Amino Acid Disorders

• Definition: Inborn errors of amino acid metabolism are single-gene enzyme (or cofactor) deficiencies in the catabolic pathways of individual amino acids, producing toxic accumulation of substrate proximal to the block and, less often, deficiency of an essential downstream product.
• Why it matters: The accumulating metabolites are preferentially neurotoxic to the developing brain, and the damage is largely irreversible once established. Nearly all of these conditions are treatable — by diet, cofactor, or scavenger — so the entire clinical value lies in detection before symptoms, which is why they dominate newborn screening policy and exam questions.
• Screening context: Phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria, tyrosinemia type I, and several urea cycle disorders (citrullinemia, argininosuccinic aciduria) sit on the HRSA/ACHDNC Recommended Uniform Screening Panel, screened by tandem mass spectrometry on a dried blood spot in every U.S. state. Alkaptonuria is not screened — it is clinically silent in childhood.

Epidemiology worth recalling

• Inheritance: Autosomal recessive for essentially all of them; the important exception is ornithine transcarbamylase (OTC) deficiency, which is X-linked and the most common urea cycle disorder.
• PKU: the prototype, on the order of 1 in 10,000–15,000 U.S. births; more frequent in Irish and Turkish ancestry, rare in those of African and Ashkenazi Jewish ancestry.
• MSUD: rare in the general population (roughly 1 in 185,000) but strikingly common in Old Order Mennonite communities through a founder variant — a favorite stem detail.
• Classic homocystinuria: on the order of 1 in 200,000–300,000 worldwide, with markedly higher incidence in Ireland.
• Alkaptonuria: very rare overall, with clusters described in Slovakia and the Dominican Republic; presents in the third to fourth decade rather than in infancy.
• Age of presentation: symptomatic neonatal presentation (MSUD, urea cycle defects) versus insidious childhood/adult presentation (untreated PKU, homocystinuria, alkaptonuria) is the single most useful triage axis on exams.

Causes grouped by mechanism

• Defective hydroxylation (aromatic amino acids): loss-of-function PAH variants cause PKU. A biochemically identical picture arises from defects in synthesis or recycling of the cofactor tetrahydrobiopterin (BH₄) — GTP cyclohydrolase, 6-pyruvoyl-tetrahydropterin synthase, or dihydropteridine reductase — the so-called malignant hyperphenylalaninemia, which diet alone will not fix.
• Defective oxidative decarboxylation: the branched-chain α-ketoacid dehydrogenase complex fails in MSUD. Like pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, it is a thiamine (TPP)-dependent complex, explaining thiamine-responsive variants.
• Defective transsulfuration: cystathionine β-synthase deficiency blocks homocysteine → cystathionine, the classic homocystinuria. Remethylation defects (MTHFR deficiency, cobalamin C disease, B₁₂ deficiency) raise homocysteine too, but with low or normal methionine rather than high.
• Defective tyrosine degradation: homogentisate 1,2-dioxygenase loss causes alkaptonuria; fumarylacetoacetate hydrolase loss, further downstream, causes tyrosinemia type I.
• Defective ureagenesis: enzyme or transporter defects anywhere in the urea cycle (OTC, CPS1, NAGS, ASS1, ASL, arginase) block ammonia disposal.

Non-modifiable risk factors examiners plant

• Consanguinity or a founder population: Mennonite (MSUD), Irish (PKU, homocystinuria), Slovak/Dominican (alkaptonuria).
• Affected sibling or unexplained neonatal death, particularly a male infant who "crashed" in the first week.
• Male sex in OTC deficiency; heterozygous females may be asymptomatic or decompensate later depending on X-inactivation.
• Maternal PKU: uncontrolled maternal phenylalanine is teratogenic to a genotypically normal fetus — microcephaly, congenital heart disease, intrauterine growth restriction.

Modifiable / precipitating factors

• Catabolic stress: intercurrent infection, fasting, vomiting, surgery, trauma, or the postpartum period unmask urea cycle defects and trigger MSUD crises.
• Protein load: a high-protein meal, TPN, or gastrointestinal bleeding.
• Drugs: valproate and salicylates precipitate hyperammonemia; corticosteroids drive protein catabolism; nitrous oxide inactivates methionine synthase and worsens remethylation defects.
• Dietary non-adherence, the leading cause of preventable neurologic decline in adolescents with PKU.

