Ruben Bonilla Guerrero, MD, FACMG, FAACC
Sanjeda R. Chumki, PharmD, RPh
Inborn errors of metabolism (IEM) are a group of inherited disorders in which molecular abnormalities occur in genes related to metabolic pathways, most often leading to enzymatic deficiencies that disrupt the body’s normal metabolic processes. When a metabolic step fails, the substrates of the affected enzyme build up and, in some cases, enter alternate metabolic pathways that are not utilized or are under-utilized in normal circumstances; some of these intermediate metabolites are toxic at high levels, either directly or indirectly and can affect multiple organ systems.
Pharmacogenomics is the study of how genes affect a person’s response to drugs. Pharmacogenomics testing combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to help to establish an effective, safe, and cost-effective therapeutic plan based on a person’s genetic makeup.
Currently, the treatment of an inborn error of metabolism divides into two areas. The approach to address the specific metabolic derangement (substrate reduction/product supplementation, enzyme replacement therapy, chaperon replacement therapy, substrate replacement therapy, and gene therapy), and the treatment of the associated symptoms which still follows the traditional and historical empirical success/fail therapeutic method “one size fits all,” to reduce the different manifestations produced by a metabolic derangement. This approach leads to a delay in mitigating the symptoms due to the lack of medications efficacy and an increased risk of adverse drug reactions. This combination produces a lack of patient’s adherence to therapeutic measures, continuous modifications of the patient’s therapeutic regiment to find the correct medication and dose., and overall increasing the cost of healthcare.
The therapeutic areas used to address the clinical manifestations of inborn errors of metabolism depends on symptoms of the disorder. For instance and to mention a few, patients with tyrosinemia type-II, and acute intermittent porphyria will require chronic pain management; patients with certain organic acidurias and mitochondrial fatty acid oxidation disorders will require simultaneous glycemic, cardiovascular, and stomach acid secretion control. Patients with phenylketonuria, ornithine transcarbamylase deficiency, acute intermittent porphyria, and hereditary coproporphyria will require behavioral and psychotropic control medications; patients with homocystinuria will require anticoagulant medications, and patients will non-ketotic hyperglycinemia, and guanidinoacetate
methyltransferase deficiency will need anti-seizure medications.
Pharmacogenomics is not a new area of laboratory medicine, and it has been around since the discovery of the cytochrome P450 superfamily of metabolic enzymes in 1955. However, the application and implementation of pharmacogenomics into everyday clinical practice are relatively new. The clinical applications of pharmacogenetics are rapidly growing and include pain management, anesthesia, cardiovascular disorders, oncology, psychotropics, infectious diseases, gastrointestinal medications, neurology to mention some of them, and it expands to all ages of life.
In this presentation, we will provide a practical perspective of pharmacogenomics, its application, and implementation to treat the symptoms of patients with an inborn error of metabolism with the goal to offer a fast-efficient therapy to mitigate the clinical manifestations, to prevent adverse drug reactions, while taking in consideration other non-genetic patient’s factors that contribute to drug response.