Pyruvate dehydrogenase complex deficiency
Pyruvate dehydrogenase complex deficiency should be suspected in a comatose neonate with elevated serum lactate and pyruvate and a lactate-to-pyruvate ratio below 25. It can only be excluded by the presence of a normal cerebrospinal fluid lactate. Dysmorphic facial features (frontal bossing, upturned nose, thin upper lip, and low-set ears), short fingers and nails, simian creases, and hypospadia may be present. Neonates with pyruvate dehydrogenase deficiency have an appearance similar to that of neonates with fetal alcohol syndrome. Brain imaging may show evidence of prenatal brain damage. The diagnosis is established by finding decreased activity of one or more of the pyruvate dehydrogenase complex enzymes in cultured fibroblasts, liver tissue, skeletal muscle, lymphocytes, or brain tissue. Multiple tissues may have to be analyzed to establish the correct diagnosis since the enzyme deficiency may not be detected in all tissues. Treatment, in addition to metabolic support, consists of a high-fat (to introduce compounds to the citric acid cycle bypassing pyruvate), low-carbohydrate diet, thiamine, lipoic acid, carnitine, and dichloroacetate. Pyruvate dehydrogenase complex deficiency has an autosomal-recessive or a sex-linked inheritance. Pyruvate dehydrogenase complex deficiency may also occur in isovaleric acidemia and in dihydrolipoyl dehydrogenase deficiency.
Pyruvate carboxylase deficiency
Pyruvate carboxylase deficiency in a comatose neonate is characterized by high serum ketones, pyruvate, and lactate, and a lactate-to-pyruvate ratio above 35. Brain imaging shows evidence of prenatal damage. The complex metabolic findings in a patient with pyruvate carboxylase are due to high levels of acetyl-CoA and low levels of oxaloacetate. High levels of acetyl-CoA produce ketosis. Low levels of oxaloacetate cause low levels of aspartate. Low aspartate prevents nicotinamide adenine dinucleotide from entering the mitochondria. An excess of nicotinamide adenine dinucleotide in the cytosol increases the conversion of pyruvate to lactic acid. It is this increase in the conversion of pyruvate to lactic acid that leads to a lactate-to-pyruvate ratio above 35. Low oxaloacetate also impairs the citric acid cycle, glycine cleavage system, and the urea cycle. The diagnosis is established by finding decreased pyruvate carboxylase activity in cultured fibroblasts. Treatment consists of metabolic support and a diet low in fat and high in carbohydrates and protein. Aspartic acid and biotin should be added. Pyruvate carboxylase deficiency also occurs in multiple carboxylase deficiency. Prognosis is dismal.