out GM2-gangliosides from the central nervous system (Peters et al., 2008, Vu et al., 2018). There are three main forms of Tay-Sachs disease which are infantile, juvenile, and adult-onset of the disorder.  The adult-onset of Tay-Sachs disease is the most rare, however, it has the best prognosis with a slow neural decay.  In cases of infantile and juvenile Tay-Sachs disease, the condition is fatal (Solovyeva et al., 2018).  There are no clinically significant drugs approved for Tay-Sachs disease to alter the amount of HexA functioning, therefore expectant parents should consider genetic counseling prior to conceiving especially if they hail from Ashkenazi Jewish, Cajun, or French-Canadian population (ACOG, 2017; DynaMed, 2017; Solovyeva et al., 2018,).