Micronutrient Deficiency in Inherited Metabolic Disorders Requiring Diet Regimen: A Brief Critical Review

Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits.


Introduction
Trace elements and vitamins, called together "micronutrients", are essential components of human nutrition in health and disease [1,2].They play a variety of biochemical roles as cofactors and coenzymes in metabolism, as antioxidants, and in genetic regulation and protein folding, being crucial for maintaining tissue function and metabolism [3].
For the general population, international recommendations for micronutrient intake are available in the form of Recommended Dietary Allowances (RDA) or Dietary Reference Intakes (DRI), but the impact of micronutrient deficiencies in disease settings remains limited [4].
The roles of water-soluble vitamins in cellular metabolism have been clarified for many years.In fact, vitamin-derived cofactors intervene in a series of biochemical reactions and, consistently, their genetically determined deficiencies, at various levels, are linked to clinical pictures of variable severity, sometimes with serious and fatal results [5][6][7][8][9][10].
It should also be mentioned that inherited metabolic disorders (IMDs), when treated with a specific diet, may result in secondary vitamin deficiencies.The major therapy strategy for a significant number of IMDs essentially involves a specialized diet treatment, requiring the reduction or exclusion of certain macronutrients, focused on the enzyme deficiency causing the disorder [11,12].
On the one hand, this regimen makes it possible to reduce the effects of the enzymatic defect, significantly improving the clinical outcome of the disorder; on the other hand, a selective diet, especially at the growing age, could be associated with a reduced intake of micronutrients.To escape this problem, over the years, guidelines for the management of different IMDs have reported recommendations on the integration of vitamins and trace elements, aimed at reducing this nutritional risk [13][14][15][16].
Nevertheless, there are currently few data on the most common micronutrient abnormalities in different IMDs and there is still great heterogeneity in clinical practice regarding micronutrient supplementation.

Aim of the Study and Strategy Search
In this review, we aim to: (1) define which are the most commonly reported micronutrient deficits to which the different types of diet therapy predispose; (2) report the available evidence regarding the management of their deficiency; and (3) highlight the main critical points related to each nutritional supplementation.
A search was performed in PubMed/Medline and Embase to identify studies investigating the nutritional aspects of patients with IMDs undergoing dietotherapy.In particular, we focused on nutrient intake and nutritional deficiency related to vitamins and oligoelements.We searched for publications in English only.Every accessible publication published before 1 September 2023 was studied for this review.

Micronutrients, Their Nutritional Sources, and Their Function
The thirteen vitamins currently reported in human nutrition are divided into two categories, based on their relative solubility: water-soluble vitamins and fat-soluble vitamins [3].
The usefulness of the above classification mainly concerns the absorption and metabolic fate of vitamins taken with the diet [17,18].Table 1 shows the most important vitamins and minerals for human health, along with their main characteristics, nutritional sources, biological biomarkers, and their deficiencies' main clinical manifestations.RDA/DRI/AI (Recommended dietary allowances/Dietary Reference Intakes/Adequate Intakes); DFE (dietary folate equivalent) is defined as 1 mg DFE = 1 mg food folate = 0.6 mg folic acid from fortified food or a supplement consumed with food = 0.5 mg of a folic acid supplement taken on an empty stomach or provided via IV.RAE (retinol activity equivalents) 1 mcg/RAE = 1 mcg retinol, 2 mcg supplemental beta-carotene, 12 mcg dietary beta-carotene, or 24 mcg dietary alpha-carotene or beta-cryptoxanthin.NE (niacin equivalents) = 1 milligram of niacin or 60 mg of tryptophan.IM (intramuscular) SC (subcutaneous).IU VIT D (international unit of vit D) = 1 IU of vitamin D is equivalent to 0.025 micrograms.
Many vitamins (especially those of group B) regulate hundreds of metabolic reactions by acting as coenzymes, contributing to energy-producing reactions and facilitating metabolic and physiological processes throughout the body [9,[36][37][38][39].
The daily requirement of vitamins varies from species to species and from individual to individual, based on numerous factors (age, state of health, diet, sporting activity).
Due to their short stay in the body, a regular intake of water-soluble vitamins in the diet is necessary to avoid deficiencies.They are, for the vast majority, not accumulated in the body and are easily excreted in the urine.Humans have evolutionarily lost the ability to synthesize vitamins and have to obtain them from foods of animal and vegetal origin (except for vitamin B12) and to a lesser extent from the gut microbiota's production [9,40,41].
Fat-soluble vitamins, thanks to their affinity for fats, are deposited in the liver and in the adipose tissue; as a result, the body can build up significant reserves of fat-soluble vitamins [42].
Trace elements are micronutrients that are needed in very small amounts through the diet but are critical for the prevention of acute and chronic diseases [43].There are currently nine trace minerals for which humans are considered to have a nutritional requirement for, classified by the World Health Organization (WHO) [44]: iron, zinc, copper, selenium, iodine, manganese, molybdenum, chromium, and cobalt, with the first four being the most common mineral deficiencies.
Furthermore, because each essential trace element is linked to multiple enzymes, a deficiency of one of these elements can contribute to different metabolic abnormalities and clinical conditions.In particular, they are cofactors of a number of enzymes involved in the antioxidant system and in the body's homeostatic mechanisms, especially inflammation and oxidative stress, which are vital for human health [45][46][47].

