A 3-week-old newborn is brought to the pediatrician by his mother. His mother is concerned about her son’s irritability and vomiting, particularly after breastfeeding him. The infant was born at 39 weeks via spontaneous vaginal delivery. His initial physical was benign. Today the newborn appears mildly jaundiced with palpable hepatomegaly, and his eyes appear cloudy, consistent with the development of cataracts. The newborn is also in the lower weight-age percentile. The physician considers a hereditary enzyme deficiency and orders blood work and a urinalysis to confirm his diagnosis. He recommends that milk and foods high in galactose and/or lactose be eliminated from the diet. Which of the following is the most likely deficient enzyme in this metabolic disorder?

Galactose-1-phosphate uridyl transferase

Glucose-6-phosphate dehydrogenase

A 2-day-old male is seen in the newborn nursery for repeated emesis and lethargy. He was born at 39 weeks to a 24-year-old mother following an uncomplicated pregnancy and birth. He has been breastfeeding every 2 hours and has 10 wet diapers per day. His father has a history of beta-thalassemia minor. Laboratory results are as follows: Hemoglobin: 12 g/dL Platelet count: 200,000/mm³ Mean corpuscular volume: 95 µm³ Reticulocyte count: 0.5% Leukocyte count: 5,000/mm³ with normal differential Serum: Na+: 134 mEq/L Cl-: 100 mEq/L K+: 3.3 mEq/L HCO3-: 24 mEq/L Urea nitrogen: 1 mg/dL Creatinine: 0.6 mg/dL Ammonia: 150 µmol/L (normal: 50-80 µmol/L) Which of the following is the most likely diagnosis?

Ornithine transcarbamylase deficiency

An 8-month-old female infant from a first-degree consanguineous couple was brought to the physician because the mother noticed abnormalities in the growth of her child as well as the different lengths of her child's legs. The infant had gingival hyperplasia, restricted movement in both shoulders, a prominent, pointed forehead, and enophthalmos with a slight opacity in both corneas. A blood test revealed 10 fold higher than normal levels of the following enzymes: N-acetyl-ß-glucosaminidase, ß-glucuronidase, ß-hexosaminidase A, and alkaline phosphatase. Which of the following is most likely deficient in this patient?

N-acetyl-glucosamine-1-phosphotransferase

Lysosomal alpha-1,4-glucosidase

Glucose-6-phosphate dehydrogenase

A 2-week-old boy presents to the emergency department because of unusual irritability and lethargy. The patient is admitted to the pediatric intensive care unit and minutes later develops metabolic encephalopathy. This progressed to a coma, followed by death before any laboratory tests are completed. The infant was born at home via vaginal delivery at 39 weeks' of gestation. His mother says that the symptoms started since the infant was 4-days-old, but since he only seemed ‘tired’, she decided not to seek medical attention. Further testing during autopsy shows hyperammonemia, low citrulline, and increased orotic acid. Which of the following enzymes is most likely deficient in this patient?

Branched-chain alpha-ketoacid dehydrogenase

Inborn errors of metabolism for USMLE Step 1: High-Yield Pediatrics Lessons

IEM Basics - Metabolic Mayhem

Core Defect: Monogenic enzyme/transporter deficiency → substrate accumulation or product deficiency.
Classic Presentation: Acutely ill neonate mimicking sepsis. Key features: poor feeding, vomiting, lethargy, seizures, altered sensorium.
Initial Lab Red Flags:
- Hypoglycemia
- Metabolic acidosis (especially with ↑ anion gap)
- Hyperammonemia
- Ketosis (or inappropriate absence of ketones)

⭐ Suspect an IEM in any term neonate with a sepsis-like picture but negative cultures.

Carbohydrate Disorders - Sugar Rush Gone Wrong

Galactosemia (GALT deficiency): Presents in neonates after milk feeds.
- Features: Jaundice, hepatomegaly, vomiting, cataracts, FTT.
- Dx: ↑ Galactose-1-P in RBCs; reducing substances in urine.
- Rx: Lifelong lactose-free diet.
⭐ High-Yield: Classic Galactosemia is strongly associated with E. coli neonatal sepsis.
Hereditary Fructose Intolerance (Aldolase B deficiency): Symptoms start with weaning (fruits/honey).
- Features: Hypoglycemia, vomiting, jaundice, hepatomegaly.
- Rx: Avoid fructose, sucrose, sorbitol.
Glycogen Storage Diseases (GSDs):
- Type I (von Gierke): G6Pase def. Severe fasting hypoglycemia, lactic acidosis, hepatomegaly, doll-like face.
- Type II (Pompe): α-glucosidase def. Cardiomegaly, hypotonia, macroglossia.
- Type V (McArdle): Muscle phosphorylase def. Exercise intolerance, cramps, myoglobinuria.
- 📌 Mnemonic: McArdle = Muscle.

