Ornithine Transcarbamylase (OTC) Deficiency

1. DEFINITION AND EPIDEMIOLOGY

Definition: The most common Urea Cycle Disorder (UCD), characterized by the inability to convert ornithine and carbamoyl phosphate into citrulline.
Inheritance: X-Linked Recessive (The only X-linked UCD; all others are Autosomal Recessive).
Incidence: Approx 1 in 14,000 to 1 in 77,000 live births.
Genetics:
- Gene: OTC gene at chromosome Xp11.4.
- Males: Hemizygotes (Severe, neonatal onset).
- Females: Heterozygotes (Variable phenotype due to skewed X-inactivation/Lyonization); ranges from asymptomatic to fatal.

Primary Defect: Deficiency of hepatic mitochondrial enzyme Ornithine Transcarbamylase.
Metabolic Consequences:
1. Hyperammonemia: Failure to detoxify ammonia into urea -> Neurotoxicity (cerebral edema, astrocyte swelling).
2. Orotic Aciduria: Accumulated Carbamoyl Phosphate shunts into the pyrimidine synthesis pathway -> Excess Orotic Acid.
3. Amino Acid Imbalance: Depletion of Citrulline and Arginine (which becomes an essential amino acid).

Presentation: Healthy at birth, symptoms begin after 24–48 hours (after protein feeding starts).
"Sepsis Mimic": Poor feeding, lethargy, vomiting, hypothermia.
Neurologic:
- Central Hyperventilation: Due to cerebral edema (Respiratory Alkalosis).
- Progression to somnolence, seizures, and deep coma.
- Bulging fontanelle (Increased ICP).
Outcome: Rapidly fatal if untreated; high risk of severe intellectual disability in survivors.

Triggers: High protein load, catabolic stress (infection, surgery, steroids), postpartum, or valproate use.
Symptoms:
- History: Voluntary protein aversion ("Vegetarian by choice"), recurrent vomiting, failure to thrive.
- Episodic: Ataxia, confusion, aggression, irritability ("Psychiatric" presentation).
- Cyclical vomiting or migraine-like headaches.

Initial Screen:
- Plasma Ammonia: Markedly elevated (>150–200 µmol/L; often >1000 in neonates).
- Blood Gas (ABG): Respiratory Alkalosis (classic for UCDs) vs Metabolic Acidosis (Organic Acidemias).
Biochemical Diagnosis:
- Plasma Amino Acids:
  - Low Citrulline (often absent).
  - Low Arginine.
  - High Glutamine (ammonia storage).
- Urine Organic Acids: Markedly Elevated Orotic Acid.
  - Differentiation: High Orotic Acid distinguishes OTC Deficiency from CPS-I Deficiency (where Orotic Acid is low/normal).
Confirmatory:
- Molecular Genetics: OTC gene sequencing (Standard of care).
- Liver Biopsy: Enzyme assay (rarely needed now).
Allopurinol Challenge Test: Used to detect carrier females (induces orotic aciduria).

Medical Emergency: Immediate stabilization required.

Stop Nitrogen Intake: Suspend all natural protein immediately (24–48 hrs max).
Reverse Catabolism: High calorie IV fluids (10%–20% Dextrose + Lipids) to suppress endogenous protein breakdown.
Ammonia Scavenging:
- IV Sodium Phenylacetate & Sodium Benzoate: Conjugate glutamine/glycine for urinary excretion.
- IV Arginine: Essential to prime the rest of the urea cycle and prevent catabolism.
Dialysis: Continuous Renal Replacement Therapy (CRRT) or Hemodialysis is mandated if Ammonia >500 µmol/L or failing medical therapy. (Exchange transfusion is ineffective).

Diet: Severe protein restriction + Essential Amino Acid supplements.
Medications: Oral nitrogen scavengers (Sodium Benzoate, Phenylbutyrate, or Glycerol Phenylbutyrate).
Supplementation: L-Citrulline or L-Arginine (to maintain urea cycle function).
Liver Transplantation:
- Curative for the metabolic defect.
- Performed usually by 6 months–1 year of age to prevent further neurocognitive damage.

Neonatal Onset: High mortality. Survivors often have significant developmental delay and intellectual disability inversely proportional to the duration of neonatal coma.
Late Onset: Better prognosis if recognized early; risk of hyperammonemic crises remains lifelong.