6.2 Inborn Errors of Metabolism

Newborn Screening: The Entry Point

Nearly every inborn error of metabolism (IEM) a pediatric dietitian will manage enters care through newborn screening. A dried blood spot is collected at 24-48 hours of life (screening before 24 hours produces false negatives for some conditions, and specimens from preterm or transfused infants may need repeating). Tandem mass spectrometry (MS/MS) revolutionized the field by measuring dozens of amino acids and acylcarnitines from a single spot, enabling one test to screen for phenylketonuria, maple syrup urine disease, many organic acidemias, and fatty acid oxidation defects. The Recommended Uniform Screening Panel now includes dozens of core conditions, though state panels vary. A positive screen triggers confirmatory testing and immediate referral to a metabolic center, because for most of these disorders early dietary treatment prevents irreversible neurologic injury.

Phenylketonuria

Phenylketonuria (PKU) results from deficiency of phenylalanine hydroxylase (PAH), which converts phenylalanine (Phe) to tyrosine. Untreated, accumulating Phe causes severe intellectual disability; treated from the newborn period, outcomes are excellent. Management principles:

• Phenylalanine-restricted diet for life: natural protein is counted in milligrams of Phe (or exchanges), with most fruits, vegetables, and low-protein specialty products forming the diet base. High-protein foods (meat, dairy, eggs, nuts, grains in quantity) are largely excluded.
• Medical formula: a Phe-free amino acid-based protein substitute supplies the majority (often 80% or more) of protein needs; because tyrosine cannot be synthesized, tyrosine becomes conditionally essential and is supplied by the formula.
• Blood Phe targets: the widely cited ACMG treatment target is 120-360 umol/L (2-6 mg/dL) across ages, monitored by regular blood spots.
• Aspartame (an artificial sweetener containing phenylalanine) must be avoided.
• Maternal PKU: elevated maternal Phe is teratogenic, causing fetal microcephaly, congenital heart disease, growth restriction, and intellectual disability even when the fetus does not have PKU. Women must achieve strict metabolic control before conception and maintain it throughout pregnancy.
• Pharmacotherapy: sapropterin dihydrochloride (Kuvan), a synthetic form of the BH4 cofactor, lowers Phe in a responsive subset (more often mild phenotypes); pegvaliase (Palynziq), an enzyme-substitution injection approved for adults, can normalize Phe and liberalize the diet but carries anaphylaxis risk requiring risk-management protocols.

Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is caused by deficiency of the branched-chain alpha-ketoacid dehydrogenase complex, so the branched-chain amino acids leucine, isoleucine, and valine accumulate (leucine is the neurotoxin; the urine smells of maple syrup or burnt sugar). Chronic management restricts natural protein to titrate leucine to target plasma levels while a BCAA-free medical food supplies the remaining protein, plus isoleucine and valine supplementation as needed to keep them sufficient. The highest-stakes skill is the sick-day protocol: intercurrent illness triggers catabolism, which floods the blood with leucine from endogenous protein breakdown. Families are taught to reduce natural protein, keep the BCAA-free formula and high-calorie carbohydrates flowing, and seek immediate care for vomiting, lethargy, or ataxia. In-hospital crises are treated with IV glucose (often with insulin) and lipids to shut down catabolism; severe leucine elevation with encephalopathy may require hemodialysis. Liver transplantation halts crises and is an option in classic disease.

Urea Cycle Disorders

In urea cycle disorders (UCD), the liver cannot convert ammonia to urea; ornithine transcarbamylase (OTC) deficiency, an X-linked disorder, is the most common. Chronic management combines:

• Protein restriction matched to age and residual enzyme activity, sometimes with essential amino acid formula.
• Citrulline or arginine supplementation to replace urea cycle intermediates downstream of the block (arginine becomes essential in most UCDs).
• Nitrogen-scavenging medications: sodium benzoate and sodium phenylbutyrate (or glycerol phenylbutyrate) divert nitrogen into alternative excretion pathways.

The hyperammonemia emergency protocol is a must-know: stop all protein intake immediately, give IV glucose (D10) with or without insulin plus IV lipids to reverse catabolism, start IV nitrogen scavengers, and use hemodialysis for severe or refractory hyperammonemia. Protein is reintroduced within about 24-48 hours, because prolonged protein withdrawal itself drives catabolism.

Classic Galactosemia

Classic galactosemia (galactose-1-phosphate uridyltransferase, GALT, deficiency) makes dietary galactose toxic. Treatment is immediate and lifelong elimination of lactose and galactose: in infancy this means soy-based formula (breast milk and standard cow's-milk formulas contain lactose), followed by lifelong dairy avoidance with careful label reading. Calcium and vitamin D adequacy must be engineered from substitutes. Critically for counseling, long-term complications occur despite diet: speech and language deficits, learning differences, tremor/ataxia, and primary ovarian insufficiency in most females.

Fatty Acid Oxidation Disorders

In medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the most common fatty acid oxidation defect, fasting depletes glucose and the body cannot mobilize medium-chain fat for energy, risking hypoketotic hypoglycemia, encephalopathy, and death. The dietary prescription is deceptively simple: avoid fasting. Infants feed frequently with age-appropriate overnight fasting limits, and any illness with poor intake or vomiting triggers an emergency protocol of glucose-containing fluids and immediate evaluation. Medium-chain triglyceride oil is avoided, and routine carnitine supplementation is controversial (secondary carnitine depletion argues for it; acylcarnitine accumulation argues against), so practice varies by center.

Glycogen Storage Disease Type I

Glycogen storage disease type I (GSD I, von Gierke disease) is glucose-6-phosphatase deficiency: the liver stores glycogen but cannot release glucose, so hypoglycemia develops within a few hours of fasting. Management is nutritional engineering of a continuous glucose supply: frequent daytime feeds every 2-4 hours, scheduled doses of uncooked cornstarch (a slow-release glucose polymer), and continuous overnight tube feeds in infants. Because fructose and galactose cannot be converted to glucose and instead drive lactate, uric acid, and triglyceride production, sucrose, fruit (fructose), and lactose (galactose) are restricted.

Homocystinuria and Mitochondrial Disorders

Classical homocystinuria (cystathionine beta-synthase deficiency) is treated with a methionine-restricted diet (cystine becomes conditionally essential) plus a methionine-free medical food; roughly half of patients are pyridoxine (vitamin B6)-responsive and can relax restriction, while betaine lowers homocysteine and B12/folate support remethylation in related defects. Mitochondrial disorders have no single evidence-based diet: practical principles include avoiding prolonged fasting and catabolic stress; mitochondrial cocktails (coenzyme Q10, riboflavin, and others) are used despite limited evidence, and ketogenic diets are reserved for selected epilepsy phenotypes under close supervision.

Comparison of Major Inborn Errors

General IEM Diet Principles

Across disorders the pattern is constant: identify the blocked pathway, restrict the nutrient upstream of the block, and replace what the restriction removes. Medical foods (amino acid formulas missing Phe, BCAA, or methionine) supply protein without the offending nutrient; natural protein is counted in milligrams or exchanges; and metabolic crisis prevention during catabolic stress (illness, surgery, fasting) with written sick-day plans is as important as the daily diet. Growth, bone health, and micronutrient status are monitored lifelong, with planned transition from pediatric to adult metabolic care.