Urea Cycle Disorders

Definition

• Definition: Inherited metabolic disorders characterized by defects in the enzymes or transporters of the urea cycle, leading to the accumulation of toxic nitrogenous waste (ammonia) and deficiency of arginine/citrulline.
• Function: The urea cycle converts toxic ammonia (produced from protein catabolism) into water-soluble urea for excretion.

Epidemiology and Genetics

• Incidence: Collectively ~1 in 35,000 live births; individual disorders are rare.
• Inheritance:
  • Autosomal Recessive (AR): All UCDs (CPS1, ASS, ASL, ARG1, NAGS deficiencies).
  • X-Linked Recessive: Ornithine Transcarbamylase (OTC) deficiency (most common UCD).
    • Males: Severe, neonatal presentation.
    • Females: Variable, ranging from asymptomatic to fatal hyperammonemic coma (due to skewed X-inactivation).
      

Etiology and Classification

Defects in the following enzymes/transporters:

1. Proximal (Mitochondrial):
   • N-acetylglutamate synthase (NAGS): Essential for activating CPS1.
   • Carbamoyl phosphate synthetase 1 (CPS1): Rate-limiting step.
   • Ornithine transcarbamylase (OTC).
2. Distal (Cytosolic):
   • Argininosuccinate synthetase (ASS): Causes Citrullinemia Type I.
   • Argininosuccinate lyase (ASL): Causes Argininosuccinic aciduria.
   • Arginase 1 (ARG1): Causes Argininemia.
3. Transporters:
   • ORNT1: Hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome.
   • Citrin (SLC25A13): Citrullinemia Type II.

Pathophysiology

• Hyperammonemia: Accumulation of ammonia crosses the blood-brain barrier, causing astrocyte swelling (cerebral edema), neurotransmitter dysregulation (glutamate/glutamine imbalance), and mitochondrial dysfunction.
• Respiratory Alkalosis: Direct stimulation of the respiratory center by ammonia causes central hyperventilation.
• Amino Acid Imbalance: Depletion of urea cycle intermediates (arginine, citrulline) disrupts protein synthesis and nitric oxide production.

Clinical Features

1. Neonatal Onset (Severe Form)

• Timing: Symptom-free interval of 24–48 hours (while placental clearance is lost and protein feeding begins), followed by rapid deterioration.
• Symptoms:
  • Neurological: Poor feeding, lethargy, irritability, exaggerated startle, progressing to seizures, hypotonia, and coma.
  • Respiratory: Hyperventilation (central) leading to respiratory alkalosis; apnea in late stages.
  • Systemic: Vomiting, hypothermia, sepsis-like picture (but negative cultures).
  • Signs of Cerebral Edema: Bulging fontanelle, posturing.

2. Late-Onset (Partial Defects)

• Precipitating Factors: Catabolic stress (infection, fever, surgery), high protein load, or postpartum stress.
• Symptoms:
  • Episodic: Recurrent vomiting, headaches, ataxia, slurred speech, lethargy.
  • Psychiatric: Agitation, combativeness, hallucinations, psychosis (often misdiagnosed).
  • Dietary: Self-selected low-protein diet (protein aversion).
  • Chronic: Failure to thrive, developmental delay, intellectual disability.

3. Enzyme-Specific Phenotypes

• Arginase Deficiency: Progressive spastic diplegia/tetraplegia, intellectual disability, seizures; severe hyperammonemia is less common.
• ASL Deficiency: Trichorrhexis nodosa (brittle hair), hepatomegaly, hypertension.

Investigations

1. Screening Tests (Immediate)

• Plasma Ammonia: Markedly elevated (>150 µmol/L in neonates, often >1000 in crisis). Note: Sample on ice, analyze immediately.
• Arterial Blood Gas: Respiratory Alkalosis (High pH, Low pCO2). Differentiates from Organic Acidemias (which show Metabolic Acidosis with high anion gap).
• Blood Glucose: Normal (excludes hypoglycemia causes).
• Liver Function: Normal or mild elevation (excludes liver failure).

2. Diagnostic Biochemistry (Differentiation)

Use Plasma Amino Acids and Urine Orotic Acid.

Note: Citrulline is the key discriminator.

• Low Citrulline: Proximal defect (CPS1, NAGS, OTC). Check Orotic acid. High = OTC; Low = CPS1/NAGS.
• High Citrulline: Distal defect (ASS, ASL).
  

3. Confirmatory Tests

• Molecular Genetics: Gene panel (OTC, CPS1, ASS1, ASL, etc.).
• Enzyme Assay: Liver biopsy (rarely needed now) or RBCs (for Arginase/ASL).
• Newborn Screening: Can detect Citrullinemia and ASAuria (via elevated citrulline/argininosuccinate), but often misses OTC and CPS1.

Management

1. Acute Hyperammonemia (Medical Emergency)

Goal: Rapidly lower ammonia to prevent brain damage.

• Stop Nitrogen Intake: Suspend all protein intake (transiently, 24–48h).
• Reverse Catabolism: High caloric intake using IV 10% Dextrose (+/- Insulin) and Intralipid. Aim for high energy (100–120 kcal/kg).
• Ammonia Scavenging Pharmacotherapy:
  • Sodium Benzoate: Conjugates with glycine $\to$ hippurate (excreted renal).
  • Sodium Phenylacetate/Phenylbutyrate: Conjugates with glutamine $\to$ phenylacetylglutamine (excreted renal).
  • IV Arginine: Essential for urea cycle function (except in Arginase deficiency) and prevents protein catabolism.
  • Carglumic Acid (Carbaglu): Specific analog of N-acetylglutamate; rapidly normalizes ammonia in NAGS deficiency.
• Dialysis: Indicated if ammonia >500 µmol/L or failure of medical management after 3-6 hours. Hemodialysis is superior to peritoneal dialysis.
• Supportive: Treat seizures (avoid valproate as it inhibits urea cycle), treat cerebral edema, maintain ventilation.

2. Long-Term Management

• Dietary:
  • Protein restriction (titrated to growth/neurodevelopment).
  • Essential amino acid supplementation.
• Pharmacotherapy:
  • Chronic scavengers: Oral Sodium Phenylbutyrate or Glycerol Phenylbutyrate.
  • Arginine supplementation (for OTC, CPS1) or Citrulline (for OTC, CPS1) to drive the cycle.
• Monitoring: Plasma amino acids (keep glutamine normal), ammonia, growth, neurodevelopment.
• Liver Transplantation: Curative for hepatic enzyme defects (e.g., OTC, CPS1). Indicated for recurrent decompensations or poor metabolic control. Does not reverse pre-existing brain damage.

Prognosis

• Mortality: High in neonatal onset without rapid treatment.
• Morbidity: Strictly correlated with duration and severity of hyperammonemic coma.
• Sequelae: Intellectual disability, cerebral palsy, cortical blindness, and epilepsy are common in survivors of severe neonatal coma.
• Prospective: Liver transplant significantly improves quality of life and prevents further hyperammonemia.