• PKU — a transport and neurotransmitter problem, not simple toxicity: without phenylalanine hydroxylase, phenylalanine accumulates and is shunted to phenylketones (phenylpyruvate, phenylacetate — the mousy/musty odor). Massive plasma phenylalanine saturates the large neutral amino acid transporter (LAT1) at the blood–brain barrier, competitively excluding tyrosine and tryptophan, so brain dopamine and serotonin synthesis fall. Phenylalanine also inhibits tyrosinase, and tyrosine becomes conditionally essential — hence hypopigmented skin, blue eyes, fair hair. Chronic exposure impairs myelination, producing the periventricular white-matter changes and intellectual disability of untreated disease.
• MSUD — leucine is the culprit: the branched-chain α-ketoacid dehydrogenase block raises leucine, isoleucine, valine and their ketoacids. Leucine and α-ketoisocaproate are the neurotoxic species; they disturb brain amino acid transport and cell volume regulation, generating cerebral edema and the encephalopathy of a metabolic crisis. Alloisoleucine, formed by transamination of accumulated ketoacids, is the biochemical fingerprint. Sotolone from isoleucine metabolism produces the maple syrup/burnt sugar odor.
• Homocystinuria — a crosslinking defect: homocysteine accumulates and methionine backs up above the block. Homocysteine interferes with lysyl oxidase-mediated collagen and fibrillin crosslinking, weakening connective tissue: marfanoid habitus, osteoporosis, and zonular fiber failure with downward, inward lens dislocation. Endothelial injury and a prothrombotic milieu drive arterial and venous thrombosis, which is the leading cause of death. Cysteine becomes conditionally essential because the transsulfuration pathway is blocked.
• Alkaptonuria — polymer deposition: homogentisic acid cannot be converted to maleylacetoacetate, so it accumulates, is renally excreted (urine darkens on standing or alkalinization from oxidation and polymerization), and the pigmented polymer binds avidly to collagen in cartilage, sclerae, and heart valves — ochronosis. Pigment-stiffened cartilage degenerates mechanically, producing a destructive spondyloarthropathy decades later.
• Urea cycle defects: ammonia is not condensed into urea, so it is buffered by glutamine synthetase in astrocytes. Glutamine accumulation causes astrocyte osmotic swelling and cerebral edema, while ammonia directly stimulates the brainstem respiratory centers, producing the characteristic respiratory alkalosis — the opposite of the acidosis seen in organic acidemias.

The neonate who was normal at birth (days 2–7 of life)

• MSUD: poor feeding, vomiting, lethargy alternating with irritability, hypertonia with opisthotonos and "bicycling" movements, then seizures and coma. The stem names a Mennonite infant or a home-birth infant who missed newborn screening, and mentions a sweet, maple-syrup or burnt-sugar odor in urine or cerumen.
• Urea cycle disorder: an identical clinical picture but with vomiting, tachypnea/hyperventilation and respiratory alkalosis, normal anion gap, no ketosis, and no unusual odor. A male infant with a maternal family history of unexplained infant deaths suggests X-linked OTC deficiency. Later-onset forms present after weaning to high-protein food, at illness, postpartum, or with valproate.

The untreated child or adolescent

• PKU: normal at birth (maternal enzyme cleared the fetus in utero), then progressive intellectual disability, microcephaly, seizures with hypsarrhythmia, tremor, and autistic or hyperactive behavior. Physical exam shows fair skin, blond hair, blue eyes, and eczema from tyrosine deficiency and phenylalanine accumulation, plus the musty/mousy body odor.
• Homocystinuria: tall, thin, long-limbed marfanoid habitus with arachnodactyly, pectus deformity, scoliosis, high-arched palate — but distinguished from Marfan syndrome by intellectual disability, osteoporosis, malar flush/livedo reticularis, and thromboembolism. Ectopia lentis is downward and inward (upward and outward in Marfan). A teenager with a stroke or DVT and no other risk factor is the classic stem.
• Alkaptonuria: the only one that presents in adulthood. Parents recall diapers or urine turning black on standing; decades later, blue-black scleral and ear-cartilage pigmentation, dark cerumen, and a degenerative arthropathy of the lumbar spine and large joints with intervertebral disc calcification. Pigment in the aortic valve may cause stenosis, and ochronotic renal/prostatic stones occur.

