Tay-Sachs disease (NORD)

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Tay-Sachs disease (NORD)



Tay-Sachs disease (NORD)


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Tay-Sachs disease (NORD)

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An 8-month-old girl is brought to the emergency department with a seizure-like episode. The parents state the patient started contracting her upper and lower extremities for 30 seconds. Her mother has noticed she has been having difficulty feeding over the past several weeks due to an inability to suckle. Her parents state she was able to sit up on her own without support until a month ago, when they noticed that she could no longer sit up or roll over. Her birth was unremarkable. Temperature is 36.4°C (97.5°F), pulse is 135/min and blood pressure is 94/84.  Motor examination reveals hypotonia in all 4 limbs, as well as increased intensity of deep tendon reflexes in all extremities. Abdominal examination is unremarkable. Bilateral fundoscopic examination reveals a bright reddish area at the center of macula surrounded by retinal opacification. Which of the following is the most likely diagnosis in this patient? 

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Tay-Sachs disease

frameshift mutation p. 38

lysosomal storage disease p. 86

presentation p. 714


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.


Tay-Sachs disease (TSD) is a rare and fatal genetic disorder that primarily affects the nervous system. It 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 (HEX-A). HEX-A normally breaks down a lipid called GM2 ganglioside found in neurons. Without HEX-A, GM2 ganglioside accumulates inside neurons' lysosomes, resulting in symptoms like seizures, motor delay, low muscle tone, and rapid degeneration of the nervous system.

Diagnosis involves determining the activity of HEX A in serum. Genetic testing for HEX A gene mutations and sequencing of the HEX A gene are used for diagnosis and heterozygous carrier detection. There is currently no cure for Tay-Sachs disease, and treatment options are limited. Supportive care, such as physical therapy, feeding assistance, and seizure control, can help to manage symptoms and improve quality of life.


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