Publication date: Nov 01, 2019
Disturbances in motor movement can have similar clinical presentations, albeit having different pathways and temporal onset. Hypokinetic movements present with rigidity, resting tremors, postural instability and bradykinesia, as seen in parkinsonism, while hyperkinetic movements typically present with chorea, ballismus, tic, athetosis and dystonia. Nonetheless, movement disorders are thought to be a continuum. Long-term therapy of parkinsonism with L-DOPA or dopamine (DA) agonists leads to late-onset dyskinesia – a hyperkinetic movement disorder, while patients with late-stage Huntington disease (HD) often develop non-DOPA responsive parkinsonism. In this paper, it is proposed that late-onset parkinsonism is driven by the overactivity of the nigrostriatal dopaminergic pathway. The excessive synthesis, storage, release, reuptake and degradation of dopamine in the presynaptic terminal and synaptic clefts lead to cellular stress and damage, resulting to progressive neuroapoptosis aggravated by pro-parkinsonism drugs used to treat hyperkinesia. Glutamate excitotoxicity may provide initial stress to neurons during early HD – but as the disease advances, lower glutamate levels are observed, making it less likely to cause the hypokinetic shift on its own. Over time, dopaminergic neurons are depleted and cholinergic influence to striatal GABA release is unopposed, leading to late-onset parkinsonism that is unresponsive to DOPA challenge, due to drastic DA neuron loss previously masked by the dominating choreic presentation. This paper thus provides a mechanism of action to a common clinical sequela and complication of long-term choreic diseases, whose pathophysiologic mechanism is presently lacking.
Manalo, R.V.M. Cytosolic non-vesicular dopamine accumulation as the predominant mechanism for developing non-DOPA responsive parkinsonism in late-stage Huntington disease. 06743. 2019 Med Hypotheses (132):
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