Role of Metabolic Nutrition in Newborn Screening and Inherited Metabolic Disorders
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
Department of Pediatric and Adolescent Medicine, Western Michigan University, Kalamazoo, MI, USA
Department of Medical Ethics, Humanities, and Law, Western Michigan University, Kalamazoo, MI, USA
Academic Editor: Paola Ungaro
Special Issue: Newborn Screening and Inherited Metabolic Disorders
Received: June 29, 2023 | Accepted: September 30, 2023 | Published: October 10, 2023
OBM Genetics 2023, Volume 7, Issue 4, doi:10.21926/obm.genet.2304196
Recommended citation: Norris MK, Kanungo S. Role of Metabolic Nutrition in Newborn Screening and Inherited Metabolic Disorders. OBM Genetics 2023; 7(4): 196; doi:10.21926/obm.genet.2304196.
© 2023 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
The primary objective of the newborn screening (NBS) program is to achieve affordable and timely detection of treatable disorders, emphasizing the importance of prompt intervention to enhance long-term outcomes . The NBS program operates at the state level in the United States, resulting in some variation in the disorders screened. However, the Advisory Committee on Heritable Disorders in Newborns and Children recommends a set of conditions that all states include in their screening protocols . Since the initial development of the first NBS test for phenylketonuria (PKU), significant progress has been achieved in newborn screening, and patient outcomes have improved for all of the disorders in the core NBS panel [1,2]. Recent technological advancements have facilitated the expansion of NBS to include disorders of carbohydrate, lipid, and protein metabolism, among others. Most of these newly screened metabolic disorders are treatable with comprehensive nutrition and medical management.
Medical management of patients with metabolic disorders requires a team approach, including geneticists, metabolic dietitians, genetic counselors, nurses, and social workers. Metabolic dietitians are registered dietitians with specialized training in providing medical nutrition therapy to patients with inherited metabolic disorders using the latest evidence-based methods. They utilize a comprehensive approach, incorporating physical, clinical, and laboratory data to administer complex medical nutrition therapy that provides appropriate nutrition to support growth and development while limiting the offending substrate. While not exhaustive, this review will highlight the complex medical nutrition therapy of several common metabolic disorders and the central role metabolic dietitians play in managing these patients.
2. Nutrition Management of Specific Metabolic Disorders
2.1 Fatty Acid Oxidation Disorders (FAODs)
Fatty acid oxidation disorders (FAODs) are autosomal recessive inherited inborn errors of lipid metabolism due to deficiencies of either mitochondrial β-oxidation enzymes or carnitine transport enzymes. Most patients with FAODs are detected through NBS by measuring elevated acylcarnitines specific to each FAOD (Table 1). Molecular testing is necessary for confirmation and can help determine genotype-phenotype correlations . Every year, approximately 100 infants are diagnosed with long-chain fatty acid oxidation disorders (LC-FAODs) in the United States, while the current population of individuals living with LC-FAOD is estimated to range between 2,000 and 3,5000 . Some FAODs, such as medium-chain acyl-CoA dehydrogenase deficiency (MCADD), are more common than the LC-FAODs individually (Table 1); however, the worldwide incidence of LC-FAODs is about 1 in 9,300 individuals (Table 1) .
When fatty acids are needed as an energy source during exercise, prolonged fasting, or increased energy demands due to illness, surgery, or injury, fatty acids are oxidized in the mitochondria to supply energy to the cell . Mitochondrial β-oxidation generates the reducing agents flavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide (NADH), which donate electrons to the respiratory chain for oxidative phosphorylation and ATP generation, supplying a significant source of energy . With deficient β-oxidation, patients with FAODs experience decreased energy production and increased production of abnormal fatty acid metabolites, yielding cardiomyopathy, heart failure, hypoketotic hypoglycemia, rhabdomyolysis, muscle weakness, liver dysfunction, and fatality depending on severity .
