General principles of nutritional management<\/p>\n
Early diagnosis and management of IEM are essential. Newborn screening programs for IEM enable early detection, before the development of symptoms, and can improve quality of life and life expectancy is individuals with IEM as well as prevent death, disability or intellectual disability [31<\/a>].<\/p>\n A collaborative approach involving healthcare professionals and caregivers is imperative to successful nutritional management of IEM. Multidisciplinary care of IEM patients should involve a clinician and a dietitian in a cooperative partnership with nurses, physiotherapists, social workers, and psychologists [32<\/a>, 33<\/a>]. Additionally, care should be centred around the patient with active and on-going communication between the patient, their family, and the multidisciplinary healthcare team [32<\/a>].<\/p>\n Caregivers should be provided with a detailed treatment plan as well as emergency and sick day regimens. The treatment plan should include details of specific medical formulas, how to prepare and store them, breastfeeding recommendations, supplements, foods which can be consumed, foods to be avoided as well as monitoring [34<\/a>]. Since children with IEM are a greater risk of hypoglycaemia or metabolic decompensation during sick days, parents should be instructed on the necessary steps to take and written instructions regarding an emergency regimen including recommended fluid, glucose polymers recipe, contact numbers and recipes [35<\/a>].<\/p>\n Regular laboratory monitoring and evaluation of nutritional status are recommended in all patients with IEM. According to the GMDI guidelines frequent monitoring of biochemicals, growth as well as clinical symptoms are essential to ensure levels of toxic metabolites remain low, patient nutritional status and growth are adequate and the patient is showing no signs of metabolic decompensation or other complication [36<\/a>,37<\/a>,38<\/a>,39<\/a>]. Biochemicals which require monitoring for each disease are detailed in the Appendix 1 and references ranges in children are shown in Appendix 2 of the supplementary file.<\/p>\n PA\/MMANutritional management in below 6 months of age<\/p>\n The GMDI recommends aggressive treatment and nutrition management at initial neonatal presentation [37<\/a>]. Acute management includes intravenous administration of high calorie and high carbohydrate fluids (additional intake of 100\u2013120\u00a0kcal\/kg\/day; 10% dextrose) and lipids to prevent catabolism as well as insulin to correct hypoglycaemia and hyperglycaemia [40<\/a>]. Nutrition management in infants below 6 months of age also involves the restriction of dietary propiogenic amino acids (isoleucine, valine, threonine, and methionine) and odd chain fatty acids by reducing the intake of intact protein [37<\/a>]. Intact protein at 60\u2013100% of the normal daily recommended amount is recommended [41<\/a>], since over-restriction of protein is thought to affect patient growth [42<\/a>]. For patients who are not able to achieve their daily recommended intake of intact protein, medical nutritional propiogenic amino acid-free-based formula can be used [41<\/a>].<\/p>\n In infants below 6 months, breastfeeding can be used to provide intact protein, however, there is the need for additional monitoring. The GMDI reached consensus on use of breast milk in PA patients [37<\/a>]. Experience of breastfeeding in infants with MMA has also been described, with breastfeeding being well tolerated in individuals with MMA for up to 18 months [43<\/a>]. For stable individuals below 6 months of age recommended protein and energy requirements are as shown in Table\u00a03<\/a>, according to the GMDI [26<\/a>]. These values represent 60\u2013100% intact protein, 100\u2013120% total protein and 80\u2013120% estimated energy requirements from the Institute of Medicine\u2019s Dietary Reference Intakes [44<\/a>] and aim to achieve adequate protein and energy intake to ensure growth and anabolism whilst avoiding high intake of propiogenic amino acids and accumulation of toxic compounds [26<\/a>].<\/p>\n Regular patient follow-up is recommended for infants with PA and MMA, including the monitoring of biochemicals and nutritional status [37<\/a>]. The GMDI recommends weekly to monthly follow-up in children under one year of age to assess diet and nutrient intake, weight, length, head circumference, plasma amino acids, and pre-albumin [26<\/a>]. The trans-European guidelines recommend follow-up is determined on an individual basis, taking into account patient factors and treatments [45<\/a>].<\/p>\n Weaning practice<\/p>\n Weaning, with very-low protein vegetables and fruits, is recommended from 6 months of age if it is safe and possible to do so and taking into consideration weight and tolerance status of the patient [45<\/a>]. Very-low protein vegetables and fruits include apples, grapes, peaches, pears, lettuce, mushroom, pepper, and asparagus [46<\/a>]. Tube feeding maybe recommended in severe cases as well as speech and language therapy which can help to improve potential feeding problems [45<\/a>]. For stable individuals aged 7 months to less than 12 months of age, recommended protein and energy requirements are as shown in Table\u00a03<\/a>, as per the GMDI [26<\/a>].