A 2-year-old boy from a consanguineous family presents with progressive neurological deterioration, cherry-red spot on the macula, and hepatosplenomegaly. Enzyme assay reveals deficiency of hexosaminidase A and B. Which of the following metabolic pathways is primarily affected?

Explanation

## Diagnosis: GM2 Gangliosidosis (Sandhoff Disease) ### Clinical Presentation The patient presents with the classic triad of **GM2 gangliosidosis**: - Progressive neurological deterioration (developmental regression) - **Cherry-red spot on the macula** (pathognomonic finding) - Hepatosplenomegaly **Key Point:** The cherry-red spot results from accumulation of lipid in retinal ganglion cells, creating a pale fovea surrounded by red peripheral retina. ### Enzyme Defect The enzyme assay showing deficiency of **both hexosaminidase A and B** is diagnostic of **Sandhoff disease** (GM2 gangliosidosis type AB variant). This occurs due to deficiency of the GM2 activator protein or the β-subunit of hexosaminidase. **High-Yield:** Hexosaminidase A deficiency alone = Tay-Sachs disease; both A and B deficiency = Sandhoff disease. ### Affected Metabolic Pathway ```mermaid flowchart TD A[Sphingolipids: Gangliosides]:::outcome --> B[Normal catabolism via<br/>Hexosaminidase A & B]:::action B --> C[Sialic acid & N-acetyl<br/>galactosamine removed]:::action C --> D[Complete degradation]:::outcome E[Hexosaminidase A & B<br/>DEFICIENCY]:::urgent --> F[Ganglioside accumulation<br/>in neurons & macrophages]:::urgent F --> G[CNS deterioration<br/>Hepatosplenomegaly<br/>Cherry-red spot]:::urgent style A fill:#e1f5ff style D fill:#c8e6c9 ``` **Key Point:** The primary defect is in **sphingolipid catabolism**, specifically the lysosomal degradation of gangliosides (GM2 ganglioside). Hexosaminidase A and B are lysosomal enzymes responsible for removing terminal sialic acid and N-acetyl-galactosamine residues from gangliosides. ### Why Sphingolipid Catabolism? Gangliosides are complex sphingolipids abundant in neuronal membranes. Their accumulation in lysosomes leads to: 1. Neuronal dysfunction and death (progressive neurological decline) 2. Macrophage infiltration (hepatosplenomegaly) 3. Retinal lipid deposition (cherry-red spot) **Clinical Pearl:** GM2 gangliosidosis is an example of a **lysosomal storage disease** with sphingolipid accumulation — the hallmark of sphingolipidoses. ### Prognosis Infantile-onset Sandhoff disease (as in this case) is rapidly progressive with death typically by age 3–5 years due to severe CNS involvement. [cite:Harrison 21e Ch 432]