Common elements of nutrition management of all FAODs include fasting avoidance, aggressive treatment during illness, and carnitine supplementation only if deficient . Fasting avoidance consists of a maximum of 3-4 hours between feedings for infants up to 4 months, with an increase of 1 hour of fasting for every additional month of age up to 10-12 hours after one year during times of wellness [3,8]. Patients with mild/moderate severity can often tolerate longer fasting times. FAOD patients require carbohydrate-rich fluids/foods every 3-4 hours during mild illnesses. During severe illnesses, FAOD patients may require intravenous (IV) fluids with 10 percent dextrose at a 1.5 times maintenance fluid rate (equivalent to a glucose infusion rate of 8 mg/kg/min) with appropriate electrolytes as outlined in their emergency treatment letter [3,8]. Infusion of IV lipids is contraindicated; however, a source of essential fatty acids should be provided if intake remains inadequate after seven days .
In addition to common nutrition therapy elements, treatment for Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) also includes avoidance of medium-chain triglyceride (MCT) oil, which can be challenging as specialty infant and pediatric formulas often contain high sources of MCT (outlined in detail in Merritt, et al., 2018) . Overall, patients with MCADD are educated to consume a regular, healthy diet .
In contrast to MCADD, patients with long-chain fatty acid oxidation disorders (LC-FAODs) require a fat-restricted diet as a means for limiting substrate for mitochondrial β-oxidation and MCT supplementation to bypass the deficient enzyme and still produce acetyl CoA . The degree of dietary fat restriction depends on the patient's disease severity as determined by gene variants or clinical symptoms . It gradually increases as the patient ages, with severe patients still limited to 10% of total energy from long-chain fat and 20-30% from MCT (Table 2) . Infants require low-fat, MCT-supplemented formulas (medical food), and older children/adults receive their MCT from pharmaceutical grade MCT® oil or powdered MCT products (Table 3) . Given the extent of fat restriction, patients may need to include oils rich in essential fatty acids as part of their daily fat allowance to prevent deficiency [3,8]. Supplementation of essential fatty acids and fat-soluble vitamins may be necessary.
Table 3 Selected Medical Foods for FAODs .
Triheptanoin (DOJOLVI® Ultragenyx Pharmaceutical Inc.) is a newly FDA-approved therapeutic for treating LC-FAODs (Table 4) . Triheptanoin comprises three odd-chain 7-carbon fatty acids on a glycerol backbone that enter the mitochondria without a carnitine carrier (similar to MCT), bypassing the enzymes that metabolize long-chain fatty acids and are oxidized to generate both acetyl-CoA and propionyl-CoA which enter the tricarboxylic acid (TCA) cycle . Due to the formation of both acetyl-CoA and propionyl-CoA instead of solely acetyl-CoA, Triheptanoin is more effective than MCT oil at replenishing TCA cycle intermediates. One challenge of using Triheptanoin is that patients must discontinue all MCT-containing medical foods due to potential competitive inhibition . The dietitian must construct a complete nutrition prescription by combining various MCT-free medical foods to meet 100% nutrient needs, including fat, protein, carbohydrates, vitamins, and minerals. In addition to standard low-fat, MCT-supplemented medical foods for patients with LC-FAODs, Table 3 includes MCT-free medical foods that are low or devoid of fat and can be used as a base for a patient on Triheptanoin. In a Triheptanoin extension study, there was a 70% median annualized reduction in the incidence and frequency of hospital days due to major clinical events (rhabdomyolysis, hypoglycemia, and cardiomyopathy) in patients who previously were on MCT oil . Despite significant advances, rhabdomyolysis, and cardiomyopathy continue to cause morbidity and mortality among patients with severe forms of LCFAOD’s [3,13].
Routine monitoring of echocardiogram, acylcarnitine profile, creatine kinase, essential fatty acids, complete blood count (CBC), comprehensive metabolic panel (CMP), 25-OH vitamin D, fat-soluble vitamins, troponin, and B-natriuretic protein is crucial . Typically, the laboratory tests are monitored weekly to monthly for the first three months and then spaced out to every six months or yearly, depending on clinical symptoms .