<\/p>\n Nutritional management in above one year of age<\/p>\n For stable individuals aged 1 to 8 years recommended protein and energy requirements are shown in Table\u00a03<\/a>, as per the GMDI [26<\/a>]. These values represent 60\u2013100% intact protein, 100\u2013120% total protein and 80\u2013120% estimated energy requirements from the Institute of Medicine\u2019s Dietary Reference Intakes [44<\/a>] and aim to achieve adequate protein and energy intake to ensure growth and anabolism whilst avoiding high intake of propiogenic amino acids and accumulation of toxic compounds [26<\/a>]. The Saudi experts recommend follow-up every 3 to 4 months for individuals aged\u2009>\u20091 to 7 years to assess diet and nutrient intake, weight, length, head circumference (for patients up to 3 years), plasma amino acids, and pre-albumin [26<\/a>].<\/p>\n Emergency nutrition management<\/p>\n During acute illness, aggressive treatment and nutrition management is required to treat symptoms of metabolic acidosis, hyperammonaemia, and dehydration. Similar to neonatal presentation, intravenous administration of high calorie (additional intake of 100\u2013120\u00a0kcal\/kg\/day), high carbohydrate fluids (10% dextrose) and lipids to prevent catabolism as well as insulin to correct hypoglycaemia and hyperglycaemia [40<\/a>]. The use of high calories provides additional energy to promote anabolism [45<\/a>]. Fluid infusion at 150\u00a0ml\/kg\/24 hours is recommended to treat dehydration and intravenous bicarbonate is given to treat metabolic acidosis [45<\/a>].<\/p>\n During emergency nutritional management, protein intake should be restricted for no longer than 48\u00a0h. Since amino acids are essential building blocks for the body to grow and develop, protein intake should only be stopped temporarily, for a maximum of 24 to 48\u00a0h [47<\/a>]. In cases where protein intake is restricted for too long or inadequate, the patient is at greater risk of nutrient deficiency, impaired growth, impaired immunity as well as bone fractures [48<\/a>]. Enteral feedings should be promptly started following this period of protein restriction and use of parenteral feeding is recommended with severe illness or where enteral feeding is not possible [45<\/a>]. Intact protein should be re-introduced gradually to 50% natural protein then 100% natural protein each day, as tolerated by the patient [37<\/a>].<\/p>\n Ammonia levels should be monitored during emergency nutritional management to determine when it is safe to start feeding. High ammonia levels can lead to nervous system damage and even death if left untreated.<\/p>\n Sick day management<\/p>\n Parents should be provided with a sick day management plan to initiate at home [26<\/a>]. Such a plan might include reduced propiogenic amino acids and additional medical foods in order to provide sufficient calories and avoid complications necessitating hospitalisation [49<\/a>]. Natural protein intake should be restricted to approximately 50% with mild illness, vaccination or minor operation [37<\/a>]. In such situations, a resulting fever, dehydration or reduced energy intake may put the patient at risk of metabolic decompensation [45<\/a>]. Since immune deficits are thought to occur in 30\u201365% of PA and MMA cases, responses to vaccination may be unpredictable and therefore patients require careful monitoring or cautious administration of vaccines [50<\/a>]. If a patient develops gastrointestinal symptoms, intact protein should be stopped for 24\u00a0h, and the patient should go directly to the emergency room for emergency nutrition management [37<\/a>].<\/p>\n GA1Nutritional management in below 6 months of age<\/p>\n Nutritional management of GA1 involves a reduced lysine and tryptophan diet. A low lysine diet reduces the accumulation of toxic metabolites whilst ensuring adequate micronutrient intake [27<\/a>]. In a German study of 33 infants identified via NBS and followed prospectively until 6 years of age, a low lysine diet led to normal weight gain but reduced body length in asymptomatic individuals with GA1 as well as normal biochemical parameters [51<\/a>].<\/p>\n Medical nutritional lysine-free low tryptophan amino acid-based formula can be used to achieve the recommended total protein intake and supplementation with L-carnitine are recommended by the GA1 guideline development group [27<\/a>]. Supplementation with lysine-free tryptophan-reduced amino acids in conjunction with a low-lysine diet and carnitine supplementation has shown beneficial effects on the development and uptake of essential micronutrients in children with asymptomatic GA1 [51<\/a>]. A meta-analysis of outcomes of patients identified by NBS and undergoing maintenance treatment of low-lysine diet, lysine-free, trytophan-reduced, arginine-fortified amino acids and L-carnitine supplementation showed positive effects on neurological outcomes, including mortality, motor development and complex movement disorder [52<\/a>]. A further analysis of a cohort of patients identified by NBS and treated with lysine-free, arginine-enriched formula in addition to L-cartinine showed normal growth, cognitive function and motor development, preventing 90% of striatal injuries in the first two years of life [53<\/a>].<\/p>\n For stable individuals below 6 months of age recommended protein and energy requirements are shown in Table\u00a05<\/a>, as recommended by the GA1 guideline development group [27<\/a>]. Clinical monitoring is recommended every 3 months for those aged less than 1 year and includes weight, length or height and head circumference, lysine, protein, fat and calorie intake, clinical status and laboratory parameters [27<\/a>].