Inborn Errors of Cell Trafficking and Complex Lipids: A Further Step in Redefining Hereditary Metabolic Disorders

Abstract

This special issue on Trafficking and Complex Lipid Metabolism represents a milestone in the evolution of Inherited Metabolic Disorders (IMD) as defined in the Journal of Inherited Metabolic Disease (JIMD). Following the 2015 redefinition of IMD (Quo Vadis 2015), the last 10 years have brought a revolution in our understanding of IMD, reshaping definitions, concepts, paradigms, and classifications. This issue underscores the ubiquity of biochemical reactions in cellular processes, showing that many human genetic disorders, traditionally not classified as metabolic diseases, are rooted in biochemical disturbances.

Before 2015, JIMD primarily focused on disorders of intermediary metabolism and organelles, diagnosed using metabolic markers. In contrast, this special issue on trafficking disorders addresses disturbances in cellular machinery, diagnosed through molecular techniques that may lack measurable metabolic markers. Within each cell, biochemical functions are compartmentalized into organelles that work interdependently, forming a complex network where metabolites and biochemical pathways interact seamlessly. This “solidarity” between organelles—where changes in one impact others—is regulated by cellular trafficking, which facilitates the exchange of signals and metabolites between compartments.

This evolving understanding challenges metabolic physicians and clinical geneticists, who traditionally categorize genetic patients into inborn errors of metabolism (IEM) and dysmorphology cases. Practically, patients are often referred to separate genetic clinics based on this dual categorization. IEM is typically associated with metabolic markers (e.g., intoxication disorders, mitochondrial disorders), while dysmorphology patients are usually seen as those with congenital anomalies or intellectual disabilities. However, a holistic, integrative approach is increasingly essential to unravel the complexity of IMD mechanisms and phenotypes.

Today, the dual approach of IEM/dysmorphology in clinical genetics feels outdated. As many new monogenic genetic diseases emerge across specialties, notably in neurodevelopmental and neurodegenerative diseases, a broader framework is required. Cellular trafficking disorders exemplify how IMD can integrate diseases across various medical fields, offering a transversal discipline that connects cell trafficking mechanisms with biochemistry and symptomology. This integrative metabolic insight lays the groundwork for common treatments across different trafficking genes, similar to how mitochondrial disorders are managed with vitamins, cofactors, and specific diets, irrespective of the specific gene involved.

About 400 disorders, many of which present with multisystem phenotypes, are described in this special issue. Up to 85% of IMDs impact neurodevelopment or are responsible for neurodegeneration. Acute, chronic, or progressive neurological syndromes, psychiatric presentations, developmental delay, intellectual disability, neurodevelopmental disturbances, and neurodegeneration at any age deserve special attention.

The authors declare no conflicts of interest.