Pediatric Neurogenetic Disorders: Diagnosis, Disease Models and Therapeutic Interventions
Biomedical research often focuses on common disorders that affect a significant portion of our population (e.g., diabetes, cancer, heart disease). This approach prudently allocates our limited research funds toward disorders that have the most widespread impact on our collective medical needs. Unfortunately, this path often neglects rare disorders that affect only a handful of patients, the study of which can be very valuable in providing insight into cellular and molecular functions.
Rare neurogenetic disorders are often caused by a genetic alteration that prohibits the proper function of the central or peripheral nervous systems (the brain, spinal cord, muscle and/or peripheral nerves). Because many of the genes involved in these disorders are crucial to neurological development and human behavior, the effects of these disorders can often be observed early in life with neurodevelopmental disorders. Alternatively, pediatric neurodegenerative disorders can occur after normal neurodevelopment, with subsequent loss of motor and cognitive abilities. Consequently, pediatric neurogenetic disorders are a major subset of rare disorders, with many being severely debilitating and/or life-threatening.
The recent emergence of genomic methods such as high-density single-nucleotide polymorphism arrays, exome sequencing, and whole-genome sequencing has allowed the scientific community to identify pathogenic mutations in genes that would often not be included in the diagnostic workup. Subsequently, with further research, the association of these genes with their pathogenic mechanisms has provided valuable insight into the molecular and cellular function of the nervous system. Likewise, the development of induced pluripotent stem cells (iPSCs) has provided us a platform from which to generate patient-specific stem cells that are capable of generating human disease models for these rare disorders. For example, iPSCs can be differentiated into neural progenitor cells to determine how a particular gene may affect their proliferation and differentiation into neurons. Alternatively, iPSCs can be used to generate neurons that express specific disease markers that can subsequently be screened with thousands of approved drugs to see which might be valuable in the treatment of disorders. The Pierson Lab collaborates with several groups to provide a wide range of methods to investigate disease (including mouse models, mitochondrial and transcriptional function), as well as providing expertise in the use of inducible systems (mifepristone and doxycycline) for regulated expression of therapeutic proteins in the central nervous system. This work may prove invaluable in determining new methods of understanding these disorders and intervening therapeutically in a personal and precise manner.
Schematic overview of the Pierson Lab’s pediatric neurogenetic disorder research. The Pierson Lab works with the Cedars-Sinai Pediatric Neurogenetic and Neuromuscular Clinic. The lab uses modern genomic platforms and induced pluripotent stem cell technologies to achieve genetic diagnoses and create cell culture models of these rare disorders, respectively.