<\/p>\n Weaning practice<\/p>\n Weaning can begin at 6 months if considered safe and appropriate and taking into consideration weight and tolerance status of the patient. During weaning, patients face the challenge of different protein sources and variation in lysine content of different foods [54<\/a>]. Therefore, proper dietary management is essential during weaning to prevent complications and support healthy development. Weaning with very-low protein vegetables and fruits is recommended [55<\/a>].<\/p>\n Where lysine content of different foods may be difficult to calculate, total protein intake may be calculated instead. According to the Metabolic Dietitians National Centre for Inherited Metabolic Disorders, dietary management should involve a low protein diet [56<\/a>]. However, in general, dietary treatment of GA1 has moved from a protein restricted diet to a low lysine and tryptophan diet since calculating lysine intake is much more accurate [57<\/a>, 58<\/a>]. The GA1 guideline development group only recommend a low-protein diet from the age of 6 years [27<\/a>].<\/p>\n For stable individuals aged 7 months to less than 12 months of age recommended protein and energy requirements are shown in Table\u00a05<\/a>, as recommended by the GA1 guideline development group [27<\/a>]. In a cohort of infants with GA1 from the USA, who were identified using NBS and for whom dietary management involved a restricted natural protein intake of 1.0\u20131.3\u00a0g\/kg per day, supplemented by a lysine-free, arginine-enriched metabolic formula, reduced striatal degeneration while supporting normal growth and development was observed compared to GA1 patients identified by NBS and treated with natural protein restriction or those with neither NBS nor dietary management [53<\/a>].<\/p>\n Nutritional management in above one year of age<\/p>\n For stable individuals aged 1 to 6 years recommended protein and energy requirements are shown in Table\u00a05<\/a>, as recommended by the GA1 guideline development group [27<\/a>]. According to recent guidelines, cohort studies and dietitian surveys, protein intake should be accurately controlled, typically between 1.0 and 1.3\u00a0g\/kg\/day, to minimize lysine and tryptophan intake while ensuring adequate nutrition [27<\/a>, 53<\/a>, 59<\/a>].<\/p>\n Routine six-monthly follow-ups are critical for assessing the health and nutritional status of children aged 1\u20136 years with GA1. Key areas for review during these follow-up visits include protein and energy intake, vitamins, minerals, and micronutrient intake, anthropometric measurements, plasma amino acids, and pre-albumin. Confirming adherence to dietary restrictions and ensuring sufficient energy intake to prevent catabolism are vital [53<\/a>, 60<\/a>, 61<\/a>]. Evaluating essential nutrient intake is also important to prevent deficiencies, which are common with dietary limitations [27<\/a>, 57<\/a>, 62<\/a>]. Tracking weight, height or length, and head circumference to monitor growth, is essential for ensuring the child is developing appropriately for their age [51<\/a>, 53<\/a>, 61<\/a>].<\/p>\n After the age of 6 years, dietary restrictions can be gradually relaxed, lysine and tryptophan limitations may be eased, and medical nutritional formulas can be phased out [27<\/a>, 53<\/a>, 59<\/a>]. However, continued L-carnitine supplementation remains essential to support metabolic function and prevent the buildup of toxic metabolites. The long-term effects of dietary liberalization and when to relax dietary management in GA1 patients are still under investigation [57<\/a>], but existing evidence supports that it can be done safely with medical oversight [27<\/a>, 53<\/a>, 63<\/a>].<\/p>\n Emergency nutrition management<\/p>\n During acute crises, immediate and intensive treatment is essential to prevent irreversible damage caused by the buildup of toxic metabolites. In a meta-analysis, delays in the initiation of emergency treatment have been shown to increase the risk of acute onset movement disorder in individuals with GA1 who were identified by newborn screening [52<\/a>]. During acute metabolic crisis, restricting natural protein intake by 50% for up to 24\u00a0h, followed by gradual reintroduction over 48 to 72\u00a0h, is recommended by the GA1 guideline development group [63<\/a>]. Additional caloric intake from carbohydrate modulars is also important to prevent catabolism and meet energy demands [58<\/a>,59<\/a>,60<\/a>].<\/p>\n Sick day management<\/p>\n Since fever, illness or surgery are known to precipitate acute crises, appropriate management during these times is essential [27<\/a>]. Experts recommend a formula containing no natural protein for the first 24\u00a0h of admission to hospital. Strauss et al. recommend restricting natural protein to 0.5\u20130.6\u00a0g\/kg\/day, a 50% reduction, as well as use of medications to control fever, antibiotics to control infection and greater frequency of feeding [53<\/a>].<\/p>\n PKUNutritional management in below 6 months of age<\/p>\n Following a diagnosis, a low-phenylalanine diet is critical for PKU management and should begin promptly to prevent cognitive and developmental complications [28<\/a>, 64<\/a>]. Phenylalanine-free or low-phenylalanine medical formulas are prescribed to meet the protein needs of infants with PKU, supporting healthy growth while maintaining safe phenylalanine levels [28<\/a>, 65<\/a>]. Breast milk is low in phenylalanine [66<\/a>], therefore, breastfeeding can be continued safely in infants with PKU, accompanied by a low- phenylalanine formula to ensure adequate phenylalanine and intact protein intake. This approach, endorsed by European guidelines, has demonstrated safety and potential benefits for growth and neurodevelopment [67<\/a>].