Galactosemia is an inherited disorder of galactose metabolism. There are four types of galactosemia, each affecting a different step in galactose metabolism: Classic or type I galactosemia due to a deficiency in the enzyme galactose-1-phosphate uridylyltransferase (GALT), type II galactosemia due to a deficiency in galactokinase (GALK), type III galactosemia due to a deficiency in UDP-galactose 4 epimerase (GALE), and type IV galactosemia due to a deficiency in galactose mutarotase (GALM) [14,15]. Classic galactosemia is the most severe type and is the focus of this review.
As a result of deficient GALT activity, galactose-1-phosphate (gal-1-P) and galactitol build up, leading to various health issues affecting multiple organs . These complications include liver disease, sepsis caused by E. coli infection, cataracts, speech impairment, renal tubular dysfunction, impaired growth, and ovarian dysfunction in females . Diagnosis of classic galactosemia is confirmed with the measurement of gal-1-P or GALT enzyme activity through NBS in addition to GALT gene analysis . Classic galactosemia is an autosomal recessive disorder with a prevalence of 1:16,000 to 1:50,000 live births in Western countries .
In cases where classic galactosemia is suspected in an infant, clinicians should promptly discontinue breastmilk or milk-based infant formulas and initiate a diet that restricts galactose intake (such as soy-based or elemental formula) without waiting for confirmation of the diagnosis [14,16]. A lifelong galactose-restricted diet is recommended for patients with classic galactosemia and should primarily focus on eliminating lactose (glucose + galactose) and galactose from dairy products while allowing for minimal dietary galactose from non-milk sources (Table 5) . Galactose within the plant cell wall (called “bound” galactose) is found in many fruits, vegetables, legumes, nuts, and seeds . Recent studies demonstrate that bound galactose does not add to the free galactose pool in the body, so the treatment of classic galactosemia allows any amount and type of fruits, vegetables, legumes, unfermented soy-based products (Table 5) . Additionally, some mature cheeses and sodium or calcium caseinate are allowed since they are extensively aged or processed to significantly reduce the lactose and galactose content (Table 5) . The goal is to restrict galactose to the lowest amount compatible with a nutritionally adequate diet to support age-appropriate growth and development . As a galactose-restricted diet is naturally low in calcium and vitamin D, it is essential to meet both calcium and vitamin D needs through soy-based formulas, elemental formulas, or individual supplementation .
Laboratory monitoring is essential in the management of classic galactosemia including measurement of Gal-1-P in red blood cells at diagnosis, 3 months and 9 months . Additionally, it is crucial to measure 25-OH vitamin D levels at least annually [14,16]. Despite the strict elimination of galactose from the diet, patient outcomes are variable [14,16]. More details on Galactosemia are discussed in another article in this special issue by Hong & He.
2.3 Glutaric Acidemia Type 1 (GA-1)
GA-1 is an autosomal recessive neurometabolic disorder of lysine metabolism caused by pathogenic variants in the glutaryl-CoA dehydrogenase (GCDH) gene, resulting in a deficiency of mitochondrial GCDH with an estimated worldwide incidence of 1:90,000-1:120,000 newborns . This deficiency leads to the accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA), glutaconic acid, and glutarylcarnitine (C5DC) . These metabolites can be detected in urine and plasma using gas chromatography/mass spectrometry (for organic acids) and tandem mass spectrometry (for acylcarnitines and NBS) .
Most untreated individuals experience the sudden onset of striatal damage before 3 to 6 years, triggered by infectious diseases, fever, or surgery . This damage results in an irreversible and disabling movement disorder, primarily dystonic, with a limited life expectancy .
