Agnies M van Eeghen, Hilgo Bruining, Nicole I Wolf, Arthur A Bergen, Riekelt H Houtkooper, Mieke M van Haelst, Clara D van Karnebeek
February 8, 2022
Abstract
Rare neurogenetic disorders are collectively common, affecting 3% of the population, and often manifest with complex multiorgan comorbidity. With advances in genetic, -omics, and computational analysis, more children can be diagnosed and at an earlier age. Innovations in translational research facilitate the identification of treatment targets and development of disease-modifying drugs such as gene therapy, nutraceuticals, and drug repurposing. This increasingly allows targeted therapy to prevent the often devastating manifestations of rare neurogenetic disorders. In this perspective, successes in diagnosis, prevention, and treatment are discussed with a focus on inherited disorders of metabolism. Barriers for the identification, development, and implementation of rare disease-specific therapies are discussed. New methodologies, care networks, and collaborative frameworks are proposed to optimize the potential of personalized genomic medicine to decrease morbidity and improve lives of these vulnerable patients.
INTRODUCTION
With advances in genetic and -omics technologies, more children with rare neurogenetic disorders—that is, neurodevelopmental disorders (NDDs) and inherited metabolic disorders (IMDs)—can be diagnosed at an earlier age (Blau et al. 2022). Early genetic diagnosis is paramount for the movement toward disease-modifying and other personalized treatments that have great potential for improving health and quality of life (Sahin and Sur 2015; Vissers et al. 2016). These approaches may help many individuals, because NDDs are collectively common, affecting 3% of the population directly and another 5% indirectly—that is, as family members coping with care and potential recurrence risks. Patients are often affected by severe and complex somatic and neuropsychiatric comorbidity, including intellectual disability (ID), epilepsy, cognitive and behavioral disturbances, sensory deficits, and other organ dysfunction. Because of their lifelong care needs on multiple life domains, these patient populations present a challenging task for health-care providers and systems to provide optimal personalized care, taking both the characteristics of the disorder as well as the individual care needs into account.
The opportunities for personalized therapeutic interventions, both symptomatic and disease-modifying, are drastically increasing for NDDs, and even more for IMDs. These vary from diets and vitamins, (repurposed) medications, organ and stem cell transplants, to RNA and gene therapy (Sun et al. 2017). However, implementation via therapeutic trials for these often-small patient populations face specific challenges in methodology and outcome measures. Additionally, implementation of personalized medicine is hampered by financial, organizational, and regulatory barriers. Translation of novel treatments to patient care with guaranteed access and reimbursement is cumbersome and often unsuccessful at both the local and international levels. This results in an unacceptable situation: Novel treatments do not reach the patient, and there is lack of evidence-based care.
To address the current state of personalized medicine for IMDs, we review several success stories to show opportunities for improvement in trial design, outcome measures, and collaborative efforts. We put forward how this knowledge can be extended to other NDDs and propose acceleration of personalized medicine via our flywheel model as depicted in Figure 1.
van Eeghen AM, Bruining H, Wolf NI, Bergen AA, Houtkooper RH, van Haelst MM, van Karnebeek CD. Personalized medicine for rare neurogenetic disorders: can we make it happen? Cold Spring Harb Mol Case Stud. 2022 Mar 24;8(2):a006200. doi: 10.1101/mcs.a006200. PMID: 35332073; PMCID: PMC8958924.
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