A Screening Tool to Quickly Identify Movement Disorders in Patients with Inborn Errors of Metabolism

Koens, Lisette H; Klamer, Marrit R; Sival, Deborah A; Balint, Bettina; Bhatia, Kailash P.; Contarino, Maria Fiorella; Egmond, Martje E van; Erro, Roberto; Friedman, Jennifer; Fung, Victor S.C.; Ganos, Christos; Kurian, Manju A.; Lang, Anthony E.; McGovern, Eavan; Roze, Emmanuel; Koning, Tom J. de; Tijssen, Marina A. J.

doi:10.1002/mds.29332

Cited by 3 publications

(3 citation statements)

References 18 publications

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“…Therefore, the association of ATPase defects with early‐onset severe encephalopathies and uncoupling syndromes is not surprising. In these complex pictures, the detection rate of dystonia may be poor 57 . We posit that ATPase defects underlie a much larger number of phenotypes also featuring dystonia, warranting reverse phenotyping in diagnosed cases.…”

Section: Discussionmentioning

confidence: 95%

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Dystonia in ATP Synthase Defects: Reconnecting Mitochondria and Dopamine

Indelicato,

Boesch,

Mencacci

et al. 2023

Movement Disorders

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Four decades of research highlighted a significant role for mitochondrial dysfunction in the pathogenesis of movement disorders. A first milestone was set by the discovery that the neurotoxin N-methyl-4-phenylpyridinium (MPP + ), an apoptosis-inducing mitochondrial complex I inhibitor, induces parkinsonism by selectively damaging the substantia nigra. 1,2 This report sparked intensive investigations on the role of mitochondria in Parkinson's disease (PD), 3 fueled by the recognition of mitochondrial functions for several PD-associated genes. 2 Sequencing of the mitochondrial genome was completed in 1981. 4 Reports linking mitochondrial DNA (mtDNA) variants to neurological phenotypes rapidly followed. Notably, two early works identified dystonia as a prominent feature of distinct mitochondrial syndromes, 5,6 leading to the speculation that "movement disorders might have a mitochondrial etiology". 7 The association between mitochondrial diseases and various movement disorders has been confirmed by several case reports and few larger series. [8][9][10][11] Nonetheless, systematic explorations of the underlying pathophysiological mechanisms are scarce.Recently, independent studies elucidated a direct causal relationship between isolated dystonia and variants in genes encoding components of the mitochondrial ATP synthase (ATPase). 12,13 These remarkable findings encouraged us to reappraise the "mitochondria-movement disorder connection" 7 from a geneticsdriven perspective. We posit that mild energetic failure caused by specific ATPase variants may influence the synaptic activity of several nodes of the motor circuits involved in dystonia pathogenesis. ATPase activity modulation driven by other genetic or environmental stressors may play a role in the functional network alterations seen in more common idiopathic dystonias. Dystonia in Mitochondrial DiseasesUnique among the cellular organelles, mitochondria underlie a dual genomic control by both autochthonous mtDNA and the nuclear genome. 14,15 MtDNA encodes 13 subunits of the enzymatic complexes governing oxidative phosphorylation (OXPHOS) and 24 mitochondrial specific RNAs. 4 Further >1000 mitochondrial proteins are nuclear-encoded. 16 They are involved not only directly in OXPHOS, but also in respiratory chain-complex assembly, mtDNA replication, expression, and repair, as well as in other metabolic

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Section: Discussionmentioning

confidence: 95%

“…In these complex pictures, the detection rate of dystonia may be poor. 57 We posit that ATPase defects underlie a much larger number of phenotypes also featuring dystonia, warranting reverse phenotyping in diagnosed cases. Monogenic disorders offer unique insights into the pathophysiology of phenotypically related sporadic conditions.…”

Section: Discussionmentioning

confidence: 99%

Dystonia in ATP Synthase Defects: Reconnecting Mitochondria and Dopamine

Indelicato,

Boesch,

Mencacci

et al. 2023

Movement Disorders

View full text Add to dashboard Cite

show abstract

“…Differences may be explained by heterogeneous recruitment criteria for genetic testing and variable representation of pediatric versus adult cases. Furthermore, the diagnosis of dystonia within early-onset severe multisystemic phenotypes (such as most mitochondriopathies) is challenging, likely resulting in unreported individuals [ 22 ]. By analyzing a large cohort referred for WES with the primary indication of dystonia, we also tackled the research question from the opposite perspective.…”

Section: Discussionmentioning

confidence: 99%