Uncovering the Tale of a Young Boy with a Husky Voice and an Aversion to Dirt

Dear Editor,

Urea cycle disorders (UCDs) are a type of inborn error of metabolism (IEMs) where ammonia, which is particularly toxic to the central nervous system, gets accumulated due to defective functioning of any one or more of the six enzymes or two transporters involved in its removal. ¹ Various IEMs may present with isolated psychiatric signs before more specific signs become obvious but usually develop irreversible lesions. ² Cases of UCDs presenting with isolated psychiatric manifestations have been reported mostly in women who are heterozygous for ornithine transcarbamylase deficiency. Mental retardation is the most common presentation though attention-deficit hyperactivity disorder has not been uncommon, along with autistic features with a predominance of episodes of agitation or tics, while older children have also presented with delirium-like pictures. ³

To the best of our knowledge, no case with obsessive-compulsive disorder (OCD) as a first manifestation of (UCD) has been reported. The following case describes a patient who presented with OCD and autistic features and later was found to have a UCD, though his blood ammonia levels were in the normal range. We obtained the patient’s assent and written informed consent from the mother for the publication of this case report.

Case Report

A 15-year-old adolescent boy, born out of a third-degree consanguineous marriage and initial normal development till the age of around 10 years, after which he became socially withdrawn with limited interaction (only for his necessities), preferred remaining confined to his room and engaged less actively in household chores. His scholastic performance declined with poor attention span and reduced comprehension abilities. He would also drop his food while eating and would fall from his bicycle, reflecting motor incoordination. He soon started exhibiting poor eye contact during conversations, contrasting with his previous confidence in public speaking. He was diagnosed with a case of autism spectrum disorder according to International Classification of Diseases 11th Revision (ICD 11) diagnostic criteria, ⁴ and severity graded on the Indian Scale for Assessment of Autism, ⁵ score-84 (suggestive of mild autism). Although his earlier development milestones were age-appropriate, a history of autistic traits was revealed on inquiry beginning from his toddler days in the form of fixated interest, abnormal eye gazing, adverse reaction to loud sounds, and obsession with lining up toys. Despite these challenges, he enjoyed socializing with family and friends, possessed a good singing voice, and demonstrated diligence in his studies, albeit with below-average grades. He showed minimal improvement with occupational therapy, and investigations then revealed mild cerebral atrophy with T2-FLAIR posterior periventricular signal changes on the MRI brain, normal ceruloplasmin level, and a normal sleep EEG.

Around the age of 13, his family became concerned about his meticulous and repetitive hand washing, driven by fear of contamination, even in the post-lockdown era of the COVID-19 pandemic, inappropriate to his household and socio-cultural environment. He would remain standing near the sink, appearing tense and sweating, finding relief only in washing his hands. He would spend around two to three hours in handwashing and prolonged periods in the washroom. He avoided contact with public surfaces like doorknobs, taps, and handrails & carrying cash, escalating to avoiding even seats on public transport, opting to sit on his mother’s lap instead. The boy was diagnosed with OCD and was treated with Fluoxetine 20 mg/ day, supplemented with Risperidone 0.5 mg/day, due to a partial response.

At the age of 14 years, abnormal facial grimacing and anxiety symptoms ensued. With these complaints, the patient presented to us. On mental status examination, he was making unusual sounds intermittently during the interview, displayed repetitive behavior of touching the table for a specific number of times every three to five minutes, would reply only briefly in one or two words to the questions asked, and rapport was established with great difficulty with his speech characterized by a decrease in rate and volume, with a harsh tone and lack of clarity but was coherent and goal-directed with worrisome mood and affect being anxious with thought possession revealing obsessive doubts, fear of contamination & thought content revealing magical thinking. On the Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS), ⁶ he scored-29; obsession-14, compulsion-15. He exhibited features of executive dysfunction without any involvement of corticospinal tract, extrapyramidal, or cerebellar signs on neurologic examination.

Clinical differentials of a primary neurodevelopmental disorder versus a neurometabolic disorder were considered, given the atypical presentation of mild autistic traits in childhood, adolescent new symptoms of OCD, and hoarse voice with abnormal MRI brain findings. Whole exome sequencing was sent, which identified a hemizygous variant of uncertain significance in exon 4 of the ornithine transcarbamoylase (OTC) gene. Further metabolic evaluation revealed serum ammonia levels of 31 µmol/L with normal plasma tandem mass spectroscopy and urine gas chromatography results.

The patient was re-initiated on Sertraline 150 mg/day, Risperidone 0.5 mg/day, and Propranolol 20 mg/day and followed up after four weeks. Improvement was noted by the patient and his family members, and objectively on the CYBOCS scale (score 21; obsession-10, compulsion-11). However, anxiety persisted, which reduced gradually in the three-month follow-up period.

Discussion

The most common UCD is due to ornithine transcarbamylase (OTC) gene deficiency (X-linked IEM), with the most common phenotypic variant affecting males more severely with presentation in the neonatal period. ² However, now milder phenotypic variants are seen in male patients, as was seen in our case, which has a late onset of presentation and can have neuropsychiatric symptoms.

Intellectual disability is the most common symptom associated with UCDs, especially with ornithine transcarbamylase deficiency, most commonly affecting nonverbal capabilities and other fine motor functions. ⁷ Speech and communication problems and other autistic features have also been reported in patients with UCDs, as was with our case. Still, they have been few and far along with the hyperactive-compulsive type of attention-deficit hyperactivity disorder and even delirium-like symptoms with frank encephalopathic changes.^3,8,9 Hyperammonemia has been a consistent finding in most of these cases, the correction of which leads to some improvement of psychiatric symptoms as well. However, glutamine has also been described to be neurotoxic. ³ It is important to rule out hyperammonemia in children who present with such a clinical picture, which can usually precipitate after any significant stressors like viral infections, trauma surgical intervention, or consumption of a protein-rich diet.

A diagnostic strategy and schematic classification have been proposed with three groups of disorders, with group one primarily with acute and recurrent episodes of confusion and behavioral changes, isolated psychiatric signs in adolescence in group two, and intellectual disability and personality changes in group three. ¹⁰ Group two presents with diagnostic problems due to a lack of specificity of psychiatric signs, especially if they remain isolated for many years. Considering this scheme, our case can be classified into group two.

Conclusions

This case report highlights that neuropsychiatric manifestations can be a common finding and can, in fact, be the first clinical picture that a child with UCD presents with. Therefore, any unexplained neuropsychiatric or neurodevelopmental symptoms in childhood or adolescence should always be investigated for a urea cycle defect or other inborn errors of metabolism.