Patient Reports Fatal case of mitochondrial DNA depletion with severe asphyxia in a newborn Yuya Nakano, 1,3 Kei Murayama, 4 Tomkoko Tsuruoka, 3,4 Madoka Aizawa, 3 Hironori Nagasaka, 4 Hiroshi Horie, 5 Akira Ohtake 6 and Kayoko Saitou 2 1 Department of Pediatrics, Showa University School of Medicine, 2 Department of Genetics, Tokyo Women’s Medical University, Tokyo, Departments of 3 Neonatology, 4 Metabolism, and 5 Pathology, Chiba Children’s Hospital, Chiba, and 6 Department of Pediatrics, Saitama Medical University, Saitama, Japan Key words asphyxia, mitochondrial DNA depletion, mitochondrial respiratory chain disorder. Many factors, particularly maternal and placental conditions, are associated with asphyxia. However, the etiology of asphyxia is occasionally unclear. It has been shown that mitochondrial res- piratory chain disorders (MRCD) probably cause severe asphyxia and sudden death in newborns. 1 Mitochondrial DNA (mtDNA) depletion is a prevalent cause of multiple respiratory chain defi- ciency during this period; 2 however, there is little information on the correlation between mtDNA depletion and asphyxia. We report a case of severe asphyxia caused by mtDNA depletion syndrome (MDS). Case Report A healthy male newborn was delivered by vacuum extraction to nonconsanguineous parents at 40 gestational weeks because of prolonged labor. His birthweight was 2.6 kg, which is <10th percentile according to Japanese reference data. His 37-year-old mother had no history of gestational or pregnancy complications, and gestation was achieved by intracytoplasmic sperm injection. Chronological clinical observation and echocardiography during pregnancy revealed no abnormalities. However the mother noticed paucity in his intrauterine movement. Immediately after birth, the boy was resuscitated for severe asphyxia, with Apgar scores of 2 and 5 at 1 and 5 min, respectively. He was admitted to our hospital 2 h after birth. The infant was intubated immediately and given sodium bicarbonate intravenously for acidosis (pH 7.08, PCO 2 77.1, base excess -9.4). On admission, he presented with severe hypotonia, multiple arthrogryposis, and insufficient spontaneous respiration. Simultaneously, he was found to have bilateral undescended testes and cephalhematoma. Results of routine laboratory exami- nations were normal, except for a slightly elevated blood lactate level (25 mg/dL in the venous blood; normal 7–16 mg/dL); common enzymes, including serum creatine kinase, lactate dehy- drogenase, and glutamic oxaloacetic transaminase were main- tained at normal levels throughout the clinical course. A general X-ray and cardiac and cranial echograms showed normal results. His vital signs were maintained within normal ranges by artificial ventilation. Magnetic resonance imaging (MRI) at days 9 and 18 of age showed no findings suggestive of ischemia, anomaly, or damage in the brain, except for subdural hematoma. However he remained hypotonic and unable to respire spontane- ously. At 23 days of age, bradycardia occurred suddenly after tracheal suction; sudden death followed despite appropriate resuscitation. The electrocardiograph showed sinus bradycardia, and laboratory findings showed normal electrolytes. His metabolic screening tests, such as amino acid profiles, acylcarnitines analy- sis, and urinary organic acids analysis, showed no findings suggestive of congenital metabolic disorders. The histological examinations of muscular tissues obtained at autopsy revealed marked muscular atrophy (Fig. 1). Activities of respiratory chain complexes I, II, III and IV in the skeletal muscle, cardiac muscle, and liver were determined as described previously. 3 The activity of each complex was pre- sented as a percent ratio relative to the mean value obtained from 35 healthy controls. The percent ratios of complex I, II, III and IV activities to the citrate synthase, that is, a mitochondrial enzyme marker, or complex II activity, were calculated for each patient. 4 All the respiratory chain complexes in the skeletal muscle showed low activities and respiratory chain complex I activity was low in the cardiac muscle. Complex I and IV activities in the skeletal muscle were strikingly low in contrast to those of other respiratory chain complexes (Table 1). mtDNA was quantitatively estimated by real-time amplifica- tion of nicotinamide adenine dinucleotide dehydrogenase (ND) 1 fragments in the mtDNA genome, as previously described. 4,5 To determine the overall abundance of mtDNA, we compared the real-time amplification of ND1 with a single-copy nuclear refer- ence gene (exon 24 of the cystic fibrosis transmembrane conduc- tance regulator gene; selected because it lacks single-nucleotide Correspondence:Yuya Nakano, MD, Department of Pediatrics, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan. Email: nakano-yt@tulip.sannet.ne.jp Received 1 May 2009; revised 12 February 2010; accepted 31 March 2010. doi: 10.1111/j.1442-200X.2010.03183.x Pediatrics International (2011) 53, 240–263 © 2011 The Authors Pediatrics International © 2011 Japan Pediatric Society