Mendeliome sequencing enables differential diagnosis and treatment of neonatal lactic acidosis.

Walid Fazeli,Sebahattin Cirak,Peter Herkenrath,Mert Karakaya,Jörg Dötsch,Anne Vierzig,Jürgen-Christoph Von Kleist-Retzow

doi:10.1186/s40348-016-0050-x

Abstract

BackgroundNeonatal 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.MethodsWe 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.ResultsOn 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.ConclusionsMendeliome 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 materialThe online version of this article (doi:10.1186/s40348-016-0050-x) contains supplementary material, which is available to authorized users.

Highlights

Neonatal lactic acidosis can be associated to severe inborn errors of metabolism
An increasing number of mutations have been found in genes that encode for co-factors of pyruvate oxidation, resembling the wide clinical spectrum of pyruvate dehydrogenase (PDH) deficiency [2] that embraces phenotypes which are primarily metabolic and those which are rather neurologic
We show the excellent coverage of the Mendeliome sequencing for the pyruvate dehydrogenase complex-component X (PDHX) gene in Additional file 2: Figure S1

Summary

Introduction

Neonatal lactic acidosis can be associated to severe inborn errors of metabolism. Neonatal lactic acidosis can be associated to a heterogeneous spectrum of causes, ranging from benign (e.g., protracted postnatal adaptation) to severe, potentially life-threatening conditions, e.g., disorders of energy metabolism such as deficiency of the pyruvate dehydrogenase (PDH) complex. An increasing number of mutations have been found in genes that encode for co-factors of pyruvate oxidation (e.g., thiamine), resembling the wide clinical spectrum of PDH deficiency [2] that embraces phenotypes which are primarily metabolic (i.e., severe neonatal lactic acidosis) and those which are rather neurologic (i.e., muscular hypotonia and congenital brain malformations, e.g., agenesis of corpus callosum). The E3BP of the PDH complex is encoded by the pyruvate dehydrogenase complex-component X (PDHX) gene. A genotypephenotype correlation has not been established due to the different affected domains of E3BP and the heterogeneity of the clinical features [4]

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