Urea cycle disorders

Neonates with a urea cycle disorder often appear normal at birth but rapidly develop symptoms due to hyperammonemia, including cerebral edema, lethargy, poor feeding, hyper- or hypoventilation, hypothermia, seizures, abnormal neurological posturing, and coma.

In cases of partial enzyme deficiency with residual activity, neonatal hyperammonemia may be avoided. Instead, hyperammonemic crises can occur later in life, at any age, triggered by illness, surgery, prolonged fasting, the peripartum period, excessive protein intake, or certain medications.

Neurological involvement is central to the clinical presentation. Manifestations range from acute, life-threatening encephalopathy to long-term neurodevelopmental impairment. Cognitive deficits may include impairments in executive function, working memory, attention, and fine motor skills and can also occur in individuals with later-onset or clinically milder disease. Severe neonatal-onset hyperammonemia may lead to profound intellectual disability and spastic quadriplegia.

Thus, the age of onset spans from the neonatal period to adulthood, depending on the degree of residual enzyme activity.

The estimated prevalence of urea cycle disorders ranges from approximately 1:35,000 to 1:51,946 live births. These estimates are based on US and European cohorts; however, the true incidence may be higher due to undiagnosed cases, although newborn screening programmes increasingly contribute to earlier detection.

Currently, eight core genes are known to cause classical urea cycle disorders (including CPS1, OTC, ASS1, ASL, ARG1, NAGS, SLC25A15, and SLC25A13). These disorders can be divided into defects of urea cycle enzymes and mitochondrial transporters.

The most common genetic cause is ornithine transcarbamylase (OTC) deficiency. Other examples include argininosuccinate lyase (ASL) deficiency, which may be associated with trichorrhexis nodosa (a characteristic hair shaft abnormality), hypertension, and neurocognitive impairment.

Transport-related defects such as citrin deficiency (caused by variants in SLC25A13) are not classical enzyme defects but can secondarily impair urea cycle function and lead to hyperammonemia.

Urea cycle disorders show heterogeneous inheritance patterns. Ornithine transcarbamylase (OTC) deficiency, the most common UCD, is inherited in an X-linked manner, with heterozygous females often exhibiting variable clinical manifestations. All other classical UCDs are inherited in an autosomal recessive manner.

De novo pathogenic variants are a recognised and clinically relevant mechanism, particularly in OTC deficiency.

• If a urea cycle disorder is suspected, molecular genetic testing can confirm the diagnosis and identify the underlying genetic cause.
• The specific diagnosis is essential for clinical management, including individualised dietary and pharmacological treatment strategies.
• Identification of the causative germline variant enables predictive testing of at-risk family members and provides essential information for genetic counselling and family planning.

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