Tuesday, May 14, 2019

Movement disorders in mitochondrial disease

Flønes IH, Tzoulis C. Movement disorders in mitochondrial disease: a clinicopathological correlation. Curr Opin Neurol. 2018 Aug;31(4):472-483.

Purpose of review The scope of this review is to give an updated account of movement disorders associated with mitochondrial disease, with a particular focus on recently discovered clinicopathological correlations.

Recent findings Movement disorders are common clinical manifestations of mitochondrial diseases, in part because of the high vulnerability of neurons controlling motor circuits to mitochondrial respiratory dysfunction and energy failure. Intriguingly, the clinicopathological correlations of movement disorders in mitochondrial disease do not always conform to established neurophysiological knowledge. In particular, nearly complete substantia nigra degeneration and nigrostriatal denervation can occur without being accompanied by any of the clinical signs traditionally associated with parkinsonism. This apparent paradox, may be because of compensation by concomitant impairment of other motor circuits involving the cerebellum and thalamus.

Summary Movement disorders commonly accompany mitochondrial disease and may show paradoxical clinical−anatomical correlations. Further research is warranted in order to elucidate the mechanisms underlying the phenotypic expression of movement disorders in mitochondrial disease. This knowledge will advance our understanding of the pathogenesis of movement disorders in a broader broader clinical and pathophysiological context.

From the article

Ataxia is among the most common and debilitating movement disorders in patients with mitochondrial disease, of either mtDNA or nuclear cause, because of the high prevalence of cerebellar degeneration...

Dystonia is the most common movement disorder in children with mitochondrial disease [35]. Although the population-based prevalence of dystonia in mitochondrial disease is not known, Leigh syndrome is probably the most common cause of dystonia among patients with mitochondrial disorders. Leigh syndrome, also known as subacute necrotizing encephalomyelopathy, is a genetically and phenotypically heterogeneous disorder of mostly infantile onset, which is commonly characterized by severe OXPHOS impairment. Leigh syndrome is caused by mutations in the mtDNA or a variety of nuclear genes encoding MRC subunits, complex assembly proteins, components of the Krebs cycle and other factors involved in mitochondrial bioenergetics...

In line with the profound mitochondrial vulnerability of the SNc, nigrostriatal degeneration is a common phenomenon in mitochondrial disease and shows a strong predilection for defects of mtDNA maintenance in which accumulation of somatic mtDNA damage occurs, including mutations of POLG, TWNK and OPA1. Paradoxically, in spite of the high prevalence of SNc degeneration, considered to be the principal cause of the parkinsonistic syndrome, parkinsonism is a relatively uncommon manifestation of mitochondrial disease. Parkinsonism has been described with mutations in mtDNA  and nuclear-encoded mitochondrial genes . Furthermore, parkinsonism has been described in a small number of cases with multiple mtDNA deletions, suggesting nuclear-encoded disorders of mtDNA maintenance, but with unknown genetic cause...

Although the SNc was affected in all reported cases of mitochondrial parkinsonism, severe SNc degeneration and nigrostriatal denervation can occur in patients with mitochondrial disease without any of the clinical correlates of parkinsonism. In fact, recent studies suggested that SNc degeneration is a common, possibly universal phenomenon in disease caused by POLG or TWNK mutations, yet clinical parkinsonism is an uncommon manifestation...

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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