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Chapter 238PathophysiologyThe main causes of parkinsonism, as proposed in the articles, were the underlying genetic disorder, Parkinson’s disease and drug-induced parkinsonism, with the latter reported in only two patients. The proposed pathophysiological mechanisms (summarized in Table 1 per genetic disorder and depicted in Figure 2), from most to least frequent, included: abnormalities in mitochondrial function and oxidative stress, lysosomalautophagic function, endosomal trafficking and ubiquitin-proteasome system. Disruptions of monoaminergic neurotransmitter metabolism were also implicated in several GNDs that presented with parkinsonism.Table 1. Pathophysiologic mechanisms that may underlie parkinsonism in genetic neurodevelopmental disordersGenetic condition Mechanisms/pathophysiology that may be consideredMitochondrial dysfunctionHSD10 (HSD17B10) HSD17B10 encodes an enzyme that is essential for mitochondrial maintenance.14 Pathogenic variants may affect enzyme function and result in mitochondrial dysfunction. Leigh syndrome (MTATP6 and MT-MFT)Leigh syndrome is caused by over 50 different mitochondrial and nuclear encoded genes, most often affecting the respiratory chain and oxidative phosphorylation.15 Mitochondrial dysfunction may result in brain stem and basal ganglia lesions.Leigh-like syndrome (MT-TI)MT-TI is a mitochondrial gene of which pathogenic variants may result in mitochondrial dysfunction and basal ganglia lesions, similar to what has been proposed for Leigh syndrome.MT-CYB MT-CYB is a mitochondrial gene that encodes for a component of the respiratory chain. Pathogenic variants may result in mitochondrial dysfunction and progressive basal ganglia lesions, as has been proposed for Leigh syndrome.POLG POLG encodes a DNA polymerase that is essential for replication ofmitochondrial DNA. Mice that were homozygous for variants that may disrupt the function of POLG protein exhibited premature ageing.16, 17WARS2 Pathogenic variants in WARS2, that encodes for the WARS2 protein located in the mitochondrion, may result in respiratory chain defects and nigrostriatal degeneration.18Mitochondrial dysfunction combined with other mechanisms22q11.2 deletion syndromeThe 22q11.2 deletion region encompasses several genes including COMT, essential for catecholamine degradation, and six mitochondrial genes.19-21 Haploinsufficiency of these genes may result in dopamine autotoxicity and mitochondrial dysfunction.22Down syndrome Mitochondrial dysfunction, neuroinflammation, oxidative stress and lysosomal dysfunction have all been reported in Down syndrome.23-25