Page 32 - Characterization of genetic neurodevelopmental disorders at adult age, with a focus on 22q11.2 deletion syndrome - Emma Boersma

Chapter 1
Abstract
With advances in clinical genetic testing, associations between genetic
neurodevelopmental disorders and parkinsonism are increasingly
recognized. In this review, we aimed to provide a comprehensive overview
of reports on parkinsonism in genetic neurodevelopmental disorders
and summarize findings related to genetic diagnosis, clinical features
and proposed disease mechanisms. A systematic literature review was
conducted in PubMed and Embase on June 15, 2021. Search terms for
parkinsonism and genetic neurodevelopmental disorders, using generic
terms and the Human Phenotype Ontology, were combined. Study
characteristics and descriptive data were extracted from the articles using
a modified version of the Cochrane Consumers and Communication
Review Group’s Data Extraction Template. The protocol was registered in
PROSPERO (CRD42020191035). The literature search yielded 208 reports
for data-extraction, describing 69 genetic disorders in 422 patients. The five
most reported from most to least frequent were: 22q11.2 deletion syndrome,
beta-propeller protein-associated neurodegeneration, Down syndrome,
cerebrotendinous xanthomatosis, and Rett syndrome. Notable findings
were an almost equal male to female ratio, an early median age of motor
onset (26 years) and rigidity being more common than rest tremor. Results
of dopaminergic imaging and response to antiparkinsonian medication
often supported the neurodegenerative nature of parkinsonism. Moreover,
neuropathology results showed neuronal loss in the majority of cases.
Proposed disease mechanisms included aberrant mitochondrial function
and disruptions in neurotransmitter metabolism, endosomal trafficking
and the autophagic-lysosomal and ubiquitin-proteasome system. We also
discuss the implications for clinical practice and highlight the potential of
research in genetic neurodevelopmental disorders that may help unravel
the complex processes underlying parkinsonism.
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