Tay-Sachs disease is an inherited neurodegenerative disease. The disease symptoms appear within the first few months and progress until patients are reduced to an unresponsive state before death at less than four years of age.
What are the Symptoms of Tay-Sachs Disease?
Tay-Sachs disease is the most common form of hexosaminidase A deficiency, and is characterized by an early onset, rapid disease progression and death at a young age. There are also other forms of hexosaminidase A deficiency that do not manifest until childhood, adolescence or adulthood and are associated with less severe symptoms.
Infants affected by severe Tay-Sachs disease appear normal at birth but start to show development delays and muscle weakness at three to six months of age. They overreact to loud noises, and sudden muscle contractions cause severe twitches, jerks and seizures. By six to ten months, these infants develop vision problems, such as decreasing visual attentiveness, and unusual eye movements associated with the cherry-red spot abnormality. They are unable to achieve new motor skills and begin to lose previously demonstrated skills. The disease symptoms rapidly progress after eight to ten months, and severe seizures are common by the age of 12 months. The damage to the central nervous system causes excess proliferation of glial cells (essential non-neuronal cells) and by 18 months the head of an affected infant is significantly enlarged. They deteriorate further in the second year of life, leading to an unresponsive, vegetative state, until death between two and four years of age.
Juvenile (subacute) hexosaminidase A deficiency begins between the age of two to ten years with loss of control of body movements (ataxia) and incoordination. Speech, cognition and other learned behavior decline, and by ten years of age, seizures and random muscle contractions (spasticity) are common. The cherry-red spot eye abnormality only occurs occasionally, and other vision problems (optic atrophy and retinitis pigmentosa) occur much later than in the severe infantile form of the disease. Affected individuals usually end up in a vegetative state by 10 – 15 years of age, followed by death within a few years. In some cases, the disease progresses at a quicker rate and death occurs within two to four years after the onset of symptoms.
Chronic and adult-onset hexosaminidase A deficiency have a later-onset and neurodegeneration occurs more slowly. The age-of-onset, severity and progression of the disease can vary significantly between individuals, even within the same family. These forms of the disease are associated with low levels of hexosaminidase A, and early symptoms range from muscle weakness, altered cerebellar manifestations and defects with the extrapyramidal nervous system that controls involuntary motor functions. Some individuals only show neuromuscular symptoms, while others are affected by psychiatric symptoms (bipolar, schizophrenia, hallucinations, paranoia etc.), memory loss or dementia.
What Causes Tay-Sachs Disease?
Tay-Sachs disease and other hexosaminidase A deficiencies are caused by mutations in the HEXA gene. HEXA encodes the alpha subunit of an enzyme called beta-hexosaminidase A that plays a critical role in the brain and the spinal cord. This enzyme is found in the lysosome, a compartment that breaks down and recycles toxic substances in the cells. Within the lysosome, beta-hexosaminidase A breaks down a fatty substance called GM2 ganglioside. Mutations in HEXA decrease or abolish the activity of the enzyme, so GM2 ganglioside is not broken down properly. High levels of GM2 ganglioside are toxic, especially to the neurons in the brain and spinal cord. GM2 ganglioside destroys these neurons, causing progressive neurodegeneration that is characteristic of Tay-Sachs.
The Jewish disease panel tests for seven mutations in HEXA. Four of these mutations, 1278insTATC, IVS12+1G>C, IVS9+1G>A and delta7.6kb, are known as null mutations. Individuals who inherit two copies of one of these mutations (homozygous) or one copy of two different mutations (compound heterozygous) are unable to produce any functional beta-hexosaminidase A and will suffer from severe infantile Tay-Sachs disease. 1278insTATC and IVS12+1G>C are the two most common mutations causing Tay-Sachs disease in Ashkenazi Jewish people, accounting for 89-96% of all cases. IVS9+1G>A is infrequent in Jewish populations but is more common in non-Jewish people, and delta7.6kb is the most common Tay-Sachs allele in French-Canadians.
The G269S mutation is associated with the less severe, adult onset form of hexosaminidase A deficiency, when it is inherited in the homozygous state or as a compound heterozygote with one of the null alleles mentioned above. The last two mutations (R249W and R247W) in the Jewish disease panel are called pseudodeficiency mutations. These two mutations do not cause any reduction in functional beta-hexosaminidase A and do not cause any disease symptoms. They are included in this panel, as they show reduced activity against the artificial substrate used during beta-hexosaminidase A enzyme assays (a common diagnostic tool for Tay-Sachs disease). However, these alleles do not show reduced activity against the natural substrate (GM2 ganglioside).
The seven mutations tested in this Jewish disease panel are commonly referred to by the names used above. However, alternative names for these mutations may also be used, as per the table below.
||DNA Nucleotide Change
||Protein Amino Acid Change (HGVS Nomenclature)
How is Tay-Sachs Disease Diagnosed?
Diagnosing Tay-Sachs disease and other hexosaminidase A deficiencies involves enzyme assays to determine beta-hexosaminidase A activity and molecular genetic testing to distinguish between disease-causing and pseudodeficiency mutations in the HEXA gene.
Enzyme assays determine hexosaminidase A activity in the serum, white blood cells or other tissues. Infants affected with severe, infantile Tay-Sachs disease have less than 5% of the normal enzyme activity. Individuals with a milder form of hexosaminidase A deficiency (juvenile, chronic or adult-onset) have some hexosaminidase A activity, but still less than 15% of the normal activity. These enzyme assays can also be used to identify unaffected carriers, who have one defective copy of HEXA and one normal copy. Although enzyme assays are an accurate, cost-efficient diagnostic tool, especially for large-scale population screening, they do not distinguish the pseudodeficiency alleles (R249W and R247W) from disease-causing mutations, so molecular genetic testing is also required.
There are two pseudodeficiency (R249W and R247W) and five disease-causing mutations identified in this Jewish disease panel. Genetic testing is very useful in Ashkenazi Jewish populations as three of these mutations (1278insTATC, IVS12+1G>C and G269S) account for 94-98% of all hexosaminidase A deficiencies in people of Ashkenazi Jewish heritage. The remaining two mutations (IVS9+1G>A and delta7.6kb) are more common in other ethnicities. Sequence analysis of the complete HEXA gene can also be used if mutations are not identified through a targeted genetic analysis.
How is Tay-Sachs Disease Treated?
There is no cure for Tay-Sachs disease and treatment is primarily based on supportive care. Adequate nutrition and hydration are essential and additives and stool softeners are required as the disease progresses. It is important to maintain a clear airway and reduce the mucus in the lungs that can cause breathing problems and lung infections, which can quickly overcome affected infants and children. Respiratory problems can often occur by inhaling food or liquid into the lungs, therefore a feeding device, such as a nasogastric tube, may be required. Physical therapy is recommended to maintain as much movement as possible, and this therapy can help delay joint stiffness and the loss of muscle function. Conventional antiepileptic drugs can be used to control seizures, but often the drugs and dosage need to be continually adapted as the seizures become worse over time.
Psychiatric problems that commonly occur in people affected by later onset disease, can be treated with conventional antipsychotics or antidepressants. However, the responses can vary and are often ineffective. Electroconvulsive therapy and lithium salts have shown some benefit for decreasing episodes of psychotic depression.
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