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.

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.

Summary
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.