Early detection through newborn screening is crucial for starting metabolic treatment before symptoms appear. This treatment includes a low lysine diet (Table 6 and Table 7), supplementation with carnitine (Table 8), and intensified emergency treatment during illnesses or surgeries . These interventions have significantly improved the neurological outcomes in patients with GA-1. However, metabolic treatment cannot reverse the motor dysfunction caused by striatal damage . The goal of nutrition therapy for GA-1 is to restrict lysine intake using lysine-free medical foods (Table 6 and Table 7) while providing sufficient lysine through intact protein sources such as breast milk, infant formulas, or food to meet lysine goals (Table 7). Arginine competes with lysine for uptake across the blood-brain barrier and is, therefore, supplemented in GA-1 medical foods  There is no evidence for maintenance or emergent supplementation of arginine orally or IV . Although riboflavin supplementation has been reported to decrease GA and 3-OH-GA concentrations, there is no evidence that riboflavin improves patient outcomes . The dietary restrictions can be eased after the vulnerable period for striatal damage, typically around 6 years of age . Nevertheless, the long-term effects of relaxing the dietary restrictions on overall outcomes remain uncertain.
Table 6 GA-1 Nutrient Needs by Age .
Table 7 Selected Medical Foods for GA-1 .
Routine laboratory monitoring of plasma amino acids and carnitine is crucial in GA-1 . Typically, these laboratory tests are monitored every three months until age one and then spaced out to every six months or yearly, depending on clinical symptoms. Research does not support using GA or 3-OH-GA as a biomarker for management as they do not correlate to patient outcomes .
2.4 Maple Syrup Urine Disease (MSUD)
MSUD is an autosomal recessive inborn error of branched-chain amino acid (BCAA) metabolism. MSUD is caused by a deficiency of the branched-chain keto acid dehydrogenase enzyme complex, leading to the accumulation of leucine, valine, and isoleucine as well as their ketoacids (alpha-ketoisocaproic acid, keto-isovalerate and keto-beta-methylvalerate) [21,22]. Of the accumulated BCAAs, leucine and its ketoacid, alpha-ketoisocaproic acid, are the toxic compounds that cause the clinical manifestations of MSUD . Patients with MSUD are flagged through newborn screening with the detection of elevated leucine. MSUD was first discovered in 1954 by Menkes, Hurst, and Craig, who noticed a maple syrup odor in the urine of infants who died from a neurological disease . In the general population, MSUD is quite rare, with a prevalence of 1 in 200,000 live births ; however, it is more common in the Mennonite population, with a prevalence of 1 in 350 live births .
Patients with MSUD present with classic, intermediate, or intermittent forms. The classic form of MSUD presents with neonatal onset, poor feeding, lethargy, altered tone, ketoacidosis, seizures, and developmental delays . The intermediate form of MSUD develops slower with progressive failure to thrive, ketoacidosis, developmental delays, and classic symptoms during catabolic illness . The intermittent form of MSUD presents with typical development, episodic ataxia, and ketoacidosis and is typically precipitated by illness or increased protein intake .
Treatment of MSUD consists of a low leucine diet to maintain near-normal plasma leucine levels (100-200 µmol/L for patients <5 years old and 100-300 µmol/L for patients >5 years old) . It is essential first to determine the goals for leucine (mg), total protein (g), and energy (kcal) as they will be used to calculate the amount of leucine (breast milk, infant formula, food), BCAA-free medical food and calories needed to meet the patient's individual needs (Table 9) [22,24]. The use of BCAA-free medical foods is essential to provide patients with total protein above the daily recommended intake (DRI) (Table 9 and Table 10) . Some variant forms of MSUD also respond to thiamine supplementation at 50-200 mg/d . While it is essential to reduce leucine intake to maintain leucine concentrations in the normal range, valine and isoleucine can quickly deplete and lead to protein deficiency. Therefore, valine and isoleucine supplementation are crucial to prevent deficiency and help lower plasma leucine levels [22,24].
Table 9 MSUD Nutrient Needs by Age .