Step 1 — the screen

• Newborn screening by tandem mass spectrometry on a dried blood spot, ideally at 24–48 hours of age, is the initial test for PKU, MSUD, homocystinuria, tyrosinemia, and several urea cycle disorders (per the HRSA/ACHDNC Recommended Uniform Screening Panel). A screen is presumptive only — every abnormal result requires quantitative confirmation. Alkaptonuria is not screened.

Step 2 — the sick neonate (do these in parallel, do not wait)

• Plasma ammonia is the single most important test in any encephalopathic neonate; a markedly elevated ammonia with respiratory alkalosis, normal anion gap, and no ketosis points to a urea cycle defect. Ammonia must be drawn free-flowing, on ice, and run immediately.
• Quantitative plasma amino acids, urine organic acids, urine orotic acid, glucose, lactate, blood gas, and ketones complete the panel.

Confirmatory findings that carry the diagnosis

• PKU: quantitative plasma phenylalanine elevated with a low or normal tyrosine and a high Phe:Tyr ratio. ACMG guidance defines treatment thresholds around blood phenylalanine above 360 µmol/L, with classic PKU well above 1,200 µmol/L. Mandatory next step: measure pterins (urine/blood) and dihydropteridine reductase activity to exclude BH₄ cofactor defects before committing to diet alone.
• MSUD: elevated leucine, isoleucine, and valine; plasma alloisoleucine is essentially pathognomonic. Urine dinitrophenylhydrazine turns positive; ketonuria in a neonate is always abnormal.
• Classic homocystinuria: elevated total plasma homocysteine WITH elevated methionine — the high methionine is what separates CBS deficiency from remethylation defects (MTHFR, cobalamin C), where methionine is low. Urine cyanide-nitroprusside test is the historical bedside screen.
• Alkaptonuria: urine that darkens on standing or with alkali; confirm with quantitative urine homogentisic acid by GC-MS. Radiographs show disc space narrowing with dense intervertebral calcification.
• Urea cycle localization: citrulline level triages the block (low/absent in OTC and CPS1, very high in citrullinemia), and urine orotic acid is high in OTC (carbamoyl phosphate spills into pyrimidine synthesis) but low in CPS1/NAGS deficiency.
• Molecular genetic testing / enzyme assay provides the definitive diagnosis and enables carrier and prenatal testing.

Immediate stabilization of a metabolic crisis (MSUD, urea cycle disorders)

• Stop all protein intake for roughly 24–48 hours and reverse catabolism with high-rate IV dextrose (with insulin as needed to prevent hyperglycemia) plus intravenous lipid — anabolism is the therapy.
• Nitrogen scavengers: IV sodium phenylacetate/sodium benzoate provides alternative nitrogen disposal via phenylacetylglutamine and hippurate; IV arginine (or citrulline) restores cycle intermediates except in arginase deficiency.
• Hemodialysis/CRRT is the fastest way to clear ammonia and leucine and is indicated for severe or rising levels or coma despite scavengers; the Urea Cycle Disorders Consortium supports early dialysis in neonatal hyperammonemic coma. Peritoneal dialysis and exchange transfusion are inadequate.

Chronic, disorder-specific therapy

• PKU (ACMG guideline): lifelong phenylalanine-restricted diet with a Phe-free medical formula, targeting blood phenylalanine roughly 120–360 µmol/L for life, including pregnancy. Sapropterin (synthetic BH₄) in responders raises dietary tolerance; pegvaliase, a PEGylated phenylalanine ammonia lyase given subcutaneously, is FDA-approved for adults with uncontrolled levels but carries a boxed warning for anaphylaxis and requires REMS enrollment.
• MSUD: BCAA-restricted diet with leucine-free formula, sick-day emergency protocol, trial of thiamine in suspected responders; liver transplantation is the definitive option in poorly controlled disease.
• Homocystinuria: high-dose pyridoxine (B₆) trial defines the responsive subtype; add folate and B₁₂, a methionine-restricted/cysteine-supplemented diet, and betaine anhydrous to remethylate homocysteine to methionine in non-responders. Antithrombotic therapy for thrombotic events and aggressive perioperative VTE prophylaxis.
• Alkaptonuria: symptom control with analgesics/physical therapy and joint replacement; nitisinone, which inhibits 4-hydroxyphenylpyruvate dioxygenase upstream and thereby cuts homogentisic acid production, reduces pigment deposition (used off-label in the U.S.) and requires tyrosine-restricted diet with ophthalmologic monitoring.

