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. 2021 Nov 1:764:136195.
doi: 10.1016/j.neulet.2021.136195. Epub 2021 Aug 25.

The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment

Camilo Toro  1 , Mosufa Zainab  2 , Cynthia J Tifft  3
Affiliations

The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment

Camilo Toro et al. Neurosci Lett. .
No abstract available

Keywords: GM2; Gangliosidoses; Gene therapy; HEXA; HEXB; Hexosaminidase A; Lysosomal storage diseases; Sandhoff disease; Tay-Sachs disease.

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Conflict of interest statement

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
Schematic representation of the GM2 gangliosidoses. β-Hexosaminidase A deficiency emerges from biallelic null or missense mutations in the genes HEXA (Tay-Sachs) or HEXB (Sandhoff) disease, coding the alpha or beta subunits of the enzyme. β-hexosaminidase A is the only configuration of this dimeric enzyme capable of degrading GM2 substrate. Its deficiency renders neurons and other cells in the nervous system unable to degrade GM2 gangliosides at the lysosomal level leading to substrate accumulation exemplified by membranous cytoplasmic bodies visible on ultrastructural studies (Left). GM2 gangliosidoses involve dysfunction on multiple cell types including neurons, microglia and oligodendrocytes ultimately resulting in neurodegeneration (Center). Residual enzyme activity determines disease onset, symptoms and progression which has led to the categorization into disease subtypes (infantile, juvenile, or late onset) GM2 gangliosidoses (Right). A cherry-red spot is a characteristic ophthalmological feature of infantile GM2 gangliosidosis. A yellowish tint emerges from accumulated substrate in the macular region of the retina that contrasts with the darker appearing foveal center (Bottom Right).
Fig. 2.
Fig. 2.
Natural history of three forms of GM2 gangliosidoses (Infantile, juvenile and adult or Late-onset) disease. Note the differences in age and slope of progression for the three forms. Progression is more homogeneous and steeper in earlier disease but more variable and shallower in late-onset disease. Ultimately, disease onset is a function of residual enzyme activity with early onset disease having complete or nearly complete absence of β-hexosaminidase A enzymatic activity.
Fig. 3.
Fig. 3.
Schematic representation of the progressive lower motor neuronopathy characteristic of late-onset GM2 gangliosidoses. Degeneration of anterior horn cells (lower motor neurons) due to late-onset Tay Sachs or Sandhoff disease leads to denervation and neurogenic muscle weakness (A). Muscle atrophy in is particularly severe in the quadriceps muscles (red arrow and highlighted muscle on thigh MRI) when compared to muscles on the posterior compartment of the thigh. On routine histology, bundles of degenerating fibers (enclosed in dashed oval) containing smaller angular fibers represent muscle fibers undergoing degenerating due to loss of their innervating anterior horn cell prototypical of neurogenic atrophy due to anterior horn cell neuronopathy (B & C). Hyperextension and “locking” of the knees to achieve antigravity support is characteristic of the stance and ambulation of patients with LOTS and LOSD experiencing quadriceps weakness (knee extension weakness). This finding is often accompanied by increased lumbar lordosis (D).
Fig. 4.
Fig. 4.
Panel A. Cranial T1 weighted sagittal MRI images over the right middle cerebellar peduncle in a healthy control (1), individual at the time of late-onset Tay Sachs diagnosis (2) and individual in an advanced state of late-onset Tay Sachs (3). Arrow heads point to the posterior fossa region normally occupied by the cerebellum. Images illustrate selective progressive cortical atrophy out of proportion to atrophy of other brain regions in patients with GM2 gangliosidoses (solid arrowheads) compared to a normal control subject (open arrowhead). Panel B. Large scale distributed cortico-cerebellar loops provide the neural substrate for the cerebellum to influence complex behaviors besides motor control in health and diseases including late-onset GM2 gangliosidoses. All cerebellar outputs originates from Purkinje cell connections to deep cerebellar nuclei including the dentate nuclei (DCN). In turn these nuclei have broad projections to the cortex and other CNS regions (solid arrows). Reciprocal cortical projections (dashed arrows) to the anterior pontine nuclei (APN) provide the basis for cerebellar input with robust convergence of many inputs into Purkinje cells which are particularly vulnerable to injury, including accumulation of GM2 ganglioside. Panel C. Schematic representation of the many aspects of behavior (beyond motor control) impacted by the function of the cerebellum and how cerebellar dysfunction could lead to not only to ataxia but also to the cerebellar cognitive affective syndrome (CCAS) which likely contributes to cognitive and affective symptoms of late-onset GM2 gangliosidoses. (B and C are modified from D’Angelo & Casali, 2012 [112]).
See this image and copyright information in PMC

References

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