Disorders of pyruvate carboxylase and the pyruvate dehydrogenase complex

Abstract

The most common defect associated with deficiency of the pyruvate dehydrogenase (PDH) complex occurs in the E1 component, specifically due to mutations in the X-linked E1 alpha gene. Clinical sequelae of these mutations, which range from severe neonatal lactic acidosis to carbohydrate-sensitive ataxia, can be different in males and females depending on the nature of the mutation and, in the case of females, on the X-inactivation pattern in different tissues. Males have a high representation of missense mutations among the patient cohort, while females are much more likely to have DNA rearrangements, particularly toward the 3' end of the coding sequence of the gene. Missplicing mutations involving exon 6 deletion have been reported, as has a missense mutation conferring true thiamin-responsiveness of the enzyme and the patient's clinical symptoms. Pyruvate carboxylase deficiency, on the other hand, is a true autosomal recessive disease, though it has high occurrences in particular ethnic groups, especially in Algonkian-speaking Amerindians and in Arabs. In the former group the defect is a simple type in which material cross-reactive to pyruvate carboxylase antibody is present in cultured cells (CRM+ve). In the latter group, cross-reacting material is rarely present (CRM-ve). The CRM+ve patients can survive into teenage years with careful supervision, while the CRM-ve patients have complications due to hyperammonaemia and dysfunction of the urea cycle and rarely survive beyond 3 months of life.

X chromosome evidence for ancient human histories

“…The fixed difference gives rise to a synonymous polymorphism (GCA and GCG codons for alanine) and so is probably not under selection. PDHA1 is a subunit of the pyruvate dehydrogenase enzyme, and a number of mutations have been described that disrupt gene function and cause disease (37), but no reports have been found that inform on whether, or to what extent, there exist geographically restricted functional variants.…”

A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate

“…It consists of multiple copies of three different enzymes: the thiamine-dependent pyruvate decarboxylase (E1) is a heterotetrameric (α 2 β 2 ) protein that irreversibly oxidizes pyruvate to acetyl CoA; dihydrolipoamide acetyl-transferase (E2) forms the structural core of the complex; dihydrolipoamide dehydrogenase (E3) is stably integrated into the complex by an E3-binding protein (E3bp), formally called protein X, that has no known enzymatic function [1]. Rapid regulation of the complex in eukaryotes occurs primarily by reversible phosphorylation of serine residues in the E1α subunit by PDH kinase and PDH phosphatase, in which the unphosphorylated enzyme is catalytically active [2,3].…”

“…Its clinical presentation and course are variable but most patients exhibit progressive neurological degeneration and either persistent or episodic elevation of lactate in blood, cerebrospinal fluid or both [2][3][4]. By far the majority of biochemically proven cases of PDH deficiency are due to defects in the E1α subunit.…”

Impact of selected inborn errors of metabolism on prenatal and neonatal development

“…Dysmorphism and brain malformations are found in some patients including microcephaly, narrow head, wide nasal bridge, and agenesis of corpus callosum (75,76). In some patients, there is generalised hypomyelination, and others have small cystic lesions and gliosis in the cortex, basal ganglia, brain stem, or cerebellum.…”