A 10-month-old girl presented with global developmental delay, excessive crying, decreased limb movements, and 15 days of vomiting after a febrile episode that followed varicella immunization. She had one seizure episode with postictal drowsiness. She was born to nonconsanguineous parents after an uneventful perinatal period. The child was intubated because of drowsiness, and paucity of limb movements on the left side was noted. Blood tests revealed an ammonia level of 285 µmol/L, abnormal liver function test results, and prolonged prothrombin time and activated partial thromboplastin time. There was no evidence of metabolic acidosis. As a urea cycle defect (UCD) was suspected, peritoneal dialysis was initiated, and sodium benzoate was administered to treat hyperammonemia. After regaining consciousness and extubation, she developed generalized tremor, generalized chorea, and perioral dyskinesia while her plasma ammonia level was 85.7 µmol/L (Video 1). Brain magnetic resonance imaging revealed bilateral cortical diffusion restriction and cortical edema (Fig. 1). Tandem mass spectrometry revealed an elevated citrulline level (737.6 µmol/L; normal range, 3.31 to 51.5 µmol/L), low ornithine level (20.19 µmol/L; normal range, 23 to 216 µmol/L), and low-normal arginine level (6.05 µmol/L; normal range, 2 to 54.1 µmol/L). Urine gas chromatography–mass spectrometry showed elevated orotic acid, with a 22.5-fold elevation, and elevated uracil, with a 6.5-fold elevation. These biochemical findings were consistent with citrullinemia type 1. The child was then started on a high-calorie, protein-restricted diet. Five days later, the tremor had resolved, but chorea of the limbs and perioral dyskinesia persisted (Supplementary Video 1). Whole-exome sequencing revealed compound heterozygous variants in the ASS1 gene: c.1168G>A (p.Gly390Arg) in exon 14 and c.836G>A (p.Arg279Gln) in exon 11, confirming the diagnosis. At the 3-month follow-up, she had no involuntary movements. However, she died of fulminant hepatic failure 1 month later.

The differential diagnosis of childhood-onset chorea associated with inborn errors of metabolism is extensive. However, chorea that begins during infancy is rare and substantially narrows the differential diagnosis. Chorea may be levodopa-induced, particularly in infants with monoamine neurotransmitter defects such as aromatic L-amino acid decarboxylase (AADC) deficiency, and it has rarely been reported in drug-naive infants with AADC deficiency [2]. Other causes of chorea in infancy include pyruvate carboxylase deficiency [3], kernicterus, NKX2-1–related disorder, GNAO1 variants [4], POLG variants [5], and dopamine transporter deficiency syndrome [6]. Paroxysmal dyskinesia during infancy has commonly been reported in association with ADCY5, KCNMA1, MR1, and PRRT2 variants [7].

In UCDs, movement disorders have generally been described as episodic ataxia and dysarthria due to cyclical hyperammonemia in older children; in contrast, hyperammonemia in younger children and neonates typically manifests as encephalopathy. Chorea in UCDs has rarely been reported, although one previous report described an 11-month-old girl with ornithine transcarbamylase deficiency who presented with choreoathetosis [8]. In that child, chorea developed together with altered sensorium and hyperammonemia. The symptoms resolved as ammonia levels normalized, similar to the course observed in our patient. In our patient, chorea and tremor emerged while ammonia levels remained elevated but were decreasing. The symptoms resolved after ammonia levels fully normalized, supporting a possible etiologic association between choreoathetosis and the citrullinemia crisis. Chorea involving the limbs and perioral region has also been reported in chronic liver disease during acute liver dysfunction manifested by hyperammonemia and improved after ammonia levels normalized. Chorea may precede hepatic encephalopathy. The emergence of hyperkinetic movements during a hyperammonemic crisis may result from toxic metabolites released into the circulation during liver dysfunction in citrullinemia. Elevated ammonia is converted to glutamine within neurons, leading to metabolic disturbances, oxidative stress, N-methyl-D-aspartate receptor activation, and widespread network disruption, particularly in the basal ganglia of susceptible individuals; these effects may contribute to hyperkinetic movements [9]. Choreoathetosis has been reported in a child with citrullinemia and a concurrent ADCY5 variant, and the child’s symptoms improved after caffeine administration. Unlike our patient, hyperammonemia was not present during the symptoms in that case [10].

In conclusion, we report a rare presentation of transient chorea and generalized tremor during a hyperammonemic crisis in a child with citrullinemia type 1. Persistent symptoms despite normalization of biochemical markers may indicate another genetic cause of chorea and may warrant genetic testing.

The author confirms that the approval of an Institutional Review Board was not required for this work. Written informed consent for publication was obtained from the child’s parents. The author confirms having read the journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.