Page 40 - Characterization of genetic neurodevelopmental disorders at adult age, with a focus on 22q11.2 deletion syndrome - Emma Boersma

Chapter 2
Pathophysiology
The 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, lysosomal-
autophagic 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 disorders
Genetic condition Mechanisms/pathophysiology that may be considered
Mitochondrial dysfunction
HSD10 (HSD17B10) Leigh syndrome (MT-
ATP6 and MT-MFT)
Leigh-like syndrome
(MT-TI)
MT-CYB POLG WARS2 HSD17B10 encodes an enzyme that is essential for mitochondrial
maintenance.14 Pathogenic variants may affect enzyme function and
result in mitochondrial dysfunction.
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.
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 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 encodes a DNA polymerase that is essential for replication of
mitochondrial DNA. Mice that were homozygous for variants that may
disrupt the function of POLG protein exhibited premature ageing.16, 17
Pathogenic variants in WARS2, that encodes for the WARS2 protein
located in the mitochondrion, may result in respiratory chain defects and
nigrostriatal degeneration.18
Mitochondrial dysfunction combined with other mechanisms
22q11.2 deletion
syndrome
Down syndrome The 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.22
Mitochondrial dysfunction, neuroinflammation, oxidative stress and
lysosomal dysfunction have all been reported in Down syndrome.23-25
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