Urea cycle disorders, such as ornithine transcarbamylase (OTC) deficiency

Description

Inherited defects of the urea cycle -> failure to convert ammonia -> urea -> hyperammonaemia
Ammonia drives all the neurological toxicity - cerebral glutamine accumulation -> astrocyte swelling -> cerebral oedema
OTC deficiency is the commonest and the only X-linked one (all others AR)

Why a physician sees this

Unexplained encephalopathy or coma in an adult with a normal CT and normal LFTs
Recurrent "cyclical vomiting", confusion or psychiatric episodes triggered by protein or catabolism
Post-partum encephalopathy, post-bariatric surgery, or after starting valproate or high-dose steroids
Late-onset OTC in a heterozygous female presenting for the first time in her 30s is the classic exam vignette

Urea cycle disorders combined ~1:35,000 births
OTC deficiency ~1:56,000-80,000 - accounts for roughly half of all UCDs
Neonatal presentation: hemizygous males, catastrophic, day 2-4 of life
Late (adult) presentation: heterozygous females and males with partial enzyme activity - unmasked by a metabolic stressor

The cycle and where it breaks

Enzyme deficiency	Inheritance	Citrulline	Urine orotic acid
NAGS	AR	Low	Low
CPS1	AR	Low	Low
OTC	X-linked	Low	HIGH
ASS (citrullinaemia I)	AR	Very high	High
ASL (argininosuccinic aciduria)	AR	High	High
Arginase (ARG1)	AR	Normal/high	High

**Orotic acid is the discriminator: OTC blocked -> carbamoyl phosphate spills into the pyrimidine pathway -> orotic aciduria. CPS1 is proximal, so orotic acid is low.**
Ammonia -> glutamine (via glutamine synthetase in astrocytes) -> osmotic astrocyte swelling -> cerebral oedema and raised ICP
Ammonia stimulates the respiratory centre -> primary respiratory alkalosis (a metabolic encephalopathy with respiratory alkalosis and no acidosis is a urea cycle disorder until excluded)

Precipitants of decompensation

Catabolism - fasting, infection, surgery, trauma, post-partum involution
High protein load - dietary, TPN, GI bleed
Drugs: valproate (inhibits CPS1 - the single most important iatrogenic precipitant), corticosteroids, chemotherapy, salicylates, topiramate
Bariatric surgery, pregnancy and delivery

Measure ammonia - the single test that makes the diagnosis

*Nobody diagnoses this without thinking of it - ammonia is not on any routine panel*
Free-flowing arterial or venous sample, on ice, to the laboratory immediately (falsely elevated by tourniquet, delay, haemolysis)
>100-150 micromol/L with encephalopathy -> act now; >200 = emergency; neonatal levels may exceed 1000

Distinguish from other causes of hyperammonaemia

Liver failure - LFTs and coagulation are abnormal; in UCD they are normal
Portosystemic shunt, *urease-producing urinary infection with obstruction (Proteus)*, valproate toxicity, organic acidaemias, fatty acid oxidation defects, chemotherapy (asparaginase), post-lung/bone marrow transplant hyperammonaemia syndrome

Confirmatory metabolic workup - send BEFORE treating if possible, but never delay treatment

Plasma amino acids (glutamine high; citrulline and arginine localise the block)
Urine orotic acid - high in OTC, low in CPS1/NAGS
Urine organic acids, plasma acylcarnitines (exclude organic acidaemia and FAO defects)
Blood gas: respiratory alkalosis, normal anion gap (an anion-gap acidosis points to an organic acidaemia instead)
Molecular testing of the relevant gene; allopurinol challenge historically used in female OTC carriers

Imaging

A. Acute hyperammonaemic crisis - a medical emergency, treat in parallel

Stop ALL protein intake (maximum 24-48 h only - prolonged protein-free feeding drives catabolism)
Reverse catabolism: IV 10% dextrose at high rate +/- insulin, plus intralipid; aim for anabolism
Nitrogen scavengers IV: sodium benzoate + sodium phenylacetate (Ammonul), or sodium phenylbutyrate
- Provide alternative routes of nitrogen excretion (hippurate, phenylacetylglutamine)
IV L-arginine (or citrulline) - replaces the cycle intermediate; not in arginase deficiency
Haemodialysis (not haemofiltration alone, not peritoneal dialysis) if ammonia >400 micromol/L or not falling - the most rapid method of ammonia clearance
Stop valproate and any precipitant drug; treat infection
Neuroprotection: manage raised ICP, avoid hypotonic fluids
Call the metabolic service immediately - outcome correlates with duration of hyperammonaemia, not just peak level

B. Chronic maintenance

Protein-restricted diet with essential amino acid supplementation, dietitian-led; avoid fasting
Oral nitrogen scavengers: sodium phenylbutyrate or glycerol phenylbutyrate (better tolerated, less odour)
Oral L-citrulline or L-arginine depending on the enzyme block
Sick-day plan with emergency protocol letter - every patient carries one
Avoid valproate, systemic corticosteroids and prolonged fasting for procedures
Liver transplantation is curative of the metabolic defect (does not reverse established neurological damage) - considered in severe/recurrent disease
AAV gene therapy for OTC deficiency remains investigational

C. Family

X-linked: test the mother and female relatives - carriers are at risk of symptomatic hyperammonaemia, particularly post-partum
Genetic counselling, prenatal diagnosis available

Valproate-induced hyperammonaemic encephalopathy (may unmask a partial UCD)
Post-partum psychosis/encephalopathy
Cyclical vomiting, protein aversion, migraine-like episodes
Learning difficulties, ADHD and episodic behavioural disturbance in partially affected carriers
Trichorrhexis nodosa (argininosuccinic aciduria)
Spastic diplegia (arginase deficiency)

Neonatal-onset disease: high mortality and high rate of neurological sequelae
Late-onset disease: normal between episodes, but each crisis risks permanent injury
Outcome correlates with peak ammonia AND duration of hyperammonaemia - delay in recognition is the modifiable variable
Ammonia >1000 micromol/L or coma >3 days carries a very poor neurological prognosis
Untreated first adult presentation is frequently fatal, usually attributed to "encephalitis of unknown cause"
Long-term: cognitive impairment, epilepsy, movement disorder; liver transplant prevents further crises

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