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Tay-Sachs disease (NORD)





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Autosomal trisomies: Pathology review
Muscular dystrophies and mitochondrial myopathies: Pathology review
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Tay-Sachs disease (NORD)


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High Yield Notes
6 pages

Tay-Sachs disease (NORD)

12 flashcards

USMLE® Step 1 style questions USMLE

4 questions

USMLE® Step 2 style questions USMLE

1 questions

A nine-month-old boy is brought into the pediatric clinic by his parents for a well-child exam. His family is of Ashkenazi Jewish descent. There is no family history of any genetic disorders, and no prenatal testing was initiated. He was born at term with no developmental anomalies noted during the first six months of life. At the physical examination, the patient is unable to roll over as he was able to do at six months. Abdominal examination is normal. His parents note that he startles easily at loud noises. Neuromuscular examination shows global hypotonia and hyporeflexia. Ophthalmologic examination reveals a red lesion on the maculae of both eyes. Which of the following is the most likely diagnosis?

External References

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.