IMDs Requiring Special Diets
Nutritional therapy in IMDs is based on the basic principle of reducing the concentrations of toxic substrates by reducing the assumption of nutrients that produce them or by increasing their excretion while providing deficient products through supplementation.This approach is necessary for the normal growth and development of patients affected by several IMDs [48].Special medical foods that include macro-and micronutrients but omit the offending substrate are available to help prevent such deficiencies.In addition to medical foods, other specialized nutritional products, including high doses of vitamins and amino acids, may be used in the management of IMDs.
Table 2 reports the main IMDs requiring a special diet, distinguishing them by type of disorder and the principal category of limited food.Phenylketonuria (PKU) is a rare inherited metabolic disorder characterized by the partial or total inability to convert the essential amino acid Phenylalanine (Phe) into Tyrosine (Tyr) due to biallelic pathogenetic mutations of the liver enzyme phenylalanine hydroxylase (PAH).If PKU is detected at birth and treated with a Phe-restricted diet, the neurological sequaele secondary to Phe accumulation can be controlled [13].
The Phe-restricted diet requires strict monitoring of patients' nutritional status according to the PKU severity and type of diet [56,57].The majority of patients, with the exception of those with mild hyperphenylalaninemia, consume little animal protein and mostly low natural protein diets.Therefore, supplemented Phe-free L-amino acids or formulations with no or little Phe content, such as Glycomacropeptides (GMP), are the main sources of micronutrients [58].The necessary daily intake of micronutrients can be obtained by regularly assuming these formulations [13] (Figure 1).Phenylketonuria (PKU) is a rare inherited metabolic disorder characterized by the partial or total inability to convert the essential amino acid Phenylalanine (Phe) into Tyrosine (Tyr) due to biallelic pathogenetic mutations of the liver enzyme phenylalanine hydroxylase (PAH).If PKU is detected at birth and treated with a Phe-restricted diet, the neurological sequaele secondary to Phe accumulation can be controlled [13].
The Phe-restricted diet requires strict monitoring of patients' nutritional status according to the PKU severity and type of diet [56,57].The majority of patients, with the exception of those with mild hyperphenylalaninemia, consume little animal protein and mostly low natural protein diets.Therefore, supplemented Phe-free L-amino acids or formulations with no or little Phe content, such as Glycomacropeptides (GMP), are the main sources of micronutrients [58].The necessary daily intake of micronutrients can be obtained by regularly assuming these formulations [13] (Figure 1).However, if the intake of Phe-free L-amino acid supplements is suboptimal, which is common in adolescence [58,59], the risk of micronutrient deficiency is higher, with iron, zinc, selenium, and vitamin B12 deficiency being particularly frequent in the PKU diet [13,60] (Table 3).However, if the intake of Phe-free L-amino acid supplements is suboptimal, which is common in adolescence [58,59], the risk of micronutrient deficiency is higher, with iron, zinc, selenium, and vitamin B12 deficiency being particularly frequent in the PKU diet [13,60] (Table 3).However, clinical symptoms of micronutrient deficiency are rarely reported, being mainly described for vitamin B12 deficiency, particularly after reducing or stopping micronutrient supplements or Phe-free L-amino acid supplements while following a vegan-like diet [61,62].
Markers of micronutrient status in PKU patients, such as ferritin, hemoglobin, mean corpuscular volume (MCV) for iron, methylmalonic acid, and total serum homocysteine for vitamin B12, are useful to detect iron and vitamin B12 deficiency as their plasma concentrations are not fully related to their nutritional status [63,64] (Table 1).
Studies by Evans et al. [65] and de Almeida et al. [66] showed that more than 90% of treated patients had adequate and normal ferritin levels.Crujeras et al. reported lower-than-normal selenium levels in 95% of PKU patients [60].
