Disease framing
- Anchor Sandhoff disease to MONDO:0010006.
- Make the parent relationship to GM2 gangliosidosis (MONDO:0017720) explicit.
- Keep Tay-Sachs disease (MONDO:0010100) as a sibling differential, not a synonym.
- Keep the gene-disease frame ClinGen-consistent: HEXB, autosomal recessive, definitive.
Causal graph requirements
- Start from pathogenic HEXB variants and loss of Hex A / Hex B activity.
- Pass through lysosomal GM2 and GA2 storage and explicit lysosomal dysfunction.
- Keep neural-cell and glial pathology explicit before the terminal neurodegeneration node.
- Use only exact PMID-backed snippets in YAML evidence.
Key mechanistic nodes selected
- Pathogenic HEXB variants
- Hexosaminidase A and B deficiency
- Lysosomal GM2 and GA2 accumulation in neural cells
- Lysosomal dysfunction in neurons and glia
- Neuroinflammation and reactive gliosis
- ER stress and spinal motor neuron apoptosis
- Neurodegeneration and circuit dysfunction
Clinical and treatment emphasis
- Preserve Sandhoff-specific phenotype anchors such as coarse facies and infantile Sandhoff wording where available.
- Use infantile GM2 natural-history data only where the abstract explicitly states Tay Sachs and Sandhoff variants did not differ.
- Keep supportive care as current standard, with gene therapy and 4-PBA labeled preclinical / investigational.
Citation inventory