Ataxia and confusion in a 10-year-old girl

CASE PRESENTATION

A 10-year-old girl presented to the emergency room with a 3-day history of unsteady gait and intermittent confusion lasting several minutes. She had difficulty with hand-eye coordination and vomited once. She denied fever, poisoning, or trauma. Along with increased confusion she presented with sporadic crying, screaming, slowed speech and wandered aimlessly, staring blankly into space for approximately 1 to 2 minutes. At the age of 8 years old, she was admitted for a similar episode of ataxia, intermittent confusion, and behavioural changes. She had a head CT and lumbar puncture done at that time which were normal. She was managed supportively and recovered fully. She was discharged with a diagnosis of potential conversion disorder.

On exam, her vital signs were stable. She was comfortable and oriented. Pupils were equal and reactive to light, and there was no papilledema or neck stiffness. She had an ataxic gait, but finger–nose coordination and reflexes were normal. Romberg sign was negative.

Her hemoglobin concentration, white blood cell count, neutrophils, platelets, serum electrolytes, C-reactive protein, blood urea nitrogen, creatinine concentration, and coagulation studies were within normal limits. Blood gas, serum glucose, Aspartate aminotransferase, alanine aminotransferase, Alkaline phosphatase, albumin, and bilirubin were also normal. Electroencephalogram showed generalized slowing with slight variability, no epileptiform discharges. Additional testing yielded the underlying diagnosis.

DIAGNOSIS: UREA CYCLE DISORDERS (OTC DEFICIENCY)

A serum ammonia level revealed an ammonia level of 214 μmol/L (reference <35 μmol/L). A urea cycle disorder was suspected, and additional laboratory investigations were performed at a quaternary paediatric hospital. Argininosuccinic acid was not detected. Glutamine and urine orotic acid level in urine OA were all significantly elevated, suggesting an ornithine transcarbamylase (OTC) deficiency.

During the patient’s admission, she was managed with nitrogen scavenging drugs, initially intravenous sodium phenylacetate and sodium benzoate (Ammonul) infusion for 24 hours and then subsequently transitioned to oral sodium phenylbutyrate and supplemental citrulline. She was seen by a dietician and started on protein-restricted diet with supplementation of amino acid. The patient continued to be followed in a specialized metabolic clinic. She was treated with a low protein diet (approximately 1 g/kg per day), amino acid supplementations—glycerol phenylbutyrate (Ravicti) and citrulline. Genetic testing of the OTC gene showed a nonsense variant that truncate the protein at codon 216 and expected to cause OTC deficiency, though this variant (c.646C>T leading to p.Q216*) had not been previously reported.

OTC deficiency is a urea cycle defect, which is an inborn error of metabolism and a primary defect in the breakdown of protein. OTC deficiency is an X-linked genetic disorder and the most common urea cycle defect. The urea cycle consists of the main pathway for ammonia detoxification. Urea cycle disorders are characterized by recurrent life-threatening hyperammonemic crisis (1). Patients present with hyperammonemia either shortly after birth (~50%) or later at any age (2). Typically, OTC deficiency is expressed in newborn males presenting with lethal hyperammonemic crisis, seizures and coma. Female carriers can present from infancy to later childhood, adolescence, adulthood, or remain asymptomatic (1). Yet, OTC deficiency presents with various severities of neurological and psychiatric symptoms in both genders. Urea cycle disorders, including OTC deficiency, are difficult to diagnose because patients are minimally symptomatic outside of acute hyperammonemic episodes (2). Chronic symptoms could be misattributed to other neurological or psychiatric diagnoses.

Acute hyperammonemia caused by urea cycle disorders can present with unexplained headaches, encephalopathy, lethargy, behavioural changes with confusion, weakness, ataxia, repeated vomiting, decreased appetite, and emotional instability along with various pseudo-psychotic episodes, such as delusions and incoherence. If untreated, hyperammonemia ultimately can lead to life-threatening seizures, coma, and death (2).

Management of acute hyperammonemia caused by OTC deficiency includes stopping protein intake, intravenous D10W with appropriate amount of sodium chloride to prevent catabolism, and removal of ammonia. Depending on laboratory values, ammonia removal can be accomplished via initiation of treatment with nitrogen scavengers, intravenous arginine, intralipid infusion, and hemodialysis (2). Referrals to metabolic/genetic specialists are essential; these patients will require multidisciplinary care including paediatricians, geneticists, and dieticians. Specialist care is also needed for common medical issues. For example, specific medications like Valproate, should be avoided (1). Long-term management usually includes a protein-restricted diet with amino acids supplementation to ensure adequate nutrition, oral nitrogen scavenger medications and citrulline supplementation. These patients require a ‘sick day’ plan as they are particularly at-risk during periods of metabolic stress, like intercurrent illness (2).

Asymptomatic mothers of an affected child should have genetic counselling because OTC is inherited in an X-linked manner. If the mother is found to have the same pathogenic genetic variant, siblings and future pregnancies can be tested. It is appropriate to evaluate apparently asymptomatic at-risk relatives (both male and female) of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and/or preventive measures (1).

CLINICAL PEARLS

• • When presented with repeated, episodic, unexplained neurological symptoms, and bizarre behavioural changes, ammonia levels should be done to check for urea cycle disorders.

• • Metabolic tests for suspected urea cycle disorder should include ammonia level, blood gas, lactate, urea, glucose, creatinine, Aspartate aminotransferase, alanine aminotransferase, Alkaline phosphatase, albumin, bilirubin, plasma amino acids, and urinary orotic acid. Acylcarnitine profile, total and free carnitines and urine organic acids should be collected to rule out the possibility of hyperammonemia as a result of organic aciduria or fatty oxidation defect. Adjunctive testing may include imaging and Electroencephalography (2).

• • Samples need to be obtained while the child is symptomatic. When the child is well, the metabolic test values can be normal.

Informed Consent: Written consent was obtained from the patient’s family for publication of this case.

Funding: There are no funders to report for this submission.

Potential Conflicts of Interest: MI-F received consultant and speaker fees from Horizon (HZNP Canada Limited). There are no other disclosures. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.