MITOCHONDRIAL DISORDER ASSOCIATED WITH NEWBORN CARDIOPULMONARY ARREST

A female infant who died 2.5 d after birth with hypoglycemia, lactic a cidosis, and sudden multisystem failure was studied. Biochemical studi es showed complex III and IV deficiency in liver, kidney, and muscle, with muscle most severely affected. Southern blot analysis of the pati ent's mitochondrial DNA did not reveal any deletions. Denaturing gradi ent gel analysis, which detects single base changes by differences in melting behavior, showed an extra band that was not seen in mitochondr ial DNA from the mother, the mother's identical twin sister, or an unr elated normal subject. This extra band indicated heteroplasmy for a re striction fragment containing the apocytochrome b and transfer RNA(thr ) genes. Sequencing revealed an A to G mutation at nucleotide 15923, t he last base of the anticodon loop of the transfer RNA(thr) gene. The mutation lengthens the anticodon stem by added pairing and reduces the anticodon loop size from 7 to 5 nucleotides, potentially compromising transfer RNA(thr) function in translation and/or in processing the po lycistronic RNA transcript. The patient's mother previously had a male infant who also died at 1.5 d postnatal, and both the mother and her twin have had multiple miscarriages. Amniocentesis for a genetic scree n was performed on the mother's twin sister during a recent pregnancy; some of the cultured cells were made available for this study. The mu tation was not found in the amniocytes or in umbilical cord blood obta ined at birth; the baby was normal at birth and remains healthy. It is concluded that the mutation at nucleotide 15923 was most likely the c ause of the fatal disease in the index case. The timing of the illness was consistent with postnatal depletion of glycogen reserves. The fin dings suggest that a mitochondrial disorder should be considered for i nfants who experience sudden cardiopulmonary arrest within the first f ew days of life.