Contraindicated / avoid

• Valproate in any urea cycle disorder; nitrous oxide in remethylation defects.
• Estrogen-containing contraceptives in homocystinuria (additive thrombotic risk).
• Aspartame in PKU (a phenylalanine source).
• Never rely on diet alone in hyperphenylalaninemia until a BH₄ defect has been excluded — those patients need neurotransmitter precursors (levodopa/carbidopa, 5-hydroxytryptophan) plus BH₄.

Emergencies (flagged)

• Hyperammonemic encephalopathy and cerebral edema — EMERGENCY. Glutamine-driven astrocyte swelling causes coma, posturing, and herniation; duration of hyperammonemic coma correlates directly with permanent neurologic disability. Signalled by rising ammonia, widening pulse pressure, or pupillary change.
• MSUD metabolic crisis with cerebral edema — EMERGENCY. Rising leucine with lethargy, opisthotonos, and respiratory failure; may be provoked by nothing more than a viral illness.
• Thromboembolism in homocystinuria — EMERGENCY. Endothelial injury and a prothrombotic state cause DVT/PE, cerebral venous sinus thrombosis, and premature myocardial infarction or stroke, classically in a teenager or young adult, and often triggered by surgery, immobilization, or estrogen.

Disease complications

• Irreversible intellectual disability, microcephaly, seizures, and white-matter demyelination in untreated PKU; late dietary loosening in adults produces reversible executive dysfunction, tremor, and mood disorder.
• Maternal PKU syndrome: uncontrolled maternal phenylalanine causes fetal microcephaly, intellectual disability, congenital heart disease, and growth restriction — in a fetus who does not have PKU. Preconception control is the only prevention.
• Ectopia lentis with pupillary block glaucoma, high myopia, retinal detachment, and osteoporosis with vertebral fractures in homocystinuria.
• Ochronotic arthropathy with destructive spine and large-joint disease, tendon and Achilles rupture, aortic/mitral valve calcification and stenosis, coronary calcification, and pigmented renal/prostatic stones in alkaptonuria.
• Chronic developmental delay, movement disorder, and attention deficits after any survived neonatal metabolic coma.

Treatment complications

• Over-restriction of the offending amino acid: because phenylalanine and leucine are essential, excessive dietary restriction causes catabolism, growth failure, dermatitis (an acrodermatitis-like rash in PKU), and anemia — a paradoxical rise in the toxic metabolite as endogenous protein breaks down.
• Nutritional deficiency of vitamin B₁₂, iron, zinc, selenium, and calcium in formula-dependent patients.
• Pegvaliase anaphylaxis (boxed warning, REMS) and sapropterin-associated hypophenylalaninemia.
• Nitisinone-induced hypertyrosinemia causing corneal crystal deposition and photophobia — requires slit-lamp surveillance and tyrosine restriction.
• Sodium load and hypokalemia from IV benzoate/phenylacetate scavengers; catheter-related complications of emergent hemodialysis in neonates.

