Chapter 100

## Abstract

Abstract

1. The lactic acid that circulates in the human body is the product of the anaerobic metabolism of glucose, which takes place primarily in red cells, skin, kidney medulla, and white skeletal muscle. Some of it is oxidized by red muscle and kidney cortex, but the bulk of it is taken up by the liver and made into glucose. Lactate is always produced by reduction of pyruvate through lactate dehydrogenase and is always removed by a reversal of this process. Deficiency of both the H and the M subunit forms of lactate dehydrogenase are known, but they are relatively benign conditions. The oxidative metabolism of pyruvate proceeds through pyruvate dehydrogenase, the Krebs cycle, and the respiratory chain, whereas anabolic utilization proceeds primarily through pyruvate carboxylase. A defect in any of these pathways may lead to inadequate removal of pyruvate and lactate from the circulation, resulting in a condition of lactic acidemia.

2. Deficiency of the pyruvate dehydrogenase complex is the most common of the disorders leading to lactic acidemia. It may be due to a defect in the E1 (MIM 312170), E2 (MIM 245348), E3 (MIM 246900), X-lipoate (MIM 245349), or pyruvate dehydrogenase phosphatase component of the complex. The most common of these is the defect in the E1 component. This particular defect can present in three possible ways with a graded spectrum from the most severe to the least. In its most severe form, it presents with overwhelming lactic acidosis at birth, with death in the neonatal period. In a second form of presentation, the lactic acidemia is moderate, but there is profound psychomotor retardation with increasing age and, in many cases, concomitant damage to the brain stem and basal ganglia lead to death in infancy. In the third form of presentation, which is found only in males, there is carbohydrate-induced episodic ataxia, very often coupled with mild developmental delay.

3. The E1 defects are caused by mutations in the E1α gene which is X-linked (MIM 312170). Because of its central importance in central nervous system metabolism, pyruvate dehydrogenase deficiency is a problem both in males and in females even though only one E1α allele in the females carries a mutation. For this reason, this form of pyruvate dehydrogenase complex deficiency should be classified as X-linked dominant. Most defects in the E1α gene are de novo mutations and are not carried somatically by either parent. In males, the defects are either missense mutations or mutations that affect only the 3′ end of the coding sequence. In females, deletions and insertions that completely nullify one allele are more common. The E2 (MIM 245348) and protein X-lipoate (MIM 245349) defects are rare and result in severe psychomotor retardation. A group of X-deficient patients has been characterized at the molecular level.

4. The E3 lipoamide dehydrogenase defect (MIM 246900) leads to deficient activity not only in the pyruvate dehydrogenase complex, but also in the α-ketoglutarate and branched chain ketoacid dehydrogenase complexes. Pyruvate dehydrogenase phosphatase deficiency has been documented in four patients, three of them presenting with Leigh disease and the fourth with unremitting lactic acidemia. The most common pathologic feature of deficiency of the pyruvate dehydrogenase complex is the development of cystic lesions in the cerebral cortex, basal ganglia, and brain stem. More recently, a milder version of E3 lipoamide dehydrogenase deficiency was described.

5. Pyruvate carboxylase deficiency (MIM 266150) presents in three ways. In the simple (A) form of the disease, the patient presents in the first few months of life with a mild-to-moderate lactic acidemia and delayed development. In the more complex (B) form of the disease, the patient presents soon after birth with a severe lactic acidemia accompanied by hyperammonemia, citrullinemia, and hyperlysinemia. The patients of this latter group rarely survive to 3 months of age. In a single case (C), the presentation is mild and consists only of episodic acidosis with no psychomotor retardation. There is good evidence to suggest that patients in group A have some residual pyruvate carboxylase activity while those in group B have no activity at all. Some patients in group B have absence of both mRNA and pyruvate carboxylase protein in cultured skin fibroblasts. Group A patients who survive are severely mentally retarded and missense mutations have been described for this group. This seems to be due to loss of cerebral neurons, despite the fact that in normal individuals there is pyruvate carboxylase activity in astrocytes but not in neurons. This suggests that pyruvate carboxylase has an essential anaplerotic (Greek derivation meaning “filling up”) role in astrocytes and that its absence deprives the neuron of an obligatory nutrient normally supplied by astrocyte metabolism.

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