Clinical and biochemical footprints of inherited cofactor disorders.

Inherited metabolic disorders (IMDs) affecting cofactor biosynthesis, recycling, transport, or utilization cause characteristic combinations of biochemical abnormalities and multi-system clinical signs. Here, we describe footprints of 29 ICIMD-curated cofactor disorders: tetrahydrobiopterin (BH4; n = 6), molybdenum cofactor (MoCo; n = 5), vitamin B6 (pyridoxal-5'-phosphate; n = 6), niacin/nicotinamide adenine dinucleotide (NAD; n = 7), and pantothenate/coenzyme A (n = 5), by integrating disorder-specific biomarker panels with a structured symptom matrix. Across domains, heat map-based profiling highlights recurrent neurologic hot spots (seizures, movement disorders, neurodevelopmental impairment) while also revealing pathway-anchored signatures that can rapidly narrow the differential diagnosis, such as hyperphenylalaninemia with monoamine deficiency in several BH4 disorders, sulfite intoxication markers in classic MoCo deficiency, a B6-responsive neonatal epileptic encephalopathy pattern, an ocular-predominant footprint in nicotinamide mononucleotide adenylyltransferase 1 NMNAT1-related NAD disease, and cardio-metabolic failure in multiple CoA biosynthesis defects. We summarize pathomechanisms and current treatment options, emphasizing time-critical, treatable conditions (e.g., cyclic pyranopterin monophosphate (cPMP; fosdenopterin) replacement in MoCo-A; neurotransmitter and vitamin replacement strategies). This harmonized framework is intended to support early, pathway-informed testing and management in suspected cofactor-related IMDs. By aligning clinical-system patterns with biochemical 'anchors', this framework complements genomic diagnostics, guides surveillance, and prioritizes interventions in neonatal encephalopathy, childhood movement disorders, and recurrent acute metabolic crises. While newborn screening is well established for disorders of BH4 metabolism, screening for several other disorders, such as PDE-ALDH7A1 deficiency, is still in the pilot phase and available only in a few specialized centers. In contrast, genomic screening, with all its benefits and pitfalls, is emerging as a complement to classic newborn screening.