Tay-Sachs Disease: Good Genes Gone Bad

Tay-Sachs Disease: Good Genes Gone Bad

Daniel Perlmutter

Blythe Academy

Tay-Sachs is a relatively rare, but fatal genetic disease that is characterized by the progressive destruction of the neurons in the central nervous system. In its most common form, the disease affects infants and young children and typically results in death in early childhood (``Tay-Sachs Disease``, 2015) (McKusick & Hamosh, 1986). In order to gain a comprehensive understanding of Tay-Sachs, one must review the nature of the mutation causing the disease, common symptoms of the disease, the different types of the disease, methods of diagnosis, treatment approaches, the impact of the disease on day to day life, and much more.

        Tay-Sachs disease is caused by any wide variety of mutations in a gene called the HEXA gene which is found on chromosome 15 (``Tay-Sachs Disease``, 2015) (``Tay-Sachs Disease``, http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024672/). These mutations occur during the process of meiosis, specifically during independent assortment just before the crossing over of the homologous chromosomes (Soleas, 2015).

The affected HEXA gene codes for the production of the enzyme hexosaminidase A, which plays a vital role in the central nervous system by breaking down a fatty substance called GM2 ganglioside. The disease is occasionally referred to as a lysosomal storage disorder or a GM2 gangliosidosis because it impairs hexosaminidase A, which is located in the lysosomes, from effectively doing its job (``Tay-Sachs Disease``, 2015). The result of this mutation is toxic accumulation of GM2 ganglioside, particularly in the neurons of the brain and spinal cord (Tay-Sachs Disease, 2015) (``Tay-Sachs Disease``, http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024672/).. It is this accumulation that destroys neurons and eventually the whole central nervous system, resulting in the presentation of Tay-Sachs disease (``Tay Sachs Disease``, 2015) (``Tay-Sachs Disease``, http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024672/).  

        Tay-Sachs is inherited in an autosomal recessive pattern requiring both parents to transmit the faulty gene in order for the disease to manifest itself (McKusick & Hamosh, 1986) (``Learning About Tay-Sachs Disease``, http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024672/). Although the disease can affect anyone, it is much more common in Jews of Ashkenazi descent (1 in 27) and to a lesser extent among individuals of French Canadian ancestry (1 in 73)  (``Tay-Sachs Disease``, https://www.labcorp.com/wps/wcm/connect/IntGeneticsLib/integratedgenetics/resources/diseases/tay-sachs+disease?Tay-Sachs%20Disease) (Martin, Mark, Triggs-Raine, & Natowicz, 2007). By contrast, the incidence of Tay-Sachs in the general population is extremely rare (1 in 300) (```Tay-Sachs Disease``, https://www.labcorp.com/wps/wcm/connect/IntGeneticsLib/integratedgenetics/resources/diseases/tay-sachs+disease?Tay-Sachs%20Disease).

         The classic form of Tay-Sachs begins to develop at approximately 3 to 6 months of age when the affected child shows symptoms which may include muscle weakness, low muscle tone, an exaggerated Morrow or 'startle' reflex to loud noise, and spasticity or tight muscles (``Tay-Sachs Disease``, 2015) (``Tay-Sachs Disease``, http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024672/). As the disease advances, the child often experiences loss of motor milestones such as sitting and crawling and becomes less responsive. At about a year of age, there may be vision and hearing loss and seizures. By the time the child is three or four years old, he or she will present as severely mentally disabled, will have trouble swallowing, and will decline into a totally unresponsive state. Death usually occurs at about five years of age, brought on by pneumonia (``Tay-Sachs Disease``, 2015) (``Tay-Sachs Disease``, http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024672/).

        In addition to the more customary form of Tay-Sachs targeting infants, there are two other rare forms of the disease, one that appears in childhood, known as juvenile Tay-Sachs disease, and another than appears in late adolescence or early adulthood, known as late onset Tay-Sachs disease. The signs and symptoms of these types are less clear cut. All those affected exhibit physical challenges, such as muscle weakness, loss of muscle coordination, and movement problems, but only some suffer from blindness, deafness, developmental problems, and depression (McKusick & Hamosh, 1986). The symptoms that accompany juvenile and late onset Tay-Sachs are much less severe than the early onset type because they are caused by more minor mutations on the HEXA gene. This also explains why juvenile and late onset Tay-Sachs progress much more slowly, and why life expectancies of those affected by it are much higher (``Tay-Sachs disease``, https://results.gentlelabs.com/tay-sachs-disease) (McKusick & Hamosh, 1986).  .

        Diagnosing Tay-Sachs varies, depending on the nature of onset of the disease. Patients with early onset of Tay-Sachs have a unique 'cherry red' spot in the retina that is easily detected by a physician using an ophthalmoscope (``Tay-Sachs Disease``, http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024672/).  On the other hand, it can be difficult to accurately diagnose late onset Tay-Sachs because it is prone to being misdiagnosed as Multiple Sclerosis or Amyotrophic Lateral Sclerosis (``Tay Sachs Disease``, 1984). Nonetheless, the diagnosis of Tay-Sachs, at any age of onset, can be confirmed through an enzyme assay that measures levels of hexosaminidase A in the blood. In addition, blood tests and DNA tests can determine if individuals are carriers of the disease . Prenatal testing can also be undertaken to determine whether a fetus has inherited the defective gene from both parents. This type of testing involves chorionic villus sampling which can be performed between 10 and 14 weeks of gestation, or amniocentesis which is performed at 15 to 18 weeks (``Learning About Tay-Sachs Disease``).  The advantages of these tests is that they can prevent or reduce the incidence of Tay-Sachs disease (``Tay Sachs Disease``, 1984).