General description

GM2-gangliosidosis is a group of lysosomal storage disorders caused by mutations in the HEXA, HEXB, or GM2A genes, which lead to deficient activity of β-hexosaminidase A or the GM2 activator protein. GM2-gangliosidosis arises from mutations in HEXA (Tay-Sachs disease), HEXB (Sandhoff disease), or GM2A (AB variant), leading to deficient activity of β-hexosaminidase A or the GM2 activator protein. This results in lysosomal accumulation of GM2 ganglioside, triggering neuroinflammation, microglial activation, and astrocyte-mediated chemokine release (e.g., CCL2, CXCL10), which exacerbate neuronal apoptosis and demyelination. In Sandhoff disease, systemic organomegaly may occur due to broader glycolipid storage. Dysfunctional lysosomes also impair cellular homeostasis, affecting neurodevelopmental processes such as radial glia differentiation and myelination.

Clinically, the infantile form, which accounts for the majority of cases, typically begins around five months of age with signs such as developmental delay or regression, hypotonia, heightened startle response, seizures, hyperacusis, and loss of vision often marked by cherry-red spots in the retina. These symptoms progressively worsen, leading to spasticity, profound weakness, and early death. In contrast, late-onset forms display a slower progression and more variable symptoms, including cerebellar ataxia, speech difficulties, intellectual decline, psychosis, and motor neuron disease, with patients often surviving into adulthood.

MR spectroscopy

MR spectroscopy provides additional metabolic information:

• Decline in N-acetylaspartate (NAA), indicating neuronal loss
• Increased choline, reflecting membrane turnover
• Progressive elevation of myo-inositol, suggesting gliosis

References

1. Rumboldt, Zoran, et al., eds. Brain imaging with MRI and CT: an image pattern approach. Cambridge university press, 2012. https://www.cambridge.org/core/books/abs/brain-imaging-with-mri-and-ct/gangliosidosis-gm2/8B4DAABD531E9B933E624308F8F6CC5C
2. Gupta, Laxmikant, et al. "Magnetic resonance imaging findings in Tay–Sachs disease." Neurology India 66.4 (2018): 1201-1202.