Page 46 - Demo

Chapter 244Pathophysiologic mechanismsThe 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, 111Studying 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, 3Clinical implicationsThe 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.112Clinicians 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