A high prevalence of vitamin D deficiency has been reported in PKU patients by Kose et al. (53.57%) [67] and confirmed by other authors [68,69].The same authors report adequate levels of vitamin A and zinc, with excess of folic acid, copper, and vitamin E (Table 3).Other studies have confirmed high folate levels in patients associated with the However, clinical symptoms of micronutrient deficiency are rarely reported, being mainly described for vitamin B12 deficiency, particularly after reducing or stopping micronutrient supplements or Phe-free L-amino acid supplements while following a veganlike diet [61,62].
Markers of micronutrient status in PKU patients, such as ferritin, hemoglobin, mean corpuscular volume (MCV) for iron, methylmalonic acid, and total serum homocysteine for vitamin B12, are useful to detect iron and vitamin B12 deficiency as their plasma concentrations are not fully related to their nutritional status [63,64] (Table 1).
Studies by Evans et al. [65] and de Almeida et al. [66] showed that more than 90% of treated patients had adequate and normal ferritin levels.Crujeras et al. reported lowerthan-normal selenium levels in 95% of PKU patients [60].
A high prevalence of vitamin D deficiency has been reported in PKU patients by Kose et al. (53.57%) [67] and confirmed by other authors [68,69].The same authors report adequate levels of vitamin A and zinc, with excess of folic acid, copper, and vitamin E (Table 3).Other studies have confirmed high folate levels in patients associated with the high folate content of Phe-free L-amino acid supplements [70,71].The long-term consequences of folate overload in PKU patients have not been assessed.
A study on the nutritional characteristics of adult PKU patients, according to their dietary adherence, reported that all patients in the adherent group met the Lower Reference Nutrient Intakes for the vast majority of micronutrients assessed.Nonadherent patients had significantly lower intakes of thiamine, riboflavin, niacin, vitamin B6, and phosphorus [72].
The literature review revealed poor data related to riboflavin and pyridoxine status in subjects undergoing a protein-restricted diet.Some old case series, by measuring the plasma pyridoxal 5 -phosphate (PLP), report on differences in pyridoxine metabolism in PKU children compared to healthy subjects, raising the need for personalized supplementation in this group of patients [73].Children with PKU also showed an increase in the FAD effect and a concurrent decrease in glutathione reductase activity upon stopping group B vitamin therapy [74].These findings are indicative of an inadequate riboflavin status.Since functional and direct biomarkers can be used in clinical practice to evaluate the levels of these two vitamins [75,76], it is necessary to reevaluate the patients' pyridoxine and riboflavin status.
The most recent guidelines for the above disorders emphasize the need for regular monitoring of micronutrient statuses to ensure adequate micronutrient intake [49].As a matter of fact, most amino acid-free medical foods are supplemented with nutrients and micronutrients that may be deficient in a low-protein or low-precursor amino acid diet regimen.These formulas are usually supplemented with essential fatty acids, docosahexaenoic acid (DHA), vitamin D, vitamin A, calcium, iron, zinc, and selenium.Compliance with a full medical food prescription is important to meet these nutrient requirements [78].
Limited data exist for single or combined micronutrient deficiencies in actual clinical settings, with only one case series demonstrating intakes below the recommended levels for the great majority of vitamins and minerals [79].In particular, the metabolic diet used in MSUD, MMA, and PA may be low in calcium and vitamin D levels, both of which are essential for bone health (Table 3).
Nutritional deficiencies have also been described for selenium and thiamine [80], secondary to the low animal protein intake.In addition, high-dose vitamin E and Coenzyme Q10 [49] are administered in order to prevent or treat optic neuropathy, which may alter visual acuity in MMA and PA patients [81,82].
In general, individuals who are compliant with medical foods supplemented with the recommended vitamins and minerals may not need additional supplementation (Figure 1).In contrast, those individuals who tolerate more intact protein and therefore need less medical food may need additional supplementation [83].