• Odors are free points: musty/mousy = PKU (phenylacetate); maple syrup/burnt sugar = MSUD (sotolone); sweaty feet = isovaleric acidemia; boiled cabbage = tyrosinemia. No odor + hyperventilation = urea cycle defect.
• The single best next step in an encephalopathic neonate is a plasma ammonia level — before LP, before EEG, before imaging. Then use the blood gas to split the differential: respiratory alkalosis without ketosis = urea cycle defect; high anion gap acidosis with ketosis = organic acidemia.
• Urine orotic acid is the OTC discriminator: high orotic acid + hyperammonemia + low citrulline = X-linked OTC deficiency; low orotic acid = CPS1 or NAGS deficiency. The distractor is confusing this with orotic aciduria from UMP synthase deficiency, where there is megaloblastic anemia and no hyperammonemia.
• Homocystinuria vs. Marfan: both are marfanoid with ectopia lentis, but homocystinuria gives downward and inward lens dislocation, intellectual disability, osteoporosis, and thrombosis; Marfan gives upward and temporal dislocation, normal intellect, and aortic root dilation. Homocystinuria is autosomal recessive; Marfan is autosomal dominant (FBN1).
• High homocysteine + high methionine = CBS deficiency; high homocysteine + low methionine = remethylation defect (MTHFR, cobalamin C, B₁₂ deficiency). Always check the methionine.
• Not all hyperphenylalaninemia is PKU — always exclude a BH₄ (tetrahydrobiopterin) cofactor defect, because BH₄ is also required by tyrosine and tryptophan hydroxylases; those infants deteriorate neurologically on diet alone and need BH₄ plus neurotransmitter precursors.
• Tyrosine is conditionally essential in PKU — that is why patients are pale, blond, and blue-eyed, and why aspartame is forbidden.
• Maternal PKU harms a fetus who does not have the disease; per ACMG, phenylalanine control must be achieved before conception, not at the first prenatal visit.
• Alkaptonuria is the benign-in-childhood one: dark diapers in infancy, ochronotic spine and joint disease in the fourth decade, and it is not on newborn screening.

• Phenylketonuria (PKU): Phenylalanine hydroxylase deficiency → hyperphenylalaninemia; screened on newborn screening; treated with low-phenylalanine diet
• Maple Syrup Urine Disease (MSUD): Branched-chain α-ketoacid dehydrogenase deficiency → accumulation of leucine, isoleucine, valine; "maple syrup" odor in urine
• Homocystinuria: Cystathionine β-synthase deficiency → elevated homocysteine; causes thrombosis, lens dislocation, intellectual disability
• Alkaptonuria: Homogentisate oxidase deficiency → dark urine, ochronosis (blue-black pigment), arthropathy
• Urea cycle disorders: Defects in ammonia detoxification → hyperammonemia with encephalopathy, seizures, coma

• PKU: Intellectual disability, "mousy" odor, light skin/hair, eczema (if untreated)
• MSUD: Lethargy, poor feeding, seizures, developmental delay in first weeks of life; urine smells like maple syrup
• Homocystinuria: Marfanoid habitus, downward lens dislocation (ectopia lentis), thrombosis, intellectual disability
• Alkaptonuria: Dark urine on standing/diaper, ochronosis (blue pigmentation) in cartilage, arthralgias in middle age
• Urea cycle disorders: Hyperammonemic crisis with vomiting, altered mental status, respiratory alkalosis

• Confusing respiratory alkalosis with acidosis in urea cycle disorders: Hyperammonemia causes alkalosis (ammonia consumes H⁺ in glutamine synthesis); respiratory alkalosis worsens hyperammonemia
• Missing dietary vs. genetic heterozygosity: PKU diet must begin before 3 weeks of age to prevent irreversible neurologic damage; untreated heterozygotes typically asymptomatic but maternal PKU harms fetus
• Ignoring secondary hyperammonemia: Valproate, salicylates, and infections can precipitate urea cycle decompensation; always check ammonia level, not just LFTs

• PKU: Low-phenylalanine diet started immediately after positive newborn screening; monitor phenylalanine levels; consider sapropterin (BH₄) if responsive
• MSUD: Leucine-restricted diet + avoid catabolism (feeding during illness); dialysis for acute hyperleucosis
• Homocystinuria: Vitamin B₆ (pyridoxine) supplementation first-line; if unresponsive, add betaine and folate/B₁₂; anticoagulation if thrombotic events
• Alkaptonuria: Supportive care; no cure (AR condition); NSAIDs for arthropathy; nitisinone (HGD inhibitor) emerging therapy
• Urea cycle disorders: Protein restriction + nitrogen-scavenging agents (lactulose, rifaxomycin, sodium benzoate, carnitine); critical to manage during catabolic stress