During illness, serious injury, or surgery, aggressive nutrition management is provided to prevent or reverse catabolism by removing or significantly reducing leucine intake, supplying adequate energy (1.5-3 times the EER), increasing BCAA-free protein (2.0-3.5 g/kg from medical food), increasing valine and isoleucine supplementation, and adding hypertonic saline with appropriate electrolytes and insulin to prevent hyperglycemia [22,24,26]. Avoiding hypotonic saline in IV fluids prevents cerebral edema [22,26]. During acute nutrition management, calorie and protein needs are typically met with continuous nasogastric feedings of MSUD medical foods (Table 10) and peripheral administration of dextrose and IV lipids [22,26]. BCAA-free parenteral nutrition solutions are available from specialty compounding pharmacies if the patient cannot tolerate enteral nutrition; however, the patient still requires valine and isoleucine supplementation . Leucine from intact protein is reintroduced or increased to baseline when elevated plasma leucine decreases to the upper limit of the treatment range: 200 µmol/L for infants and children ≤5 years of age and 300 µmol/L for individuals >5 years of age .
Patients with MSUD require frequent laboratory monitoring, including leucine, valine, isoleucine, prealbumin, CBC, CMP, ferritin, iron, folate, 25-OH vitamin D, trace minerals, and others as clinically indicated .
2.5 Phenylketonuria (PKU)
PKU was the impetus for newborn screening and inspired expanded newborn screening globally . PKU is an autosomal recessive inborn error of phenylalanine metabolism, which is due to a deficiency in the tetrahydrobiopterin-dependent enzyme phenylalanine hydroxylase (PAH) in the conversion of amino acid phenylalanine (Phe) to amino acid tyrosine (Tyr) . This deficiency leads to the accumulation of neurotoxic phenylalanine. Elevated phenylalanine concentrations are used to flag potential PKU patients on NBS . These patients require follow-up plasma amino acid analyses as well as genetic testing to confirm the diagnosis, with an incidence of 1:10,000 in the United States . European countries and the United States indicate newborns with plasma Phe concentration >360 µmol/L should start a low-Phe diet immediately .
Patients with classic PKU appear asymptomatic at birth; however, if a low-Phe diet is not started within the first few weeks of life, irreversible intellectual disabilities, seizures, behavioral abnormalities, eczema, "musty" odor, and hypopigmentation of the skin, hair, and irises develops [28,29]. Treatment of PKU involves severe Phe restriction from food and supplementation of Phe-free medical food while optimizing growth, development, nutritional adequacy, and mental functioning by maintaining blood Phe concentrations between 120-360 µmol/L (Table 11, Table 12) [27,30,31]. This low-Phe diet is necessary for the patient's lifetime . Patients with classic PKU receive most of their dietary protein from synthetic medical foods lacking Phe (Table 12) and a small amount of protein from vegetables, fruit.
Recently, advances in the traditional PKU diet have increased diet compliance and provided more nutritionally complete products. In the last several years, the incorporation of naturally low-Phe and whey-based glycomacropeptide (GMP) derived from the cheese manufacturing process into metabolic foods has changed the way we think about medical food formulation (Table 12) . Additionally, metabolic clinics have started implementing the Simplified PKU Diet, which promotes healthy food choices, increases flexibility, and is easier to manage than a traditional low-Phe diet . The Simplified PKU Diet involves reducing the patient’s specific Phe allowance from foods by about 30% and then allowing unmeasured intake of "free foods" (fruits, vegetables, foods with <75 mg Phe/100 g, and specialty low protein foods with <20 mg/serving) [29,33].
Treatment of PKU also involves medications in addition to a low-Phe diet. Sapropterin dihydrochloride is a synthetic form of the PAH cofactor Tetrahydrobiopterin (BH4) and enhances residual PAH activity, which allows for increased Phe tolerance (Table 13) . Typically, patients with a high residual activity of the PAH enzyme have a greater probability of response to sapropterin dihydrochloride . Response to sapropterin dihydrochloride is determined individually; however, response is typically defined as a ≥30% decrease of blood Phe . Sapropterin dihydrochloride-responsive patients can increase their daily Phe intake, but almost all patients still require Phe restriction and Phe-free medical foods . Pegvaliase (Table 13), on the other hand, is a newly FDA-approved daily injectable phenylalanine ammonia lyase enzyme substitution for PAH, and is used to treat non-pregnant adults with plasma Phe ≥600 µmol/L [30,34]. Phenylalanine ammonia lyase converts phenylalanine into ammonia and trans-cinnamic acid to be safely excreted in the urine [30,34]. Patients on pegvaliase can significantly increase their daily Phe intake and decrease their Phe-free medical food intake [30,34]. While pegvaliase allows for relaxation of the low-Phe diet, pegvaliase therapy does have a high risk for side effects ranging from injection site irritation to anaphylaxis and requires thorough education and monitoring by the medical team [30,34].
