Neonatal lethal mitochondrial trifunctional protein deficiency mimicking a respiratory chain defect

We report the third (a girl; A) and the fourth (a boy; B) children of an unrelated healthy Turkish couple with two other healthy girls. They were born after unevent- ful pregnancies and deliveries. In both neonates, an identical disorder occurred leading to death at the ages of 4 days and 2 days, respectively. At the age of 24 h, both presented with neurological distress, severe metabolic acidosis and impaired perfusion. Within the next 24 h both developed dilated cardiomyopathy and had cardiac arrhythmia and cardiac arrest leading to death in patient B. Child A was resuscitated. Renal failure occurred and peritoneal dialysis was initiated. This child died at 4 days of age owing to cardiorespiratory failure. Special laboratory evalu- ations revealed a tendency for hypoglycaemia, increased plasma ammonia concen- trations (165 kmol/L and 100 kmol/L for patients A and B respectively), greatly increased blood lactate levels (20.5 mmol/L and 14.5 mmol/L), and elevated plasma creatine kinase (1130 U/L, measured only in child A). At the second day of life, child A showed greatly increased urinary lactic acid excretion with an otherwise normal organic acid pattern; she was on intravenous glucose at this time. The urine of child B contained excessive amounts of lactic acid and substantial amounts of ketones (3- hydroxybutyric acid 500 kmol/mmol creatinine, normal \80) and dicar- C 6 ÈC 10 boxylic acids. In particular, adipic acid was greatly increased (1860 kmol/mmol cre- atinine, normal \20) and to a lesser degree suberic acid (57 kmol/mmol creatinine, normal \10). In addition, the urine contained increased amounts of unsaturated adipic and suberic acids, 3-hydroxyadipic, 3-hydroxysuberic and 3-hydroxysebacic acids as well as 3-oxoadipic acid. In both children, autopsy produced no results indicative of a speci-c disorder. The tissue analyses of child A (liver, skin -broblasts) for respiratory chain complexes including pyruvate dehydrogenase and pyruvate carboxylase (W. Ruitenbeek, Nijmegen) gave normal results. Later, fatty acid oxidation studies in cultured skin -broblasts demonstrated decreased rates for myristic and palmitic acids as sub- strates. After it had been established that the patientÏs defect in fatty acid oxidation was not due to a de-ciency of any of the acyl-CoA dehydrogenases, strikingly reduced activities were demonstrated for the enoyl-CoA hydratase measured with 2-laureoyl-CoA as a substrate (23 nmol/min per mg protein, normal 79 ^ 26 (C 12>1 ) (n \ 50)) and for the 3-hydroxyacyl-CoA dehydrogenase measured in the reverse 835