A 3-year-old boy from rural Maharashtra presents with progressive developmental regression, hepatosplenomegaly, and a cherry-red spot on the macula on ophthalmologic examination. Regarding the biochemistry of this condition, all of the following are correct EXCEPT:

Question

Accepted Answer

B. Enzyme replacement therapy with recombinant hexosaminidase A can reverse neurological damage if started before age 2 years. ## Tay-Sachs Disease — Biochemistry and Clinical Reality

### Clinical Presentation

**Key Point:** Tay-Sachs disease (TSD) is a lysosomal storage disorder caused by hexosaminidase A deficiency, presenting with developmental regression, hepatosplenomegaly, and the pathognomonic cherry-red spot on the macula.

### Biochemical Basis

| Feature | Details |
|---------|----------|
| **Enzyme deficient** | Hexosaminidase A (Hex-A) |
| **Substrate** | GM2 ganglioside (a sialic acid-containing sphingolipid) |
| **Accumulation site** | Neurons, retinal ganglion cells, viscera |
| **Inheritance** | Autosomal recessive |
| **High-risk populations** | Ashkenazi Jews (1 in 30 carriers); also French Canadians, Louisiana Cajuns |

### Pathophysiology of GM2 Ganglioside Accumulation

**High-Yield:** GM2 ganglioside is a complex sphingolipid with a terminal N-acetylgalactosamine residue attached to a sialic acid-containing oligosaccharide backbone. Hexosaminidase A normally cleaves this terminal galactosamine; without it, GM2 accumulates progressively in lysosomes, especially in the CNS.

**Clinical Pearl:** The cherry-red spot results from accumulation of GM2 ganglioside in retinal ganglion cells surrounding the fovea, which appears pale against the red choroid visible through the transparent fovea.

### Analysis of Each Option

**Option 1 (GM2 accumulation):** ✓ **CORRECT.** GM2 ganglioside accumulates in neurons and retinal cells due to Hex-A deficiency.

**Option 2 (Inheritance and epidemiology):** ✓ **CORRECT.** Autosomal recessive; Ashkenazi Jewish populations have a carrier frequency of ~1 in 30 due to founder effect.

**Option 3 (Substrate chemistry):** ✓ **CORRECT.** GM2 is a sphingolipid with sialic acid (N-acetylneuraminic acid) residues in its oligosaccharide chain.

**Option 4 (Enzyme replacement therapy):** ✗ **INCORRECT.** There is **NO effective enzyme replacement therapy (ERT)** for Tay-Sachs that can reverse neurological damage. The blood-brain barrier prevents systemically administered hexosaminidase A from reaching the CNS where most damage occurs. Gene therapy is experimental and not yet standard of care. Once neurological symptoms appear, the disease is relentlessly progressive, leading to death by age 3–4 years.

**Warning:** This is a common exam trap. Students may confuse Tay-Sachs with Gaucher disease or Fabry disease, which DO have approved enzyme replacement therapies (imiglucerase and agalsidase, respectively). Tay-Sachs has no proven disease-modifying therapy currently available.

**Mnemonic:** **Tay-Sachs = No Therapy.** Gaucher = Imiglucerase; Fabry = Agalsidase; Tay-Sachs = Supportive care only.

[cite:Robbins 10e Ch 5; Harrison 21e Ch 417]

Answer

A. The enzyme deficiency leads to accumulation of GM2 ganglioside in neurons and retinal cells

Answer

C. The accumulated substrate is a sphingolipid containing sialic acid residues

Answer

D. The condition is inherited in an autosomal recessive pattern and is more common in Ashkenazi Jewish populations

A 3-year-old boy from rural Maharashtra presents with progressive developmental regression, hepatosplenomegaly, and a cherry-red spot on the macula on ophthalmologic examination. Regarding the biochemistry of this condition, all of the following are correct EXCEPT:

Explanation

Practice similar questions