Yellow-eyed man and dromomania: A case of adult-onset psychiatric symptoms in Crigler–Najjar syndrome type II

INTRODUCTION

Crigler–Najjar syndrome type II (CNS-II) is a rare inherited disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia. Typically recognized in infancy, CNS-II may remain undiagnosed until adulthood if symptoms are subtle. Bilirubin-induced neurological dysfunction (BIND) due to elevated unconjugated bilirubin has been implicated in diverse neuropsychiatric manifestations. We present a unique case of a young adult with longstanding psychiatric symptoms ultimately linked to CNS-II.

CASE REPORT

A 30-year-old unmarried man presented to our outpatient clinic in November 2022 with a history of unusual behaviors dating back to 2015. These included prolonged periods of standing motionless, remaining in prayer position for hours, and episodes of purposeless long-distance walking, notably from Chandigarh to Basoli (~300 km), indicative of dromomania. The patient also reported forgetfulness, vivid visual hallucinations described as “scenes of past imagination,” auditory hallucinations, compulsive handwashing, and social withdrawal characterized by prolonged periods of reduced oral intake. Emotional dysregulation was evidenced by frequent weeping spells, agitation, destruction of property, and one suicide attempt. The patient had previously withdrawn from an engineering program in its final year and had received various psychiatric treatments, including electroconvulsive therapy, with limited benefit.

Family history was notable for the sudden demise of his younger brother in a road accident. His parents were deceased; his elder siblings were reportedly healthy. There was no known family history of psychiatric illness or jaundice. He occasionally consumed alcohol and cannabis.

Physical examination revealed a body mass index of 18.2 and deep yellow discoloration of the sclera [Figure 1], which relatives stated was present since early childhood. The Mini-Mental State Examination score was 28/30, with mildly impaired reverse counting (3/5). The patient avoided eye contact and exhibited bradyphrenia.

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Figure 1:

Yellow sclera before treatment with phenobarbitone.

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Slit-lamp examination ruled out Kayser–Fleischer rings. Abdominal ultrasonography and brain MRI were normal. Laboratory tests showed an elevated total bilirubin of 14.48 mg/dL (direct 1.57 mg/dL and indirect 12.91 mg/dL). Other blood parameters – including thyroid-stimulating hormone, glucose, liver enzymes, alkaline phosphatase, electrolytes, and ceruloplasmin – were within reference ranges. Serum vitamin B12 was 327.2 pg/mL (reference range: 211–911 pg/mL).

Genetic analysis through targeted sequencing of the UGT1A1 gene (ENST00000305208.10) revealed compound heterozygous mutations: A single base pair deletion in exon 3 (chr2:g.233767895del; p.Asn348ThrfsTer18) and a missense variant (chr2:g.233767936G>A; p.Gly362Ser), confirming CNS-II. Most of the CNS-II patients have homozygous or compound heterozygous missense mutations, in which the enzyme activity is reduced to <10% of normal. This residual activity can often be enhanced with phenobarbital treatment. Phenobarbitone can induce enzyme activity and enhance bilirubin clearance by increasing hepatic uptake, storage, and excretion.

The patient was started on phenobarbitone, ursodeoxycholic acid, tribasic calcium phosphate, sertraline, and olanzapine. At a 6-week follow-up, he showed marked clinical improvement. Serum bilirubin levels dropped to 2.3 mg/dL and the yellow sclera resolved [Figure 2]. Relatives noted a substantial reduction in psychiatric symptoms.

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Figure 2:

Resolution of jaundice 6 weeks after starting phenobarbitone therapy.

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DISCUSSION

Unconjugated bilirubin is neurotoxic and can cause varying degrees of encephalopathy depending on its concentration, duration of exposure, and the patient’s developmental stage.^[1,2] BIND is well characterized in neonates but increasingly recognized in adults with subtle presentations.^[3,4] Subclinical BIND may be misdiagnosed as functional psychiatric illness if hyperbilirubinemia is unrecognized. Our case underscores the importance of systemic evaluation in chronic psychiatric cases.

CNS-II, a milder form of bilirubin metabolism disorder, usually presents in infancy or early childhood.^[5,6] However, late diagnosis is possible, particularly when jaundice is overlooked or normalized in family narratives. The psychiatric symptoms in our case, including hallucinations, obsessive behaviors, and mood lability, align with proposed effects of chronic bilirubin neurotoxicity. Phenobarbitone enhances Uridine 5’-diphospho glucuronosyltransferase activity and is the mainstay of therapy in CNS-II. The striking symptomatic and biochemical improvement post-treatment supports our diagnosis.

Whether CNS-II was causative of psychiatric symptoms or merely co-existent remains uncertain. However, the clinical course suggests a contributory role. Future studies should explore neuropsychiatric profiles in adult-diagnosed CNS-II cases.

CONCLUSION

This case demonstrates the need to consider metabolic and genetic causes in chronic psychiatric presentations. CNS-II, though rare, may underlie persistent psychiatric symptoms in adults through mechanisms of bilirubin-induced neurotoxicity. Early diagnosis and treatment can significantly improve quality of life.