Page 49 - Characterization of genetic neurodevelopmental disorders at adult age, with a focus on 22q11.2 deletion syndrome - Emma Boersma

Parkinsonism in GNDs
Research implications
Phenotypic heterogeneity may be significant in GNDs given incomplete
penetrance of genetic variants, variable expression, and pleiotropy,121
and may be particularly relevant in those GNDs involving multiple genes,
such as is the case in 22q11.2 deletion syndrome. Detailed phenotype
analysis (‘deep-phenotyping’) is crucial to further our knowledge on the
complex relationships between genetics, pathophysiological mechanisms,
environmental factors and the phenotypic characteristics of parkinsonism
in GNDs. International collaborative research is needed, to overcome the
issue of the limited number of patients with individually rare conditions.
In addition to routine assessments including careful history taking that
focusses on parkinsonian/neurological features and comorbid conditions
of the genetic variant, and structured physical examinations (e.g. MDS-
UPDRS), this should include careful family history taking. Periodic video
assessments may also be considered. Despite the challenges, GNDs
are often diagnosed at an early age, long before the onset of motor and
non-motor Parkinson’s disease related symptoms, facilitating early-stage
research of parkinsonism. In addition to human studies, recognizing GNDs
makes it possible to use cell and animal models, available for many GNDs,
to expand the possibilities of studying the pathophysiologic mechanisms,
identify potential biomarkers and design rational interventions.30, 90 Disease-
specific intervention strategies have been suggested in several human and
animal models of GNDs and clearly demonstrate the benefits of these kind
of studies.85, 122
2
With an increased life expectancy for many GNDs, future research should
also focus on overlap between GNDs and other neurodegenerative
disorders, e.g., major neurocognitive disorder, in order to understand shared
underlying mechanisms and improve clinical care.
Strengths and Limitations
The strengths of this systematic review include the pre-registration
of the protocol, the comprehensive search strategy, and the extensive
data extraction on key characteristics of parkinsonism and its proposed
pathophysiologic mechanisms. Several limitations should also be
mentioned. The data need to be considered in view of the retrospective
47