Patients with PKU require frequent laboratory monitoring, including weekly Phe and Tyr in infancy and then weekly to monthly after; plasma amino acids, prealbumin, ferritin, 25-OH vitamin D, and complete blood count (CBC) every 6-12 months; and B12, MMA, red blood count, folate, iron, zinc, copper, and essential fatty acids as indicated [29,30].
2.6 Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA)
Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA) are autosomal recessive disorders resulting from a deficiency of the enzymes propionyl-CoA carboxylase (PCC) or methyl malonyl-CoA mutase (MUT), respectively, in the metabolism of propiogenic amino acids isoleucine (Ile), methionine (Met), threonine (Thr), valine (Val) and odd chain fatty acids [35,36]. Deficiency in biotin-dependent PCC leads to an accumulation of propionic acid and propionyl-CoA, and a deficiency in B12-dependent MUT leads to an accumulation of methylmalonyl-CoA and methylmalonic acid [35,36]. MMA can also be caused by a defect in the transporter or synthesis of the MUT enzyme cofactor, cobalamin (Cobalamin A, Cobalamin B, or Cobalamin D-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase . In Western populations, the estimated incidence of MMA ranges from 1:48,000 to 1:61,000 births and from 1:50,000 to 1:500,000 births for PA .
Patients suspected to have PA or MMA are flagged through newborn screening with elevated propionyl acylcarnitine and followed up with plasma homocysteine and B12 in addition to urine organic acid analysis . PA patients will have elevated urine 3-OH Propionic acid and normal plasma homocysteine . MMA patients will have elevated urine methylmalonic acid and normal plasma homocysteine . Plasma homocysteine, methylmalonic acid, and serum vitamin B12 will be elevated in the cobalamin C, D, and F deficiencies .
Patients with PA or MMA present with metabolic acidosis, hyperammonemia, hyperglycinemia, vomiting, poor feeding, hypotonia, cerebral edema, and death without aggressive management. Patients are at risk for metabolic stroke, seizures, acute or chronic pancreatitis, cardiomyopathy (PA), and chronic renal impairment (MMA) that can progress to renal failure .
Treatment of PA and MMA includes preventing catabolism; restricting propiogenic amino acids Ile, Met, Thr, and Val while balancing intact protein and essential amino acid medical food (Table 14 and Table 15); aggressively treating illnesses; maintaining normal plasma amino acid concentrations; and supplementing with L-Carnitine, 5-20 mg daily Biotin (PA -only if responsive), and 1-2 mg daily-weekly oral or IV B12 (MMA-only if responsive) (Table 16) . The protein goal is adjusted based on age, ammonia, and plasma amino acid concentrations. While it is necessary to restrict Ile, Met, Thr, and Val from food, it is crucial to optimize intake from intact protein sources and only use propiogenic amino acid-free medical foods when necessary .
During illness, serious injury, or surgery, calories are increased 20-50 percent above baseline needs using non-protein modulars (Table 15), dextrose-containing fluids are provided at 1.5 times maintenance fluid needs, and protein is eliminated or reduced to 50 percent for a maximum of 48 hours depending on ammonia concentration and clinical symptoms . IV lipids can be added as additional calories to prevent catabolism, especially if the patient cannot tolerate enteral intake . Additionally, propiogenic amino acid-free parenteral nutrition solutions are available from specialty compounding pharmacies if the patient cannot tolerate enteral nutrition or is nil per os (NPO). Nitrogen scavenging medications (Table 16) decrease ammonia concentrations in the hospital setting and may be required long-term, depending on chronic ammonia concentrations. After 24-48 hours, protein is slowly reintroduced and increased to well-day protein allowance to prevent refractory hyperammonemia due to protein deficiency.
