Citrulline is among the metabolites measured by expanded newborn screening (NBS). While hypocitrullinemia can be a marker for deficiency of proximal
urea cycle
enzymes such as
ornithine transcarbamylase (OTC), only a handful of state newborn screening programs in the United States officially report a low
citrulline value for further work-up due to low positive predictive value. We report a case of a male infant who was found to have hypocitrullinemia on NBS. After excluding proximal
urea cycle disorders by
DNA sequencing, his NBS result was felt to be a false positive. At 4 months of age, he developed poor feeding,
failure to thrive,
apnea and
infantile spasms with a progression to intractable
seizures, as well as persistent hypocitrullinemia. He was diagnosed with
Leigh syndrome due to a maternally inherited homoplasmic m.8993T>G mutation in the
ATPase 6 gene. His mother, who had previously been diagnosed with
cerebral palsy, was concurrently diagnosed with
neuropathy, ataxia, and retinitis pigmentosa (NARP) due to heteroplasmy of the same mutation. She had progressive
muscle weakness,
ataxia, and speech
dyspraxia. The m.8993T>G mutation causes
mitochondrial ATP synthase deficiency and it is hypothesized to undermine the synthesis of
citrulline by CPS1. In addition to proximal
urea cycle disorders, the evaluation of an infant with persistent hypocitrullinemia should include testing for the m.8993T>G mutation and other disorders that cause
mitochondrial dysfunction.