Urea Cycle Disorders
Urea cycle disorders (UCDs) are a group of IMDs caused by a loss of function in one of the enzymes responsible for ureagenesis [84].Long-term management of UCDs aims to prevent hyperammonemia and ensure normal development by the use of vitamin and mineral supplements, low-protein diets, essential amino acid supplements, and ammonia scavengers [15].
Supplementation is necessary for UCD patients on low-protein diets because of the risk of vitamin and mineral deficiencies, particularly iron, zinc, copper, calcium, and cobalamin [85,86].
In early-diagnosed patients, vitamin and mineral supplementations are generally started at weaning, in concomitance with milk intake reduction.Late-onset patients who are on a self-selected low-protein diet usually need vitamin and mineral supplements and regular dietary assessments [15].
Micronutrient plasma levels were investigated in very few studies, reporting conflicting data.The food intake evaluation has revealed an intake below the recommended values of at least one of the following micronutrients: calcium, magnesium, potassium, zinc, copper, manganese, iodine, and vitamin B12 (Table 3).In all patients, plasma essential amino acid (EAA) levels were, however, within normal limits [87].
In UCD patients, since EAA supplements do not contain enough micronutrients, these should be provided separately to prevent their deficiency [88] (Figure 1).

Disorders of Fatty Acid Oxidation
Fatty acid oxidation disorders (FAOD) are a group of IMDs characterized by the defective transport or β-oxidation of fatty acids and are particularly involved in producing energy during fasting and stress episodes [89,90].
Patients affected by very-long-chain Acyl CoA dehydrogenase deficiency (VLCADD), one of the most severe forms of FAOD, undergo a dietary long-chain fatty acid restriction.Since they are susceptible to deficits in essential fatty acids and fat-soluble micronutrients [91], they should be evaluated for both.These patients may require supplementation with DHA or oils rich in essential fatty acids, such as linoleic acid and α-linoleic acid, to meet their nutritional needs.However, there are no reports regarding vitamin supplementation in subjects with long-chain fatty acid restriction.Although lower than normal levels of fat-soluble vitamins have been reported, recommendations for their supplementation cannot be made at this time [92].

Galactosemias
Galactosemias are a group of four hereditary disorders of galactose metabolism [93].The most common form is Galactosemia type 1 due to deficiency of Galactose 1-phosphate urydyltransferase (GALT), which catalyzes one of the four reactions in the Leloir pathway, which converts galactose into glucose [94].Diet is the cornerstone of the treatment of galactosemias, aimed at minimizing galactose intake [95,96].
An annual dietary assessment of calcium and vitamin D intake with measurement of plasma total 25-OH-vitamin D levels is recommended.Both calcium and vitamin D should be supplemented as necessary, following the age-specific recommendations for the general population.
Supplementation with vitamin K might be beneficial when combined with an adequate intake of calcium and vitamin D, but currently there is not enough evidence to recommend the routine use of vitamin K [50].

Hereditary Fructosemia
Dietary restriction of fructose, sucrose, sucralose, and sorbitol is the cornerstone of treatment for hereditary fructosemia (HF), an IMD caused by a deficiency in aldolase B (fructose-1,6-bisphosphate aldolase), which is responsible for the cleavage of fructose-1phosphate [97].Since fruit and vegetable intake is a dietary requirement, micronutrient deficiencies, particularly of water-soluble vitamins, are likely.However, there is great heterogeneity in vitamin supplementation practices among specialized centers.
In a recent report [51], most of the HF participants presented vitamin C (96.7%) and folate (90%) dietary intake below the recommended population reference.Up to 69% of the participants received vitamin C supplementation and 50% received folic acid supplementation.The amount of vitamin C supplementation correlated positively with correspondent plasma levels.Furthermore, non-supplemented HF patients were vitamin C deficient, with a statistically significant difference with respect to supplemented HF patients and healthy controls.Ensuring adequate vitamin supplementation in a disease requiring a reduction in fruit and vegetable intake is imperative [98]; supplementation with "sugar-free" multivitamin formulations is recommended.

Glycogen Storage Disorders (GSDs)
Liver glycogenosis: GSDI and III, GSDVI, and liver GSDIXs are a group of rare conditions due to a genetic enzymatic defect in the metabolism of glycogen [99].They have in common hepatomegaly and hypoglycemia and undergo an overlapping dietetic approach.Although there is no consensus regarding the restriction of sugars in the diet, sucrose (fructose and glucose) and lactose (galactose and glucose) are often limited or avoided [52].The most common among GSDs is GSDI, in which, as a result of the deficiency of glucose-6phosphatase, fructose and galactose are not metabolized to glucose-6-phosphate [100,101].
Restricting fruit, juice, and dairy foods impacts two entire food groups and renders the diet inadequate.Careful assessment and supplementation of micronutrients are therefore required to avoid nutrient deficiencies.In a recent study, 61.5% of patients with GSDI who were tested for 25-OH-vitamin D levels were found to have insufficient levels (<30 ng/mL), despite their reported good compliance with prescribed supplements [53].
The restricted nature of the diet, aimed at maintaining normoglycemia, may also result in poor intake of iron, vitamin B12, and folic acid.In liver GSDs and in particular in GSDI, a complete multivitamin with mineral supplementation is essential.Without appropriate supplements, these patients are at risk of a variety of nutritional deficiencies.