Patients with PA or MMA require frequent laboratory monitoring, including plasma amino acids, ketones, carnitine, kidney function tests (MMA), prealbumin, CBC, 25-OH Vitamin D, B12, folate, B6, zinc, selenium, and ferritin as well as echocardiograms (PA) .
2.7 Urea Cycle Disorders (UCDs)
Urea cycle disorders (UCDs) are autosomal recessive (except for X-linked ornithine transcarbamylase deficiency) inborn errors of metabolism due to a deficiency in one of the essential enzymes required to convert toxic ammonia into benign urea . Deficiency in any of these enzymes (Table 17) leads to the accumulation of ammonia, causing neurotoxicity, poor feeding, failure to thrive, vomiting, seizures, lethargy, liver dysfunction, coma, and death . Patients with Arginase deficiency, however, are typically less characterized by acute hyperammonemia crises but instead experience spastic diplegias and intellectual disability. Patients with UCDs are detected through NBS by measuring elevated plasma amino acids specific to each disorder (Table 17). Carbamoyl phosphate Synthetase Deficiency and Ornithine Transcarbamylase Deficiency are not routinely on the NBS panel despite being two of the most severe urea cycle disorders and are therefore diagnosed clinically based on symptoms as well as elevated orotic acid and low citrulline concentrations . The overall incidence of UCDs is approximately 1:35,000 births, which is relatively common (Table 16) . Treatment includes preventing catabolism, restricting overall protein while balancing intact protein and essential amino acid medical food (Table 18 and Table 19), supplementing with citrulline (except for Citrullinemia type I and Argininosuccinate Lyase Deficiency) or arginine (except for Arginase Deficiency), and providing nitrogen scavenging medications to maintain normal ammonia concentrations for age and plasma amino acid concentrations . Nitrogen scavengers help remove nitrogen and prevent hyperammonemia by utilizing alternate pathways, allowing patients to increase their protein tolerance (Table 20) .
Table 19 Selected Medical Foods for UCDs .
Table 20 Common Medications used to treat UCDs .
During illness, serious injury, or surgery, additional fluids are provided at 1.5 times maintenance fluid needs, calories are increased 20-50 percent above baseline needs using non-protein modulars (Table 19), and protein is eliminated or reduced to 50 percent for a maximum of 24 hours depending on ammonia concentration and clinical symptoms. During severe hyperammonemic crises, dialysis may be required to normalize ammonia concentrations .
Patients with UCDs require routine laboratory monitoring, including plasma amino acids, ammonia, 25-OH vitamin D, complete blood count, ferritin, iron, folate, selenium, and zinc . Plasma amino acids and ammonia are monitored weekly in infancy and then spaced monthly as the patient stabilizes on their treatment. Maintaining plasma amino acids within goal ranges, especially glutamine, is essential given protein restriction and the potential for medications to lower branched-chain amino acids. Protein deficiency can lead to refractory hyperammonemia.
Newborn screening and medical nutrition therapy play integral roles in the treatment of inherited metabolic disorders. The expansion of newborn screening has allowed for the inclusion of a wide range of disorders, which have shown significant improvements in outcomes when detected and treated early. Coupled with medical nutrition therapy, which provides appropriate nutrition to support growth and development while limiting the offending substrate, these interventions offer a comprehensive approach to managing inherited metabolic disorders. Continued research and advancements in newborn screening and nutrition therapy will enhance our ability to diagnose and manage inherited metabolic disorders, ultimately improving patients' long-term outcomes and quality of life.
MKN and SK conceptualized the manuscript. MKN drafted the initial manuscript. MKN and SK reviewed and revised the manuscript.
MKN is a speaker for Ultragenyx Pharmaceutical Inc.
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