Urea cycle disorders (especially late-onset ornithine transcarbamylase (OTC) deficiency)

Urea cycle disorders (especially late-onset ornithine transcarbamylase (OTC) deficiency) are a group of genetic neurometabolic disorders that impair the conversion of nitrogen to urea, resulting in accumulation of ammonia and other nitrogen-containing metabolites. They typically occur as inherited conditions, although de novo pathogenic variants are also well documented in OTC deficiency, so absence of a relevant family history does not exclude the diagnosis. OTC deficiency is X-linked and can affect both males and females, although severe neonatal-onset disease is much more common in males; later-onset OTC deficiency occurs in both sexes. The other urea cycle disorders are inherited in an autosomal recessive manner.

This section focuses on late-onset OTC deficiency because it is particularly well recognized for its association with adult psychiatric presentations, including psychosis that may precede or occur without overt encephalopathy. Other urea-cycle disorders can also present with psychiatric and behavioural manifestations, often in the context of delirium or encephalopathy. These include adult-onset citrullinemia type II (citrin deficiency), argininosuccinate lyase (ASL) deficiency, and carbamoyl phosphate synthetase 1 (CPS1) deficiency. A distinctive presentation of late-onset OTC deficiency may include hyperammonemic episodes characterized by psychiatric symptoms, gastrointestinal symptoms, and neurologic features such as seizures or ataxia—typically precipitated by metabolic stress such as fasting, illness, or excessive protein intake.

It can present with psychiatric features such as anxiety, depression, sleep disturbance, behavioural change, mania, and psychosis, which can have a late onset in adolescence or adulthood and may precede or occur without overt encephalopathy. Although reported psychiatric and psychotic presentations have often been associated with hyperammonemia, the available literature does not conclusively establish whether psychosis occurring without overt encephalopathy represents a distinct neuropsychiatric manifestation or an early manifestation of hyperammonemic brain dysfunction.

Other characteristic features include episodic hyperammonemic encephalopathy with confusion or altered consciousness; headache; nausea and vomiting; dysarthria; tremor or other movement abnormalities; and, in more severe episodes, cerebral edema, coma, and potentially death. Chronic or recurrent disease may be associated with cognitive impairment, executive dysfunction, learning difficulties, and other neuropsychological abnormalities. Hyperammonemic episodes may occur after years of apparently normal health in individuals with partial enzyme deficiency and may be precipitated by illness, fasting, surgery, excessive protein intake, or the peripartum period.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

• Gastrointestinal: nausea, vomiting, anorexia, abdominal pain, and protein aversion may occur, particularly during or preceding hyperammonemic episodes.

• Respiratory: hyperventilation and respiratory alkalosis may occur early during hyperammonemic episodes; severe hyperammonemia can progress to hypoventilation and respiratory arrest with cerebral edema.

Early diagnosis is important to reduce the risk of potentially life-threatening and irreversible complications of hyperammonemia, including cerebral edema, seizures, coma, permanent neurologic injury, and death; to prevent recurrent metabolic decompensation and associated neurocognitive morbidity; to facilitate prompt, disorder-specific metabolic treatment; and to improve long-term prognosis, functional outcomes, and quality of life.