Page 46 - Characterization of genetic neurodevelopmental disorders at adult age, with a focus on 22q11.2 deletion syndrome - Emma Boersma

Chapter 2
Pathophysiologic mechanisms
The group of GNDs in this review was diverse, consistent with the
multiple pathways and mechanisms involved in the pathogenesis of both
neurodevelopmental and neurodegenerative disorders, including autophagic,
lysosomal and mitochondrial function, endosomal trafficking and the
ubiquitin-proteasome system.102-104 Dysregulation of these cellular processes,
that are especially important in long-lived cells such as neurons, may affect
neurogenesis,104, 105 synaptic function,106, 107 neuroplasticity,108 and neuronal
survival increasing the vulnerability for neurological and psychiatric disorders
across a patient’s lifespan.3, 109 Also, these mechanisms may interact and
when disrupted, contribute to a vicious cycle including the formation of
protein aggregates, as has been implicated in Parkinson’s disease.110, 111
Studying parkinsonism in patients with GNDs, and related animal models,
may be useful to unravel the complex processes underlying parkinsonism.
Interestingly, in almost all GNDs with available data on neuropathology,
neuronal loss was found, consistent with growing recognition that
neurodevelopmental and neurodegenerative disorders overlap, rather than
should be seen as opposite conditions.2, 3
Clinical implications
The large number of GNDs that may present with parkinsonism prompts
questions about prevention, diagnosis, and management. Given the young
onset and the co-occurrence of other movement disorders seen in GNDs,
early motor signs should be carefully monitored in patients with these
conditions. Periodic standardized motor evaluations (e.g., MDS-UPDRS and
video-recordings), and involvement of a movement disorder specialist, may
be considered. When parkinsonism presents and progresses, dopaminergic
imaging may assist distinguishing medication-induced parkinsonism from
degenerative parkinsonism, that may be particularly difficult in patients
with GNDs and complex neuropsychiatric expression.112
Clinicians treating patients with early-onset parkinsonism and intellectual
disabilities or other neurodevelopmental problems, should consider ordering
a genetic test. Identification of an underlying diagnosis can be important
for long-term clinical management. It allows the opportunity for preventive
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