Milder Form of Urea Cycle Defect Revisited: Report and Review of Hyperornithinaemia-Hyperammonaemia-Homocitrullinuria (HHH) Syndrome Diagnosed in a Teenage Girl Presenting with Recurrent Encephalopathy

Dear Editor, H y p e r o r n i t h i n a e m i a h y p e r a m m o n a e m i a homocitrullinuria (HHH) syndrome (OMIM #238970) is a rare autosomal recessive disorder associated with mutations of the SLC25A15 gene which encodes the mitochondrial ornithine transporter 1 (ORNT1).1 ORNT1 is responsible for the transport of cytosolic ornithine into the mitochondria in exchange for citrulline in the urea cycle and ornithine degradation pathway. A defect in this transporter results in accumulation of ornithine in the cytosol (resulting in hyperornithinaemia), disruption of the urea cycle (resulting in hyperammmonaemia) and increased secretion of homocitrulline in urine (a product of transcarbamoylation of lysine). This biochemical reaction cascade is affected by protein load in the diet.2 It is challenging to diagnose HHH syndrome as it is not detected on newborn metabolic screening.3 Hyperornithinaemia develops beyond infancy and hyperammonaemia tends to be milder compared to other urea cycle disorders. However, it is a preventable cause of intellectual disability, and prompt diagnosis with appropriate management can improve long-term outcome and quality of life for patients. HHH syndrome was first described in 1969 by Shih and colleagues4 and it constitutes only 1% to 3% of all urea cycle disorders.5 HHH syndrome has the highest prevalence among French-Canadians, followed by Italians and Japanese.6 HHH syndrome has not been reported locally and only been reported once previously in an individual of Indian descent.7 We describe an additional case of a girl of Indian descent, who presented with recurrent episodes of altered mental state in association with febrile illnesses and was subsequently diagnosed with HHH syndrome.