IMD Requiring Ketogenic Diet
A ketogenic diet (KD) is characterized by a diet with a low carbohydrate, high fat, and a defined or variable protein content [54].There are two main types of KD: the classical diet, which uses long-chain triglycerides as its primary fat source, and the medium-chain triglyceride (MCT) diet, which allows more carbohydrate and protein because of the increased ketogenic potential of MCT [102].
KD represents the recommended treatment for pyruvate dehydrogenase complex (PDHc) deficiency and glucose transporter type 1 deficiency syndrome (GLUT1-DS) as it directly targets the underlying metabolic condition.
In other IMDs, mainly of intermediary metabolism, such as glycogen storage diseases and disorders of mitochondrial energy supply, supplementation with ketone bodies may ameliorate clinical symptoms and laboratory parameters [76,103,104].
Side effects have been classically reported, including specific micronutrient deficiencies in vitamin D and calcium, vitamin C, thiamine, and selenium [105][106][107].The KD should be supplemented with vitamins, minerals, and trace elements, with plasma levels of micronutrients regularly measured [54].At the moment, there are no specific supplements designed for the KD, and concerns have been raised about the most commonly used micronutrient supplement, containing high amounts of the fat-soluble vitamins A and E [55], which are naturally high in KDs as a result of its high fat content.
A low intake of oligoelements such as zinc, selenium, and magnesium has also been reported.In a study on children on a classical KD, only 3 of the 28 micronutrients met the American dietary reference intakes [108], with zinc and magnesium particularly compromised [109].However, Liu et al. [110] reported low levels of phosphorus and folate in otherwise normal micronutrient statuses.Close monitoring of micronutrient statuses in patients undergoing KD is therefore mandatory.

