Neonatal presentations of mitochondrial metabolic disorders

Because of the high energy requirements of the growing neonate, disorders of mitochondrial metabolism caused by defects in fatty acid oxidation, pyruvate metabolism, and the respiratory chain may often present in the neonatal period. Common neonatal presentations are hypotonia, lethargy, feeding and respiratory difficulties, failure to thrive, psychomotor delay, seizures, and vomiting. Laboratory clues include alterations in the levels of lactate, pyruvate (and the lactate/pyruvate ratio), glucose, and ketone bodies. Diagnosis usually depends on specific enzyme assays or on molecular genetic analysis. Without treatment, most infants die in the first few days or months of life. In the last decade, there have been significant advances in the understanding of the molecular basis of these disorders. This review discusses the major subgroups of mitochondrial disorders, focusing on defects of pyruvate oxidation, the Krebs cycle, and the respiratory chain. Disorders caused by respiratory chain defects may involve nuclear DNA, mitochondrial DNA, or intergenomic signaling. Recognition and early diagnosis of these conditions are important in the genetic counseling of these families.