<\/p>\n For stable individuals below 6 months of age recommended protein, PHE and TYR requirements are shown in Table\u00a07<\/a>, as recommended by the GMDI. The goal of nutritional management in individuals with PKU is to maintain a plasma phenylalanine concentration between 120 and 360 \u00b5mol\/L [68<\/a>]. The Saudi experts recommend regular follow-up, with weekly visits during the first two months and bi-weekly visits thereafter until six months. GMDI guidelines recommend assessment at the clinic weekly to every 3 months including weight, length or height, and head circumference. Additionally, PHE and TYR should be routinely monitored every week to every two weeks [39<\/a>]. At follow-up visits, a review of protein and energy intake, vitamins, minerals, and micronutrient intake and growth measurements is recommended. Regular review of protein and energy intake is important to ensure the infant\u2019s nutritional needs are being met without exceeding safe phenylalanine levels [28<\/a>, 65<\/a>]. Monitoring of vitamins, minerals, and micronutrient intake is essential for the prevent deficiencies and support overall health [65<\/a>]. Tracking weight, length\/height, and head circumference are recommended to monitor the patients\u2019 growth and development [28<\/a>].<\/p>\n Weaning practice<\/p>\n Weaning for infants can be initiated from 6 months, according to the GMDI [28<\/a>], although some centres are reported to wean as early as 17 weeks [66<\/a>]. Weaning typically involves fruit and vegetables containing 75\u00a0mg phenylalanine per 100\u00a0g of food or less as first foods, such as apples, carrots, pears, and sweet potato [66<\/a>]. Nutritional management involves calculating phenylalanine intake relative to protein intake and monitoring fruit and vegetable consumption [28<\/a>, 69<\/a>, 70<\/a>]. Guidelines and recommendations state that fruits and vegetables containing 75\u00a0mg phenylalanine per 100\u00a0g of food or less can be consumed without restriction [71<\/a>, 72<\/a>]. However, recent evidence suggests that fruits and vegetables containing 76\u2013100\u00a0mg of phenylalanine per 100\u00a0g may be included in the PKU diet, depending on disease severity, but their effect on blood phenylalanine levels should be carefully monitored [69<\/a>, 70<\/a>].<\/p>\n For stable infants aged 6\u201312 months, protein needs should be met through a combination of natural protein and protein substitutes to support proper growth and development [28<\/a>, 65<\/a>]. Recommended protein, PHE and TYR requirements are shown in Table\u00a07<\/a>, as per the GMDI. Phenylalanine intake should be meticulously calculated and monitored to maintain target blood phenylalanine levels. Tyrosine supplementation may also be required if concentration in the blood is low, as individuals with PKU lack the ability to convert phenylalanine to tyrosine [28<\/a>].<\/p>\n Nutritional management in above one year of age<\/p>\n For stable individuals aged 1\u20134 years recommended protein, PHE and TYR requirements recommended are shown in Table\u00a07<\/a>, as per the GMDI. Children with PKU often require a higher protein intake than current standard recommendations, with research suggesting an average protein requirement of around 1.85\u00a0g\/kg\/day for children with PKU, exceeding the previously recommended range of 1.14\u20131.33\u00a0g\/kg\/day [73<\/a>]. Since protein intake for PKU management primarily comes from protein substitutes, this should be carefully prescribed to meet each child\u2019s metabolic needs [74<\/a>]. The target blood phenylalanine concentration for children aged 0\u201312 years is 120\u2013360 \u00b5mol\/L, as recommended by European guidelines [75<\/a>]. Additionally, phenylalanine tolerance tends to increase with age, especially during puberty, reaching its peak toward the end of adolescence [69<\/a>]. Tyrosine levels should be regularly monitored to stay within the target range. A retrospective cohort study of PKU patients from Portugal found that the introduction of glycomacropeptide (GMP) as a protein source can elevate blood tyrosine levels, however, further research on this approach is needed [76<\/a>].<\/p>\n European guidelines emphasize that regular nutritional, clinical, and biochemical follow-up is necessary for all PKU patients, irrespective of the treatment approach. The frequency of follow-up should be individualized based on age, treatment adherence, and clinical condition [75<\/a>]. Additionally, regular reassessment of natural protein tolerance is important to avoid unnecessary dietary restriction as well as to ensure optimal intake [77<\/a>].<\/p>\n Sick day management<\/p>\n For sick day management, a decrease in protein intake is recommended by the Saudi experts. Although there is little research into the management of PKU patients during sick days, it is thought that a reduced appetite during illness generally results in lower protein intake and there is no requirement to formally remove natural protein from the patient\u2019s diet [66<\/a>].