Letter: Agitation Management in a 5-Year-Old Boy with X Chromosome-Linked Monoamine Oxidase-A and Monoamine Oxidase-B Deficiency

Introduction

This is the first report reviewing the literature and providing guidance on psychopharmacologic agitation management in a pediatric patient with X chromosome-linked MAO-A and MAO-B deficiency. This article discusses challenges in managing agitation with psychotropic medications, mainly due to the increased risk of serotonin syndrome with commonly used medications for the management of agitation in hospital settings. Further case reports and series are needed to better understand the psychopharmacological challenges associated with this population.

Case Report

A 5-year-old boy with a pertinent history of Norrie’s disease with associated blindness, monoamine oxidase (MAO)-A and MAO-B deficiency, and gastrostomy–jejunostomy (GJ) tube dependence presented to the hospital with increased irritability, fussiness, decreased urine output, and excessive sweating, tachycardia, tachypnea, and hypertension. The patient’s previous genetic testing has included a chromosomal microarray, which identified a 2.1 Mb deletion of chromosome Xp11.3-Xp11.4, which includes MAO-A, MAO-B, and Norrie disease pseudoglioma (NDP) genes. The patient had been utilizing a low tyramine enteral feeding formula given his underlying X chromosome-linked MAO-A and MAO-B mutations. It was documented that the patient used to have excessive sweating episodes before switching to a low-tyramine diet. Prior to the hospital presentation, there had been no changes to his medications or feeding regimen. No cough, congestion, runny nose, difficulty breathing, fevers, foul-smelling urine, diarrhea, or constipation was noted. Medical workup was notable for isolated leukocytosis and elevated lactate levels.

During hospitalization, the patient was successfully treated with intravenous fluids and enteral free water flushes to promote adequate hydration. Antibiotic treatment with cephalexin 25 mg/kg per dose three times daily for a total of 5-day treatment course was started for suspected cellulitis around the GJ tube site. Differential diagnoses included possible delirium in the context of underlying infection and sympathetic nervous system hyperactivity due to MAO deficiency. In addition to supportive measures, non-pharmacologic interventions, including the reinforcement of the sleep–wake cycle, keeping familiar objects/toys around the patient, and encouragement of mobility, were offered. Psychiatry was consulted for assistance with presenting symptoms, including episodes of agitation with increased irritability and self-hitting behavior.

At baseline, the patient was reported to have significant developmental delays, including limited verbal and nonverbal communication, gross and fine motor delays, occasional self-hitting behavior, and intellectual disability. Leading up to the admission, caregivers reported increased fussiness, restlessness, and unprovoked agitation with self-hitting behavior. According to the patient’s mother, scheduled clonidine 0.05 mg at bedtime was initially started by his outpatient provider 2 months ago for insomnia and agitation, with improvements in irritability around bedtime and sleep onset. Given past benefits, as-needed clonidine 0.025 mg up to two times a day was offered for episodes of agitation during the hospitalization, in addition to the scheduled bedtime dose. The psychiatry team recommended avoiding second-generation antipsychotics due to their complex mechanistic effects on catecholamine release in the brain. During his admission, as-needed clonidine 0.025 mg was administered once for an increased agitation episode. The patient’s mother reported improved irritability and self-hitting behavior with the additional as-needed clonidine dose. After rehydration and initiation of antibiotics for the treatment of cellulitis, the patient’s tachycardia, hypertension, diaphoresis, and irritability significantly improved. He was discharged home on as-needed and scheduled clonidine doses after 2 days of hospitalization.

Discussion

NDP is a gene associated with X-linked familial vitreoretinopathy, known as Norrie disease, which presents with retinal malformation and lens opacity causing congenital blindness. Reports on MAO gene deletions have consistently included the nearby NDP gene (Whibley et al., 2010). MAO-A and MAO-B genes play a role in the metabolism of key brain neurotransmitters, including serotonin, dopamine, norepinephrine, and epinephrine. Deficiencies in MAO enzyme activity are characterized by various adverse effects (Bortolato and Shih, 2011). This, coupled with the deletion of the Norrie disease gene, is associated with seizures, developmental delays, intellectual disability, and behavioral problems, such as increased aggression and self-harming behavior (Whibley et al., 2010). An MAO-deficient state causes challenges in managing agitation with psychotropic medication. This is mainly due to the uncertain risk of serotonin syndrome with commonly used medications, such as first- and second-generation antipsychotics (SGAs).

Given similar underlying mechanisms, literature on MAO inhibitors (MAOI) guides the psychopharmacologic management of increased adrenergic and serotonergic states. It is recommended that agitation in the context of MAOI toxicity can be treated with benzodiazepines, in addition to supportive measures, including providing adequate hydration (Garcia and Santos, 2024). Given the concern for delirium in this case, an alternative to benzodiazepines was sought for treatment of agitation.

Clonidine was utilized in this case with good results. However, it is hypothesized that clonidine can be associated with a “spillover” release of catecholamines and, therefore, contribute to unwanted effects such as hypertensive states when combined with MAOIs (Deng et al., 2024). Clonidine was selected in this case, given the reported past benefits for insomnia and irritability with the scheduled bedtime dose. It is possible that short-term clonidine use may improve agitation episodes while increasing the risk for hypertensive states in the context of clonidine use in an MAO-deficient state. The theoretical risk of increased “spillover” release of catecholamines should be closely monitored in this population.

SGAs are commonly used in agitation management in hospital settings. Case reports have described possible serotonin toxicity associated with SGAs (Racz et al., 2018), though symptomatic overlap with neuroleptic malignant syndrome precludes a definitive link between SGAs and serotonin syndrome. Regardless, antipsychotic medications were avoided in this case, given the patient’s complex presentation.

This case report briefly reviews the literature and provides guidance on psychopharmacologic agitation management in a pediatric patient with X chromosome-linked MAO-A and MAO-B deficiency. To our knowledge, discussion of this topic is limited in the literature. Further case reports and series are needed to better understand the psychopharmacological challenges associated with this population.