**Background:** Inherited metabolic disorders (IMDs) are rare genetic conditions often managed with specialized diet therapies that restrict or exclude certain macronutrients. While these diets are essential for controlling disease manifestations, they can inadvertently lead to deficiencies in micronutrients (vitamins and trace elements). This review aims to identify the most commonly reported micronutrient deficits in different IMDs, summarize available evidence on management, and highlight critical points in supplementation. The authors performed a literature search in PubMed/Medline and Embase for publications in English up to September 1, 2023, focusing on nutrient intake and deficiencies in patients undergoing diet therapy for IMDs.
**Methods:** The review is a narrative synthesis of existing literature, not a systematic review or meta-analysis. The authors searched for studies investigating nutritional aspects of patients with IMDs on dietotherapy, specifically nutrient intake and deficiencies related to vitamins and oligoelements. They included accessible publications in English published before September 1, 2023. The review covers amino acid disorders (phenylketonuria, maple syrup urine disease, propionic and methylmalonic acidemia, urea cycle disorders), fatty acid oxidation disorders (very-long-chain acyl-CoA dehydrogenase deficiency), carbohydrate disorders (galactosemias, hereditary fructosemia, glycogen storage disorders), and IMDs treated with ketogenic diet (GLUT1 deficiency, pyruvate dehydrogenase deficiency).
**Key Results:** The review reports that in phenylketonuria (PKU), iron, zinc, selenium, and vitamin B12 deficiencies are particularly frequent. Studies by Evans et al. and de Almeida et al. showed that more than 90% of treated patients had adequate ferritin levels, while Crujeras et al. reported lower-than-normal selenium levels in 95% of PKU patients. Kose et al. found a high prevalence of vitamin D deficiency (53.57%) in PKU patients. In organic acidemias (MSUD, MMA, PA), limited data exist, but one case series demonstrated intakes below recommended levels for most vitamins and minerals, with particular risk for calcium and vitamin D deficiency. Selenium and thiamine deficiencies have also been described. In urea cycle disorders, food intake evaluation revealed intakes below recommended values for calcium, magnesium, potassium, zinc, copper, manganese, iodine, and vitamin B12. In hereditary fructosemia, 96.7% of participants had vitamin C intake below recommendations and 90% had folate intake below recommendations. In glycogen storage disorder type I, 61.5% of patients tested had insufficient 25-OH-vitamin D levels (<30 ng/mL) despite reported good compliance with supplements. For ketogenic diet, a study found that only 3 of 28 micronutrients met American dietary reference intakes, with zinc and magnesium particularly compromised. The review notes that clinical symptoms of deficiency are rarely reported, except for vitamin B12 deficiency in PKU patients who reduce or stop supplements while following a vegan-like diet.
**Clinical Implications:** The review emphasizes that micronutrient supplementation is critical for all IMD patients on diet therapy, but current evidence is suboptimal and practices are heterogeneous. In PKU, more than 70% of patients would have inadequate intakes of 11 micronutrients without supplementation of medical foods, while over 90% would obtain adequate vitamin A from natural foods alone. The authors highlight that not all formulas are equally supplemented, and some lack micronutrients entirely, increasing deficiency risk with vegan-like diets. For fatty acid oxidation disorders, no specific supplementation recommendations exist. For carbohydrate disorders, consensus supports regular supplementation, but different approaches are used. The ketogenic diet requires careful monitoring to avoid both deficits and overload of fat-soluble vitamins. The review calls for more research on the real prevalence of oligoelement abnormalities, the most effective supplementation approaches, and the role of altered microbiome in micronutrient status. It concludes that specific formulations for IMDs are needed, along with high-quality studies to optimize and harmonize supplementation approaches.