<\/p>\n MSUDNutritional management in below 6 months of age<\/p>\n For infants with MSUD, the GMDI recommends a BCAA-free protein formula supplemented with isoleucine and valine to prevent deficiencies and manage plasma leucine levels [29<\/a>, 78<\/a>, 79<\/a>]. Additionally, frequent feedings are advised to maintain energy levels and prevent catabolism, which can worsen the condition [78<\/a>, 79<\/a>]. Following a diagnosis, natural protein should be reintroduced slowly to monitor tolerance and prevent metabolic imbalances [80<\/a>, 81<\/a>]. Treatment in infants should be personalized according to the case\u2019s severity and patient-specific needs, involving regular plasma BCAA level monitoring and dietary adjustments as needed [29<\/a>, 81<\/a>, 82<\/a>].<\/p>\n Breastfeeding, which is encouraged by guideline recommendations, provides intact protein and BCAAs, but requires careful monitoring to ensure that BCAA levels remain within safe limits [29<\/a>, 81<\/a>]. For individuals below 6 months of age recommended levels of BCAA, protein, energy, and fluids are shown in Table\u00a09<\/a>, as recommended by the GMDI [29<\/a>]. MSUD management aims is to maintain plasma leucine concentrations between 100 and 200 \u00b5mol\/L for infants and children under 5 years. Adequate energy intake, approximately 125\u00a0kcal\/kg\/day, and sufficient protein intake are crucial to support growth and prevent catabolism [78<\/a>, 81<\/a>, 83<\/a>]. Bimonthly follow-ups are recommended for infants under 6 months of age, with routine checks of the amino acid profile to ensure effective management and dietary adjustments [29<\/a>, 36<\/a>, 81<\/a>, 82<\/a>].<\/p>\n Weaning practice<\/p>\n Saudi experts recommend weaning from 6 months of age with fruits and vegetables or low protein rice or cereal. The National Centre for Inherited Metabolic Disorders in Ireland suggests introducing protein-free foods as first foods between 4 and 6 months of age [34<\/a>]. For individuals aged 7 months to 12 months of age recommended intake levels of BCAA, protein, energy, and fluids are shown in Table\u00a09<\/a>, as per the GMDI [29<\/a>]. The aim is to maintain leucine plasma levels of 75\u2013300 \u00b5mol\/L and isoleucine and valine of 200\u2013400 \u00b5mol\/L [29<\/a>]. A retrospective cohort study demonstrated that leucine levels less than 200 \u00b5mol\/L are associated with better cognitive outcomes compared to higher leucine levels [84<\/a>].<\/p>\n Nutritional management in above one year of age<\/p>\n For individuals above the age of 1 year, foods high in leucine should be restricted, and medical foods free of BCAAs should be incorporated. The diet should mainly include fruits, vegetables, and low-protein foods to help regulate leucine levels [29<\/a>, 78<\/a>, 85<\/a>]. Leucine supplementation is often not required since adequate levels of found in breast milk and formula [86<\/a>]. Supplemental valine and isoleucine, however, are frequently required to balance the limited leucine intake and maintain suitable plasma levels of these amino acids [78<\/a>, 79<\/a>, 87<\/a>]. A 10% oral solution can be made by dissolving 1\u00a0g of valine and isoleucine in 100\u00a0ml of water. If supplementation is not available, medical food designed for the treatment of isovaleric acidaemia that are devoid of leucine but contains valine and isoleucine, can be used.<\/p>\n Protein intake should be individualized based on the patient\u2019s tolerance, with a general guideline of about 1\u00a0g of protein daily, equivalent to 60\u00a0mg of leucine [29<\/a>, 78<\/a>, 87<\/a>]. The Saudi experts recommend that only dietary leucine should be counted since valine and isoleucine content of the food is approximately half that of leucine and therefore the patient will not consume too much valine and leucine if they match the prescribed leucine intake.<\/p>\n For individuals aged 1 to 3 years recommended levels of BCAA, protein, energy, and fluids are shown in Table\u00a09<\/a>, as per GMDI [29<\/a>]. For children aged 1 to 3 years, experts recommend close monitoring and adjustment of BCAAs, protein, energy, and fluid intake to support healthy growth and avoid metabolic decompensation [78<\/a>, 81<\/a>, 88<\/a>]. Ensuring adequate energy intake, particularly from carbohydrates and fats, is essential to prevent catabolism and promote growth [78<\/a>, 81<\/a>]. The Saudi experts recommend regular follow-ups every 6 to 12 months for individuals over one year of age. The GMDI recommends clinical follow-up every one to six months between the ages of 1 and 8 years with monthly biochemical monitoring [36<\/a>]. Assessment of vitamin B12, zinc, selenium, pre-albumin, iron, and a complete blood count is important to monitor nutritional status and prevent deficiencies [29<\/a>, 81<\/a>, 85<\/a>, 88<\/a>].<\/p>\n Emergency and sick day management<\/p>\n Caregivers should be familiar with symptoms of acute metabolic decompensation (AMD) in MSUD, which include poor feeding, malaise, vomiting, dehydration, neurological signs, ketonuria, and ketoaciduria [89<\/a>, 90<\/a>]. Emergency or sick day management should start at home and continue in hospital if admission becomes necessary. Early initiation of emergency treatment, including dietary adjustments and intravenous fluids, is essential to prevent metabolic crises [89<\/a>, 91<\/a>, 92<\/a>].