LAUSR

Background Lactic acidosis is a common finding in neonates, in whom mitochondrial dysfunction is often secondary to tissue hypoperfusion, respiratory failure, and/or sepsis. Primary (non-physiological) lactic acidosis is comparatively rare, and suggests the presence of an inborn error of mitochondrial energy metabolism. Optimal medical management and accurate prognostication requires the correct determination of the etiology of lactic acidosis in a given patient. Unfortunately, genetic diagnoses are rare and highly variable for neonates presenting with primary lactic acidosis; individual case reports may offer the most promise for treatment considerations. The mitochondrion is a complex molecular machine incorporating the products of > 1000 distinct nuclear genes. Primary lactic acidoses are therefore characterized by high genetic heterogeneity and a specific genetic diagnosis currently remains out of reach in most cases. Most mitochondriopathies with neonatal onset follow autosomal recessive inheritance and carry a poor prognosis. Here we detail the case of a father and daughter with dominantly-inherited, resolving (i.e. transient) neonatal hyperlactatemia due to complex IV deficiency. We found no other published descriptions of benign transient complex IV deficiency with autosomal dominant inheritance. Case presentation Both individuals presented as neonates with unexplained, marked lactic acidosis suggesting a primary mitochondrial disorder. Within the first weeks of life, elevated blood lactate levels normalized. Their clinical and developmental outcomes were normal. Biochemical studies in the proband showed multiple abnormalities consistent with a complex IV respiratory chain defect. Cultured skin fibroblasts showed an elevated lactate-to-pyruvate ratio, deficient complex IV activity, and normal pyruvate dehydrogenase and pyruvate carboxylase activities. Whole-exome sequencing of the proband and both parents did not identify a causative mutation. Conclusion We conclude that the proband and her father appear to have a dominant form of transient neonatal hyperlactatemia due to heterozygous changes in an as-yet unidentified gene. This transient neonatal complex IV deficiency should be considered in the differential diagnosis of primary neonatal hyperlactatemia; notable clinical features include autosomal-dominant inheritance and an apparently benign postnatal course. This report exemplifies the growing differential diagnosis for neonatal lactic acidosis and highlights the importance of both physician counselling and the use of family history in communicating with parents.