A 28-year-old primigravida at 14 weeks gestation is brought to the emergency department by… — USMLE Step 3

A 28-year-old primigravida at 14 weeks gestation is brought to the emergency department by her husband due to progressive confusion, lethargy, and recurrent vomiting over the past 24 hours. The husband reports that her symptoms began shortly after they attended a celebratory dinner where she consumed a large portion of steak. The patient has a lifelong history of self-restricting meat and dairy from her diet, stating they make her feel "foggy and irritable." Family history is notable for a male sibling who died at 4 days of life from a "metabolic coma."

Physical examination reveals a somnolent woman who arouses to physical stimuli. She exhibits a flapping tremor of the hands when her wrists are extended.

Laboratory studies are as follows:

Test	Result	Reference Range
Sodium	140 mEq/L	136-145 mEq/L
Potassium	4.1 mEq/L	3.5-5.0 mEq/L
Chloride	104 mEq/L	95-105 mEq/L
Bicarbonate	24 mEq/L	22-28 mEq/L
Blood urea nitrogen (BUN)	4 mg/dL	7-18 mg/dL
Creatinine	0.6 mg/dL	0.6-1.2 mg/dL
Glucose	98 mg/dL	70-99 mg/dL
Arterial pH	7.49	7.35-7.45
$PaCO_2$	28 mm Hg	35-45 mm Hg
Serum ammonia	280 μmol/L	15-45 μmol/L

Urinalysis reveals markedly elevated orotic acid levels.

Which of the following genetic principles best explains why this patient survived to adulthood while her sibling experienced early neonatal mortality?

Asymmetric epigenetic silencing of a sex chromosome during early embryogenesisAnswer
B
Random partition of mutant and wild-type mitochondrial genomes during mitosis
C
Intergenerational expansion of an unstable nucleotide repeat sequence during gametogenesis
D
Parent-of-origin dependent monoallelic gene expression via DNA methylation
E
Presence of genetically distinct cell lineages arising from a post-zygotic mutation

Answer

Asymmetric epigenetic silencing of a sex chromosome during early embryogenesis

The patient is experiencing an acute hyperammonemic crisis secondary to ornithine transcarbamylase (OTC) deficiency, which has been unmasked by the physiologic stress of pregnancy and a high-protein meal. OTC deficiency is the only urea cycle disorder with an X-linked recessive inheritance pattern. Males (hemizygous) typically present with severe, often fatal, neonatal hyperammonemia, consistent with the patient's deceased brother. Female carriers (heterozygous) have a highly variable clinical phenotype ranging from asymptomatic to severe adult-onset crises. This variability is driven by skewed X-chromosome inactivation (lyonization) in hepatocytes—a process of asymmetric epigenetic silencing via DNA methylation and heterochromatin formation during early embryogenesis. If by chance the normal X chromosome is preferentially inactivated in a majority of liver cells, the female carrier will exhibit limited enzyme activity and become symptomatic under nitrogen load.

Step-by-Step Solution

Analyze the patient's laboratory profile and clinical presentation.

The patient has hyperammonemia, low BUN, respiratory alkalosis, and highly elevated urinary orotic acid in the setting of acute encephalopathy triggered by a high-protein meal.

These specific biochemical markers distinguish urea cycle defects from other metabolic causes of altered mental status.

Diagnose the specific underlying metabolic disorder.

The combination of hyperammonemia and elevated orotic acid confirms ornithine transcarbamylase (OTC) deficiency.

OTC deficiency prevents the conversion of carbamoyl phosphate and ornithine to citrulline. The accumulated carbamoyl phosphate shunts into the pyrimidine synthesis pathway, producing excess orotic acid. Other urea cycle defects (like CPS1 deficiency) present with low orotic acid.

Determine the genetic inheritance pattern of the identified disorder.

OTC deficiency is uniquely inherited in an X-linked recessive pattern.

Unlike all other urea cycle defects, which are autosomal recessive, OTC is X-linked. This explains the family history of a male sibling suffering lethal neonatal metabolic coma (hemizygous).

Identify the molecular mechanism allowing the female patient to survive to adulthood but become symptomatic under stress.

The correct mechanism is asymmetric epigenetic silencing of the X chromosome, clinically known as skewed X-inactivation or lyonization.

In heterozygous females, random X-inactivation occurs. If a disproportionately large number of normal X chromosomes are inactivated in the liver, the female will manifest symptoms of the X-linked recessive disorder, particularly when exposed to increased metabolic demand (e.g., pregnancy, high-protein diet).

Key Concept

Ornithine transcarbamylase (OTC) deficiency presentation in female carriers is dependent on the degree of skewed X-chromosome inactivation (lyonization).

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