<\/p>\n Here, the Saudi experts recommend an emergency or sick day regimen of 0% natural protein for the first 3 days along with isoleucine and valine supplementation, followed by 50% for 2 days, and 100% for 1\u00a0day. In general, emergency or sick day regimens for MSUD typically involve a protein-restricted diet along with supplementation of valine and isoleucine [89<\/a>, 91<\/a>, 93<\/a>]. The GMDI guidelines recommend a 50\u2013100% intact protein reduction for 24\u201348\u00a0h and the use of a patient-specific approach [36<\/a>]. Following the implementation of emergency or sick day management, re-assessment of amino acid levels is crucial to confirm metabolic stability and to adjust treatment as necessary [89<\/a>, 91<\/a>, 92<\/a>].<\/p>\n VLCADNutritional management in below 6 months of age<\/p>\n If VLCAD is suspected, prompt initiation of treatment is advised to prevent metabolic crisis and manage symptoms effectively [30<\/a>, 94<\/a>]. Saudi experts recommend that treatment for VLCAD should involve cessation of breastfeeding with the introduction of an medium chain triglycerides (MCT) formula, an approach that facilitates proper fat metabolism and helps patients meet their energy needs [30<\/a>, 94<\/a>, 95<\/a>]. However, breastfeeding in mild asymptomatic VLCAD patients is safe providing they are growing adequately and avoiding fasting between feeds [30<\/a>, 96<\/a>]. The use of an MCT formula and avoidance of prolonged intervals between feeds are recommended by the GMDI to help manage energy levels and prevent hypoglycemia [30<\/a>].<\/p>\n For individuals aged 0\u20136 months GMDI-recommended fat and energy requirements are shown in Table\u00a011<\/a>. These are based on adequate levels from the Institute of Medicine\u2019s Dietary Reference Intakes [44<\/a>]. In infants with VLCAD, emphasis is placed on the avoidance of long-chain fats to meet energy needs [30<\/a>, 94<\/a>, 95<\/a>]. For infants under six months, monthly follow-ups are recommended to monitor nutritional status and overall health [30<\/a>, 94<\/a>]. Comprehensive monitoring at each follow-up should include nutritional assessments and comprehensive lab tests, including vitamin and mineral levels, to ensure balanced nutrition and identify any deficiencies early [38<\/a>].<\/p>\n Weaning practice<\/p>\n GMDI guidelines suggest that weaning in individuals VLCAD should involve limited intake of dietary fats, continued use of MCT formulas, and follow-ups every 3 months, including nutritional assessments and comprehensive laboratory testing [30<\/a>]. Restriction of dietary fats, particularly long-chain fatty acids, can help to reduce the build-up of toxic metabolites. Many studies have reported an intake of long-chain fatty acids of 10% of total energy in VLCAD patients; however, severity of VLCAD must be taken accounted for in the extend of restriction [30<\/a>]. For individuals aged 7\u201312 months recommended fat and energy requirements are shown in Table\u00a011<\/a>, as per GMDI.<\/p>\n Nutritional management in above one year of age<\/p>\n For individuals aged 1\u20133 years recommended fat and energy requirements are shown in Table\u00a011<\/a>, as recommended by the GMDI. As with infants, a low-fat diet restricted in long-chain fatty acids and modified to include MCT is recommended to manage energy needs and effectively manage VLCAD [30<\/a>, 95<\/a>, 97<\/a>]. Long-term MCT supplementation should be carefully monitored, since studies in animal models indicate potential adverse effects, such as hepatic steatosis and metabolic syndrome [95<\/a>, 97<\/a>]. For individuals aged 1 year and older, triheptanoate, if available, can be used. A retrospective chart review of triheptanoin in long-chain fatty acid oxidation disorders showed that the treatment led to a reduction in hospitalisation and hypoglycaemia events [98<\/a>]. According to the GMDI, regular follow-ups are recommended with biochemicals monitored every 3\u20136 months. These follow-ups should involve a comprehensive nutritional evaluation and biochemical monitoring of vitamins, minerals, and overall metabolic status [30<\/a>]. Omega-3 supplementation is mandatory for these patients.<\/p>\n Emergency and sick day management<\/p>\n For mild illness, GMDI guidelines state that home management should include frequent high-carbohydrate meals with shorter fasting intervals [30<\/a>]. Supplementation with medium-chain triglycerides (MCT) is essential to provide an alternative energy source and prevent catabolism [99<\/a>]. In cases where individuals with VLCAD deficiency are hospitalized and unable to meet their energy needs, it is recommended to administer 10% intravenous (IV) dextrose with electrolytes at 1.5 times the standard maintenance fluid rate [30<\/a>]. This approach helps to sustain blood glucose levels and prevent metabolic decompensation [99<\/a>].<\/p>\n HCUNutritional management in below 6 months of age<\/p>\n Early detection through newborn screening and the prompt treatment initiation are critical in preventing complications associated with HCU. Treatment should ideally commence within the first few weeks of life, as soon as HCU is suspected [100<\/a>,101<\/a>,102<\/a>]. Early diagnosis and timely treatment are essential to reduce intellectual disability, skeletal abnormalities, and vascular issues. For infants diagnosed with HCU, a low-methionine diet supplemented with cystine and essential vitamins such as pyridoxine, vitamin B12, and folate is recommended. This typically involves the use of a methionine-free formula to manage plasma methionine and homocysteine levels effectively [100<\/a>, 101<\/a>, 103<\/a>, 104<\/a>].