Discussion
An adequate vitamin and trace element homeostasis represents one of the cornerstones of the management of all IMDs, especially those undergoing diet therapy, as most of them can potentially expose patients to different forms of oligoelement abnormalities; therefore, close monitoring is always necessary.
However, the evidence of vitamin and mineral status, the type of supplementation to be adopted, and the clinical benefit of this supplementation is sometimes not univocal and derives mostly from case studies.
The beneficial effect of supplementation with high doses of vitamins in the treatment of IMD goes beyond the scope of this short review and is exhaustively reported elsewhere [111].
In amino acid metabolism disorders, particularly in PKU, due to the limited intake of natural protein, micronutrients are supplemented through protein substitutes to prevent overt nutritional deficiencies.However, despite apparent adequate supplementation, maintaining sufficient vitamin and mineral levels continues to be a challenge [48].
Many substitutes for PKU diet management contain vitamins and minerals according to guidelines for the required amount of micronutrients by age.Nevertheless, these recommendations do not take into account the reduced bioavailability or lack of nutrient interactions resulting from excluding entire food groups from the diet [48,112].For this reason, serum levels of some micronutrients remain low despite adequate intake, indicating limited bioavailability [113].
Furthermore, patients who discontinue or reduce the intake of their protein substitute without a proportional increase in their natural protein intake are even more at risk for overt micronutrient deficiencies, particularly during the growing age [56].
Without micronutrient supplementation of medical foods, >70% of patients with PKU would have inadequate intakes of 11 micronutrients (biotin, choline, pantothenate, vitamins D and E, potassium, calcium, iodine, magnesium, selenium, and zinc).On the other hand, more than 90% of subjects would obtain adequate intake of vitamin A from natural foods alone due to high intakes of provitamin A carotenoids from green leafy vegetables, squashes, carrots, and tomatoes and do not require supplementation [114].
However, not all formulas are equally supplemented and some of them, due to the target age and type of diet, are not added with micronutrients.This, if combined with a strictly vegan-like diet, may increase the risk of deficiency and requires ad hoc supplementation.
Nutrition management in FAOD is characterized by a low-fat and low-protein diet.This dietetic approach is potentially at risk of lowering their fat-soluble vitamin intake, having effects on immune regulation, vision, and bone health [115].Nevertheless, no specific recommendations are so far available on micronutrient supplementation in this group of disorders and clinical practices are highly variable.
More of a consensus has been reached on the opportunity for supplementation in carbohydrate metabolism disorders.Galactosemia, hereditary fructosemia, and GSDI are treated by excluding entire groups of nutrients, thus necessitating regular micronutrient supplementation.Different approaches are nevertheless used in clinical practice [52,53,98], with formulations of which the sugar contents are sometimes unreliably reported or difficult to ascertain.
The ketogenic diet, a therapeutic approach for an increasing number of IMDs, has been shown to positively impact brain function and ketotherapeutics have been used in several conditions.Due to the restricted type of allowed nutrients, this approach may predispose one to both oligoelement deficits and their overload.
A further potential benefit of adding supplementation of vitamins B12 and B6, and/or folic acid has been postulated due to their ability to reduce homocysteine, an independent risk factor of cognitive decline [116] which is common in the vast majority of IMDs.This dietetic approach would therefore benefit specific micronutrient formulations, which should derive from individual supplementation protocols.
As diet therapy is mandatory in the treatment of many IMDs, there have been concerns about nutritional deficiencies secondary to this therapeutic approach for many years, particularly during the growing age when they can predispose one to impairment of physical development, reduced cognitive function, and lower immunity [117].For this reason, micronutrient supplementation for infants and children, mainly conveyed by amino acid formulas, is targeted and adapted to different ages by means of several special formulations available on the market [118].
The dietetic management of pregnant women affected by IMDs also deserves special mention.Pregnancy, once contraindicated for many IMDs, is in fact increasingly reported and represents a further challenge in the management of these disorders [119].Metabolic adaptations to the demands of pregnancy determine higher requirements for micronutrients and changes in the metabolisms of macronutrients.A tailored management of this period, also through a targeted composition of the formulations used, may contribute to improving both maternal and fetus outcomes [120].
The use of medical foods, modified low-protein foods, amino acid supplements, and high doses of vitamins for individuals with IMDs is not an option but rather a medical necessity.
However, the strict requirements of different diet regimens deserve specific formulations that should be different from those used in the general population.In this context, a closer engagement of decision makers and stakeholders in health policy may represent an important methodology for improving clinical-based decisions to develop new technologies and identify future directions [121].
Overall, there is a suboptimal quality and level of evidence regarding the impact of nutritional supplements on the dietary management of IMDs.
More research is needed to understand the real prevalence of oligoelement abnormalities and the most effective supplementation approach in order to prevent the development of nutritional deficiencies.Moreover, other factors that contribute to vitamin and mineral abnormalities, like an altered microbiome, have gained attention in recent years [122][123][124].
Research showing specific alterations in IMDs receiving diet therapy should pave the way to the possibility of microbiome-based interventions in IMDs to improve micronutrient status.

Conclusions
Despite improvements in the nutritional management of patients on diet therapy for different types of IMDs, our critical overview indicates the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of studies with high-quality evidence, particularly for some under-investigated deficits, with the final purpose of optimizing supplementation and harmonizing approaches.Funding: This work was supported by the University of Bari "A.Moro" to (M.B.) under the grant "Progetti Competitivi" (Effetto di mutazioni di FLAD1 e di alterazioni dell'omeostasi delle flavine sullo stato redox e sulla biogenesi mitocondriale: uno studio integrato su fibroblasti umani).

Data Availability Statement:
The data presented in Table 1

Figure 1 .
Figure 1.Main recommendations regarding micronutrient supplementation in different IMDs.

Figure 1 .
Figure 1.Main recommendations regarding micronutrient supplementation in different IMDs.

Author
Contributions: Conceptualization, original draft preparation, writing and review of the manuscript, A.T.; resources and data curation, R.C., G.P., D.D.G. and S.S.; review and editing, M.T. and P.L.; final review and supervision, M.B.; funding acquisition, M.T., P.L. and M.B.All authors have read and agreed to the published version of the manuscript.

Table 2 .
IMDs requiring special diet and associated micronutrient deficiency.

Table 3 .
Panoptic vision of the reported micronutrient abnormalities in IMDs.

Table 3 .
Panoptic vision of the reported micronutrient abnormalities in IMDs.