Fructose metabolism pathway and related disorders

Amino Acidopathies - Protein Problems

Phenylketonuria (PKU): Deficient Phenylalanine Hydroxylase → ↑ Phe.
- Features: Musty/mousy odor, intellectual disability, seizures, eczema.
- Screening: Guthrie test / Mass spectrometry. Rx: Low Phe diet.
Maple Syrup Urine Disease (MSUD): Deficient Branched-Chain α-ketoacid Dehydrogenase.
- ↑ BCAAs (Leucine, Isoleucine, Valine). 📌 I Love Vermont maple syrup.
- Features: Urine/cerumen smells of burnt sugar; neurotoxic.
Homocystinuria: Deficient Cystathionine β-synthase → ↑ Homocysteine & Methionine.
- Rx: ↓ Met, ↑ Cys diet; Vitamin B6 (pyridoxine).
Alkaptonuria: Deficient Homogentisate Oxidase.
- Urine turns black on standing; ochronosis (dark cartilage/sclera), arthritis.

⭐ Homocystinuria vs. Marfan Syndrome: Both have marfanoid habitus & ectopia lentis. Homocystinuria features intellectual disability, thrombosis, and downward lens dislocation (vs. upward in Marfan's).

Inborn Errors of Metabolism Classification

Lysosomal Storage - Cellular Cleanup Crisis

Pathophysiology: Inherited defects in lysosomal hydrolase enzymes → accumulation of undigested substrates → cellular dysfunction & organ damage.

Key Types:
- Gaucher: ↓ Glucocerebrosidase. Hepatosplenomegaly, pancytopenia, bone crises. Gaucher cells (crinkled paper cytoplasm).
- Tay-Sachs: ↓ Hexosaminidase A. Cherry-red spot, neurodegeneration. NO hepatosplenomegaly.
- Niemann-Pick: ↓ Sphingomyelinase. Cherry-red spot, hepatosplenomegaly. Foam cells.
- Fabry: X-Linked Recessive. ↓ α-galactosidase A. Angiokeratomas, neuropathic pain, renal failure.
- Hurler (MPS I): ↓ α-L-iduronidase. Coarse facies, corneal clouding, dysostosis multiplex.

⭐ Gaucher Disease is the most common LSD. Diagnosis is confirmed by finding lipid-laden macrophages with a characteristic "crinkled tissue paper" appearance.

Gaucher cell with crumpled tissue paper cytoplasm

Urea Cycle & Acidemias - Ammonia Alert

Presentation: Neonatal encephalopathy (lethargy, seizures, coma), vomiting. Key lab: ↑ Ammonia.
Key Differentiation: Acid-base status is crucial.
- Organic Acidemias (Methylmalonic, Propionic): Severe high anion gap metabolic acidosis.
- Urea Cycle Defects (OTC deficiency): Primary respiratory alkalosis, minimal acidosis.

⭐ Ornithine Transcarbamylase (OTC) deficiency is the most common urea cycle disorder and is X-linked recessive.

Urea Cycle Pathway and Enzyme Deficiencies

High‑Yield Points - ⚡ Biggest Takeaways

PKU: Presents with a characteristic mousy odor, fair skin, and eczema; neonatal screening is key.

Galactosemia: Features include jaundice, cataracts, and reducing substances in the urine.

MSUD: Characterized by maple syrup odor in urine, poor feeding, and encephalopathy.

Homocystinuria: Look for Marfanoid habitus, downward lens dislocation, and a high risk of thrombosis.

Von Gierke's (GSD-I): Severe fasting hypoglycemia, lactic acidosis, and massive hepatomegaly.

Tay-Sachs: Cherry-red spot, developmental regression, and hyperacusis, but no hepatosplenomegaly.

Gaucher Disease: Presents with massive hepatosplenomegaly, pancytopenia, and bone crises.

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Inborn errors of metabolism