The Diagnostic Value of FGF-21 and GDF-15 as Biomarkers for Rare Childhood Mitochondrial Disorder Using Cerebral Organoids

Abstract

Mitochondrial disease is an umbrella term for a rare, clinically heterogenous group of primary mitochondrial disorders, in which the affected tissues and organs have the highest energetic demands. Clinical symptoms of this spectrum of diseases can arise in early childhood or later in life and can either affect a single organ or multiple. Patients with mitochondrial disease can experience an array of symptoms such as, but not limited to, epilepsy, lactic acidosis, autism spectrum behaviors, ADHD, sensorineural hearing loss, myopathy, heart block, and nonspecific renal failure. However, symptoms involving the nervous system are the most common, presenting in nearly half of these children. Neurons heavily rely on mitochondria to produce ATP for a variety of reasons such as regulation of the Na-K ATPase pump and calcium concentration. Accordingly, mitochondrial disorders are genetically determined metabolic diseases due to a biochemical deficiency of the electron transport chain. Currently, fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) have emerged as two promising diagnostic biomarkers for mitochondrial disease. However, previous studies have largely focused on serum fibroblast samples of patients with mitochondrial disease. This study presents a novel approach to using FGF-21 and GDF-15 as potential biomarkers using cerebral organoids to determine the change in the expression of the two proteins over time using ProteinSimple Jess, an instrument used for automated western blots. Here, we see that both GDF-15 and FGF-21 cannot be used as a biomarker for pathogenic variants of GABRA1, which is associated with epilepsy, and HNRNPH2, which is associated with intellectual disability, using cerebral organoids. However, this also paves the way to several future studies on autism, metabolites of the other mutants for longer maturation periods of cerebral organoids, and additional tests using ELISA in conjunction with western blots.