Inborn Errors of Metabolism: Pathophysiological Insights, Diagnostic Advances, and Evolving Treatment Paradigms

Abstract

Inborn errors of metabolism (IEM) are a diverse group of inherited disorders resulting from defects in enzymes, transporters, or cofactors involved in essential metabolic pathways. These defects disrupt normal biochemical processes, leading to the accumulation of toxic metabolites, deficiency of vital compounds, or impaired energy production. Although individually rare, IEM collectively contribute significantly to morbidity and mortality, particularly in neonates and children. The clinical presentation is highly variable, ranging from acute metabolic crises in the neonatal period to chronic or late-onset manifestations. Common features include developmental delay, neurological impairment, metabolic acidosis, hypoglycemia, hyperammonemia, and dysfunction of organs such as the liver, heart, and muscles. Due to their nonspecific presentation, early diagnosis remains challenging and requires a high index of clinical suspicion. Advancements in diagnostic techniques, including plasma amino acid analysis; urine organic acid profiling; acylcarnitine analysis; and molecular genetic testing, have improved the accuracy of diagnosis. Expanded newborn screening using tandem mass spectrometry has enabled early detection and timely intervention, significantly improving outcomes. Management of IEM is disorder-specific and includes dietary modifications, pharmacological therapy, and enzyme replacement. Emerging therapies such as gene therapy offer promising future prospects. Despite these advances, challenges in diagnosis, treatment accessibility, and long-term care persist, highlighting the need for continued research and improved healthcare strategies.