One possible explanation is compensation by concurrent changes in other neuroanatomical pathways, in particular the cerebellum and thalamus, both of which are common in patients with POLG or TWNK-associated disease [80,117–119]. Interestingly, the phenomenon of nigrostriatal degeneration sine parkinsonism has been described in other neurological diseases with cerebellar involvement, such as inherited spinocerebellar ataxias (SCA) [120–123] and MSA-c . Moreover, ipsilateral improvement of rigidity has been reported in an individual with parkinsonism after a cerebellar stroke , and surgical dentatectomy has been reported to produce similar results . The common denominator of the above mentioned disorders is the cerebellar involvement. On the basis of this observation, we theorized that dysfunction of the cerebellum and its connections can modulate the dysfunction of the basal ganglia amelioration or preventing the manifestation of clinical parkinsonism .
Thalamic inhibition, either by deep brain stimulation or thalamotomy ameliorates tremor-dominant parkinsonism . Thalamic involvement is common in POLG encephalopathy [117,128], and could counteract parkinsonism by modulating the cortico-striato-pallido-thalamo-cortical pathway.
Degeneration of the subthalamic nucleus, a well established target for stereotactic lesions or deep brain stimulation to ameliorate parkinsonism, has been shown in patients with SCA2 and SCA3 and proposed to explain the lack of parkinsonism in spite of severe nigrostriatal loss . It is currently not known whether the STN is affected by neurodegeneration in POLG or other mitochondrial disorders. Therefore, its potential role in compensating parkinsonian symptoms in mitochondrial disease remains undetermined.
Movement disorders are common manifestations of mitochondrial disease because of a pathological predilection for energy-sensitive neurons controlling motor circuits. Although the clinicopathological correlations mostly conform to established neurophysiological knowledge, this is not always the case. Nearly complete nigrostriatal degeneration may occur in POLG-associated disease without being accompanied by any of the clinical signs traditionally associated with parkinsonism. Elucidating the mechanisms underlying this apparent lack of clinicopathological correlation in these cases will advance our understanding of the pathogenesis of movement disorders, not only with respect to mitochondrial disease but also in a broader clinical and pathophysiological context.
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