Inborn Errors of Amino Acid Metabolism Revisited: Clinical Implications and Insights into Current Therapies

Inborn errors of amino acid metabolism (IEAAMs) are a heterogeneous group of genetic disorders caused by defects in enzymes, cofactors, or transporters of amino acid catabolism, biosynthesis, or transport. These defects result in toxic metabolite accumulation and/or deficiency of essential metabolites. This review aims to provide an updated overview of diagnosis, clinical implications, management, and evolving therapeutic approaches across major IEAAMs. A narrative review of recent literature was undertaken, focusing on established and novel therapeutic strategies for key IEAAMs, including phenylketonuria, alkaptonuria, tyrosinemia, homocystinuria, and maple syrup urine disease. Key management strategies include amino acid-restricted diets/restriction of natural protein with restriction of dietary precursors, dietary supplementations, including disease-specific amino acid supplements, medications to reduce formation of offending metabolites, pharmacotherapies, enzyme/cofactor replacement or pharmacological chaperones, enhancing residual enzyme activity and promoting alternative path-ways/accessory pathways. Emergency therapy is essential in severe types and focuses on promoting anabolism, limiting catabolism, reducing formation, and enhancing clearance of toxic metabolites. Other treatment options include organ transplantation, and new emerging modalities, such as mRNA therapies and gene therapies/in vivo gene editing offer potential for definitive interventions. Despite advancements in therapy and close monitoring, many IEAAMs remain associated with significant comorbidities. Future research is essential to optimise current treatment standards, particularly neuroprotective and metabolic regulatory features. While an in-depth discussion of innovative person-alised therapies is beyond the scope of this article, we believe that collective experiences will thrust future research in this field and expand access to innovative personalised therapies.