Abstract
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.
Competing interests: None declared
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Communicated by: Daniela Karall
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Synopsis
When hypocitrullinemia is detected in NBS and persists in a confirmatory test, differential diagnoses should not be limited to proximal urea cycle disorders but also include m.8993T>G as well as other disorders that can impair P5C or CPS1 function including MELAS and Pearson syndrome.
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Mari Mori, John R. Mytinger, Lisa C. Martin, Dennis Bartholomew, and Scott Hickey declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.
Contribution of Authors
Mari Mori: Dr. Mori cared for the patient during hospital admittance and in the genetics clinic. She enrolled the patient in the EPI-743 clinical study. Dr. Mori drafted the initial draft and approved the final manuscript as submitted.
Scott E. Hickey: Dr. Hickey diagnosed the patient with Leigh syndrome and his mother with NARP, cared for the patient during hospital admittance and in the genetics clinic, aided with enrollment into the EPI-743 clinical study, aided with draft revision, and approved the final manuscript as submitted.
Dennis Bartholomew: Dr. Bartholomew reviewed the newborn screening results, performed the initial work-up, aided in draft revision, and approved the final manuscript as submitted.
Dr. John R. Mytinger: Dr. Mytinger cared for the patient during hospital admittance and in neurology clinic, aided in draft revision and approved the final manuscript as submitted.
Dr. Lisa C. Martin: Dr. Martin interpreted the brain MRI in radiology, aided in preparing the figure, and approved the final manuscript as submitted.
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Mori, M., Mytinger, J.R., Martin, L.C., Bartholomew, D., Hickey, S. (2014). m.8993T>G-Associated Leigh Syndrome with Hypocitrullinemia on Newborn Screening. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports, Volume 17. JIMD Reports, vol 17. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_332
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DOI: https://doi.org/10.1007/8904_2014_332
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