What is the pathophysiology of olivopontocerebellar atrophy (OPCA)?

Updated: Dec 17, 2018
  • Author: Sombat Muengtaweepongsa, MD, MSc; Chief Editor: Selim R Benbadis, MD  more...
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Answer

The OPCAs are progressive neurodegenerative conditions. Genetic and pathological evidence suggest that abnormalities of alpha-synuclein (αSYN) are important in the pathogenesis of these disorders. Many specific genes have been identified for the genetic forms, although how the genetic abnormalities lead to the specific αSYN abnormalities or to the specific clinical findings remains uncertain. Recently developed models using transgenic mice possessing the genes for human αSYN suggest that MSA involves dysfunction of the ubiquitin-proteasome system causing proteolytic stress that disrupts the oligodendroglial/myelintrophic support. Oligodendroglia in such models, as well as in pathological specimens of the human disease, have cytoplasmic inclusions of fibrillar αSYN. [15] There is also evidence for involvement of the ubiquitin-binding protein p62/sequestosome-1 in some cases of OPCA. [16]

On the gross level, brains show some common characteristics in all cases of OPCA. The pons is diminutive, especially in the area of the basis pontis. Degeneration of the cerebellum occurs, especially in the white matter. This white matter loss is probably due to the dying back of axons from degenerating neurons rather than a primary attack on the myelinated tracts. Loss of Purkinje cells is common. Major neuronal loss occurs in the inferior olivary, arcuate, and pontine nuclei. Dentate nuclei are well preserved. The middle cerebellar peduncles are also atrophic, possibly secondary to degeneration of the basal pontine gray matter. The substantia nigra of the midbrain shows evidence of tissue loss. Cellularly, one sees neuronal degeneration in the arcuate, pontine, inferior olivary, pontobulbar nuclei, and the cerebellar cortex.

Additional areas of degeneration probably account for the difference in subtypes. In sporadic OPCA, oligodendroglial and neuronal intracytoplasmic and intranuclear inclusions characteristic of MSA are frequently seen. Many of these are accumulations of alpha-synuclein. In autosomal dominant OPCA, spinal cord lesions, especially in the posterior columns, spinocerebellar tracts, and anterior gray horn cells, are more common. The cerebellar features may be less prominent. However, so many variations of both the sporadic and genetic forms are described that one can find cases that appear to be exceptions to these generalizations.


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