<\/p>\n Weekly follow-ups are crucial for infants with HCU, allowing for regular monitoring of plasma methionine and homocysteine levels. Formula volume should be adjusted as needed to maintain these target plasma levels [100<\/a>, 104<\/a>, 105<\/a>]. Maintaining plasma homocysteine levels at or below 10 \u00b5mol\/L is the primary goal to prevent complications [100<\/a>, 104<\/a>, 105<\/a>]. Target plasma total homocysteine levels in the range of 60\u2013100 \u00b5mol\/L are recommended by the BIMDG; volume of methionine-free formula may be adjusted to meet recommended levels [106<\/a>].<\/p>\n Weaning practice<\/p>\n Weaning can be initiated from 6 months of age, as with children without HCU [107<\/a>]. According to the National Centre for Inherited Metabolic Disorders, first foods for HCU infants should be protein-free fruits and vegetables [107<\/a>]. Subsequently, weaning should include low protein foods, low protein prescribable products, and methionine-free formula. The European network and registry for homocystinurias and methylation defects (E-HOD) guidelines recommend clinical monitoring frequency to be dependent on age, complications and severity of condition [108<\/a>]. The BIMDG recommends follow-up every 2 weeks once target levels of total plasma homocysteine and methionine have been achieved [106<\/a>]. Here, the Saudi experts recommend follow-up every 2\u20133 weeks, including a review of feeding, in infants aged 6\u201312 months.<\/p>\n Nutritional management in above one year of age<\/p>\n A low-methionine diet, supplemented with L-cystine and methyl donors like choline, has been shown to reduce plasma homocysteine levels and help prevent complications, including thrombosis [103<\/a>, 105<\/a>]. Methionine restriction is a commonly recommended practice, often accompanied by betaine and vitamins B6, B12, and folate to support homocysteine management [8<\/a>, 109<\/a>, 110<\/a>]. In a cross-sectional survey of 29 metabolic diseases centres in Europe, dietary management was found to vary across centres, however, methionine-free amino acid supplement was prescribed in many patients and many centres recommend cystine supplementation for low plasma levels [111<\/a>]. Natural protein intake is carefully monitored and adjusted according to age and plasma levels of total homocysteine and methionine [108<\/a>].<\/p>\n Regular follow-ups every 3\u20134 months are essential for reviewing dietary adherence and adjusting nutritional intake as needed [104<\/a>, 111<\/a>]. Biochemical monitoring, including homocysteine and methionine levels and BCAA, is critical to assess metabolic control and guide dietary modifications [8<\/a>, 104<\/a>]. Due to potential deficiencies and the risk of reduced bone mineral density, patients with HCU often require additional calcium and vitamin D3 supplementation [104<\/a>].<\/p>\n Role of additions to infant formula for nutritional benefit<\/p>\n Patients with IEM have been shown to be at greater risk of micronutrient deficiency due to the restrictive nature of their diets and therefore supplementation is often necessary [112<\/a>]. Some amino acids disorders such as PKU, PA, MMA, and MSUD, which are treated with medical formulas containing trace elements, minerals, and vitamins, can achieve adequate micronutrient levels if their intake of the formula is satisfactory [112<\/a>, 113<\/a>]. However, patients who consume less medical formula, due to milder disease or even non-adherence, are at greater risk of micronutrient deficiency and therefore may require additional supplementation [113<\/a>].<\/p>\n Omega-3 can be used for all metabolic patients. A recent systematic review of 11 studies showed that children with IEM often have essential fatty acid deficiency and it is suggested that long-term supplementation with omega-3 polyunsaturated fatty acids are likely to have beneficial effects such as the prevention of cognitive impairment [114<\/a>]. A study of long-chain omega-3 polyunsaturated fatty acid supplementation in children with PKU showed an improvement in motor skills, measured using the motometric Rostock-Oseretzky Scale, following 3 months of supplementation [115<\/a>].<\/p>\n On the other hand, GOS, FOS, DHA, and ARA are not generally used unless the patient is severely unwell. To our knowledge there are no studies reporting the use of prebiotics GOS and FOS in patients with IEM [116<\/a>]. Although low levels of DHA and ARA have been reported in IEM patients with protein-restricted diets, the effect of supplementation on functional outcomes is not known [117<\/a>]. In infants with VLCAD who require restriction of long-chain fatty acids and MCT supplementation, ARA and DHA supplementation are recommended by the GMDI to prevent deficiency of essential fatty acids [30<\/a>].<\/p>\n Challenges in dietary management of metabolic disorders<\/p>\n Poor adherence to diet in IEM patients can result in neurological complications as well as frequent hospitalisations. Patients taking on the responsibility for their own condition after the age of approximately 10 years as well as psychological impact of IEM are thought to contribute to reduced dietary adherence [118<\/a>]. Educational and cultural background of the patients are also factors affecting adherence to diet [119<\/a>]. In PKU, 33% of patients struggle to keep their blood phenylalanine levels within the recommended range and this lack of control worsens with patient age [118<\/a>]. Additionally, feelings of being different in IEM patients of school age can also contribute to poor adherence; family and friends are therefore essential in aiding these individuals to remain adherent to their diet [120<\/a>].