Tay-Sachs disease, or TSD for short, is a lysosomal storage disorder caused by a mutation
in a gene on chromosome 15, which codes for a lysosomal enzyme called beta-hexosaminidase
A, or HEX-A for short. This enzyme normally breaks down a lipid called GM2 ganglioside.
GM2 is found mainly in neurons, so without HEX-A, it accumulates inside lysosomes. TSD
is also known as GM2 gangliosidosis, type I. This results in progressive symptoms of
central nervous system or CNS degeneration, like decreased muscle tone, visual difficulties
and seizures, which usually begin by 3 to 6 months of age, proceeding to death by age
4.
TSD is an autosomal recessive genetic condition, so males and females are affected equally,
inheriting one mutated HEX-A gene from each asymptomatic or heterozygous parent in order
to develop the homozygous condition. This also means that TSD tends to occur in isolated,
inbred populations or communities, which accounts for the predominant occurrence of the disease
in infants of Ashkenazi Jewish heritage, and in certain French Canadian, Amish, and Cajun
populations.
These mutations can result in either no synthesis, or defective synthesis of HEX-A, resulting
in either a total deficiency of HEX A or varying degrees of enzyme activity depending on the
specific mutation. So with some mutations, GM2 accumulates over a longer period of time,
accounting for a more gradual onset of CNS symptoms in some people.
Depending on age of onset, TSD can be infantile, with onset at 3 to 6 months; juvenile, with
onset at 2-5 years; chronic, with onset in the first or second decade of life; and late-onset,
with the first indication of symptoms in the 2nd-3rd decade of life. Common signs for the
first 3 forms are signs of CNS degeneration, like decreased muscle tone, abnormally increased
reflexes, seizures and visual disturbances. For adult-onset, there may be motor difficulties
and some adults may manifest bipolar type psychological symptoms. Ophthalmologists may
be the first to consider TSD by finding a “cherry red spot” in the macula of the
eye, which results from GM2 buildup in the retinal cells around the central macular area.
Diagnosis of TSD is done by determining the activity of HEX A in serum, leukocytes, tears,
or any other body tissue. Genetic testing for HEX A gene mutations and sequencing of
the HEX A gene are used for diagnosis and heterozygous carrier detection.
There is no cure for TSD or its variants. Treatment for the infantile and juvenile form
involves supportive care to manage symptoms. Usually this involves many specialists including
neurologists to manage seizures, gastroenterologists, surgeons, and nutritionists to manage feeding,
as well as occupational and physical therapists to assist with the tasks of daily living and
mobility. Management of symptoms in later onset forms is also primarily supportive,
dealing with the slower, but progressive nature of the degeneration in these related conditions.
Enzyme replacement or gene therapy continue to be areas of research, but until they are
in hand, genetic counselling for individuals at high risk can help prevent passing on the
mutations associated with TSD. More specifically, couples at risk of having an affected child
have options like amniocentesis and chorionic villus sampling as well as artificial insemination,
ovum donation, and in-vitro fertilization to have children who don’t have Tay-Sachs
disease or related GM2 disorders.
All right, as a quick recap, Tay-Sachs disease is a lysosomal storage disease that results
in a buildup of GM2 ganglioside in neurons of the central nervous system. This results
in seizures, motor delay, low muscle tone, and rapid degeneration of the nervous system.
Diagnosis is achieved through enzyme assays and DNA sequencing. There is no cure for Tay-Sachs
disease, and treatment involves supportive therapy. Reproductive counseling, however,
is available.