Extract: A male sibling who was born of healthy parents and who died at the age of five days with the clinical picture of severe hypotonia, areflexia, hyperventilation, and grunting is described. An older female sibling with identical symptoms had died some years previously. The parents were unrelated and had three other healthy children. The patient exhibited severe metabolic acidosis which was resistant to therapy. This acidosis was caused by the presence in blood of propionic acid in a very high concentration (5.4 mM/l). The high levels of urea and potassium also present were probably the result of a markedly reduced urine production caused by dehydration. The levels of amino acid in plasma revealed low values for one amino acid, normal values for other amino acids, and high values for lysine, histidine, valine, isoleucine, and leucine.At autopsy, except for a right descending aortic arch, no gross anomalies were found, although the liver was enlarged, probably because of increased fat content. Microscopic examination showed a fatty degeneration of liver cells, degeneration of the Purkinje cells and the granular layer in the cerebellum, and macrophages containing debris of blood cells in the bone marrow and in the spleen. Gas chromatography was used to determine the nature of the accumulated fat in the liver. Among the normal constituents of liver triglycerides, three abnormal fractions were observed, two of which contained C15 and C17 straight chain fatty acids. These were not observed in normal liver fat. The combination of propionicacidemia and the storage of fatty acids with an uneven chain number in the liver pointed to a block in the conversion of propionic acid into methylmalonic acid.Speculation: It is suggested that the propionicacidemia found in this patient is due to a metabolic block in the conversion of propionic acid into methylmalonic acid. The increased concentration of odd-numbered fatty acids (C15 and C17) in the liver may arise from either a decreased breakdown of these fatty acids or an increased synthesis initiated by the high concentration of propionyl-CoA. It is proposed that the missing enzyme is propionyl coenzyme A carboxylase. The fact that a sibling with identical symptoms had died forms a strong argument to postulate that a hereditary abnormality of recessive inheritance is the cause of this as yet undescribed syndrome.