<\/p>\n Attaining nutritional adequacy and meeting growth requirements are key challenges in the management of metabolic disorders. Retrospective analysis of patients with IEM and protein-restricted diets has shown that growth retardation is common in these patients, affecting final height, and is worse during puberty [121<\/a>]. Additionally, essential amino acid deficiency and subsequent development of malnutrition can also be a challenge for IEM individuals on protein-restricted diets and therefore needs appropriate management [122<\/a>].<\/p>\n Individuals with metabolic disorders and their caregivers experience significant psychological burden and social isolation. In parent interviews, anxiety, depression, and compassion fatigue were commonly reported, resulting from uncertainty regarding their child\u2019s illness, social isolation, and the demands of looking after their child [123<\/a>]. Whilst the burden of IEM illness on caregivers is high when their child is young, a shift towards greater burden in children is seen as they get older [124<\/a>]. Greater psychosocial burden was also observed for children needing to adhere to stricter diets and those in danger of metabolic decompensation [124<\/a>].<\/p>\n In some centres in Saudi Arabia, a lack of authority of clinical dietitians to order appropriate testing relevant to metabolic diseases is a significant challenge. Whilst clinical dietitians have a significant role in the management of IEM patients, clinicians, such as metabolic geneticists, are responsible for medical management and testing in patients [125<\/a>].<\/p>\n Caregiver counselling<\/p>\n Following a diagnosis, the Saudi experts recommend that caregivers should be counselled using a counselling checklist. Initial counselling at diagnosis should focus on providing details of the nature of the disease and it\u2019s manifestations, psychosocial support, immediate management approaches (symptoms of metabolic decompensation, the importance of diet and adherence to diet, preparation of medical nutritional formula), the patient\u2019s individual treatment plan including emergency and sick day regimens, and contact details of the team [125<\/a>]. Counselling at first follow-up should then focus on discussing the inheritability of the condition, offering carrier testing, encouraging parents to make their relatives aware of the condition due to the familial risk, discuss coping strategies and connecting with other patients as well as support and advocacy groups [125<\/a>]. Once the patient is older and beginning to manage their own condition, additional counselling is subsequently recommended [125<\/a>]. Structured counselling sessions are important for building relationships with patients and setting achievable goals [126<\/a>].<\/p>\n Continuous communication between caregivers and the metabolic centre is imperative, including a call or messaging helpline. Analysis of children with PKU and their families found that bi-directional communication between caregivers or patients and the medical team might help to improve patient outcomes due to greater patient involvement and medical decisions made in the best interest of the patient [119<\/a>].<\/p>\n Whilst this expert consensus has provided important recommendations for the nutritional management of metabolic diseases in neonates and infants in Saudi Arabia, limitations include the use of a literature search rather than a systematic literature review, which limits the assessment of the strength of each recommendation. Nevertheless, the methodology used here has been used in other expert consensus publications and level of agreement from the experts has been obtained.<\/p>\n","protected":false},"excerpt":{"rendered":"General principles of nutritional management Early diagnosis and management of IEM are essential. Newborn screening programs for IEM…\n","protected":false},"author":2,"featured_media":186037,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[78],"tags":[18,910,104610,135,104606,2565,19,104604,17,104609,7482,104608,13498,104605,104607,15112,104611],"class_list":{"0":"post-186036","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-health","8":"tag-eire","9":"tag-general","10":"tag-glutaric-acidemia-type-1","11":"tag-health","12":"tag-homocystinuria","13":"tag-human-genetics","14":"tag-ie","15":"tag-inherited-errors-of-amino-acid-metabolism","16":"tag-ireland","17":"tag-maple-syrup-urine-disease","18":"tag-medicine-public-health","19":"tag-methylmalonic-acidemia","20":"tag-pharmacology-toxicology","21":"tag-phenylketonuria","22":"tag-propionic-acidemia","23":"tag-saudi-arabia","24":"tag-very-long-chain-acyl-coa-dehydrogenase"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@ie\/115567389917749921","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts\/186036","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/comments?post=186036"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts\/186036\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/media\/186037"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/media?parent=186036"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/categories?post=186036"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/tags?post=186036"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}