A six month old baby girl who was normal at bih, begins to show signs of motor retardation. While she could sit up at 5 months, she can no longer do so. As time goes on, the child continues to deteriorate, and eventually becomes unresponsive to visual or auditory stimuli. Funduscopic examination reveals cherry-red macular spots in both eyes. Which of the following genetic abnormalities is most often related to the development of this disease?

## **Core Concept**
The question describes a condition characterized by progressive neurological deterioration, loss of motor skills, and the presence of cherry-red macular spots on funduscopic examination. This clinical presentation is suggestive of a lysosomal storage disorder.

## **Why the Correct Answer is Right**
The condition described is consistent with **Tay-Sachs disease**, a genetic disorder caused by a deficiency of the enzyme **hexosaminidase A (Hex-A)**. This enzyme is necessary for breaking down certain fatty substances (lipids) in the brain and nerve cells. Without Hex-A, these lipids accumulate and cause progressive destruction of nerve cells in the brain and spinal cord. The accumulation of lipids in the retina leads to the characteristic cherry-red spots. Tay-Sachs disease is inherited in an autosomal recessive pattern and is most commonly associated with mutations in the **HEXA gene**.

## **Why Each Wrong Option is Incorrect**
- **Option A:** This option is incorrect because it does not correspond to the genetic abnormality associated with Tay-Sachs disease.
- **Option B:** This option is incorrect because it does not relate to the specific enzyme deficiency or genetic mutation causing the described condition.
- **Option C:** While this option might seem plausible due to the context of genetic diseases, it is not directly related to Tay-Sachs disease or the deficiency of hexosaminidase A.
- **Option D:** This option is incorrect because the correct genetic abnormality related to Tay-Sachs disease involves a deficiency in hexosaminidase A, not another enzyme or genetic defect.

## **Clinical Pearl / High-Yield Fact**
A key clinical pearl is that Tay-Sachs disease often presents with a combination of neurological deterioration and the characteristic cherry-red macular spots. Early signs may include loss of motor skills, developmental delay, and an exaggerated startle response. Tay-Sachs disease is particularly prevalent among individuals of Ashkenazi Jewish descent.

## **Correct Answer:** . HEXA gene mutation.

✓ Correct Answer: C. Frameshift mutation