Mendeliome sequencing enables differential diagnosis and treatment of neonatal lactic acidosis

BACKGROUND: Neonatal lactic acidosis can be associated to severe inborn errors of metabolism. Rapid identification of the underlying disorder may improve the clinical management through reliable counseling of the parents and adaptation of the treatment. METHODS: We present the case of a term newborn with persistent hypoglycemia on postnatal day 1, who developed severe lactic acidosis, aggravating under intravenous glucose administration. Routine metabolic investigations revealed elevated pyruvate and lactate levels in urine, and magnetic resonance spectroscopy showed a lactic acid peak and decreased N-acetylaspartate levels. Mitochondrial disorders, e.g., pyruvate dehydrogenase (PDH) deficiency, were the major differential diagnoses. However, both hypoglycemia and the elevated lactate to pyruvate ratio in serum (=55.2) were not typical for PDH deficiency. We used “Mendeliome sequencing”, a next-generation sequencing approach targeting all genes which have been previously linked to single-gene disorders, to obtain the correct diagnosis. RESULTS: On day 27 of life, we identified a homozygous stop mutation in the PDHX gene, causing pyruvate dehydrogenase E3-binding protein deficiency. After starting the ketogenic diet, the infant recovered and is showing delayed but progressive development. CONCLUSIONS: Mendeliome sequencing was successfully used to disentangle the underlying cause of severe neonatal lactic acidosis. Indeed, it is one of several targeted sequencing approaches that allow rapid and reliable counseling of the parents, adaptation of the clinical management, and renunciation of unnecessary, potentially invasive and often costly diagnostic measures. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40348-016-0050-x) contains supplementary material, which is available to authorized users.