Defects in the E2 lipoyl transacetylase and the X-lipoyl containing component of the pyruvate dehydrogenase complex in patients with lactic acidemia.

Robinson, Brian H.; MacKay, N.; Petrova‐Benedict, Roumyana; Ozalp, I; Coşkun, Turgay; Stacpoole, Peter W.

doi:10.1172/jci114641

Cited by 62 publications

(32 citation statements)

References 11 publications

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“…Alternatively, an abnormal total number of chromosomes results in non-specific genetic imbalance, which may also induce enhanced apoptosis at the early stage of neural stem cell differentiation. This study suggests that autosomal imbalance triggers apoptosis during early neuronal differentiation by altering the expression of a set of genes, which were identified as a common cluster and reported to be involved in cell proliferation, as well as neurite outgrowth and differentiation [11][12][13][14][15][16][17][18]. We suggest that dysregulation of these genes leads to excess apoptosis during early neurogenesis by altering the cell cycle progression and differentiation program.…”

Section: Discussionmentioning

confidence: 93%

Enhanced apoptosis during early neuronal differentiation in mouse ES cells with autosomal imbalance

Kai

Wang

Kishigami³

et al. 2008

Cell Res

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Section: Discussionmentioning

confidence: 93%

Enhanced apoptosis during early neuronal differentiation in mouse ES cells with autosomal imbalance

Kai

Wang

Kishigami³

et al. 2008

Cell Res

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“…This suggests that mutations in the other PDH subunits can also cause this disease. Indeed, defects have also been reported in the E2 subunit (27), E3 subunit (28), and the E3-binding protein (29).…”

Section: Resultsmentioning

confidence: 98%

A zebrafish model for pyruvate dehydrogenase deficiency: Rescue of neurological dysfunction and embryonic lethality using a ketogenic diet

Taylor

Hurley

Epps

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Defects in the pyruvate dehydrogenase (PDH) complex result in severe neurological dysfunction, congenital lactic acidosis, growth retardation, and early death. Current treatments for PDH deficiency are administered postnatally and are generally unsuccessful. Because many patients with this disease are born with irreversible defects, a model system for the development of effective pre-and postnatal therapies would be of great value. In a behavioral genetic screen aimed to identify zebrafish with visual function defects, we previously isolated two alleles of the recessive lethal mutant no optokinetic response a (noa). Here we report that noa is deficient for dihydrolipoamide S-acetyltransferase (Dlat), the PDH E2 subunit, and exhibits phenotypes similar to human patients with PDH deficiency. To rescue the deficiency, we added ketogenic substrates to the water in which the embryos develop. This treatment successfully restored vision, promoted feeding behavior, reduced lactic acidosis, and increased survival. Our study demonstrates an approach for establishing effective therapies for PDH deficiency and other congenital diseases that affect early embryonic development.H uman diseases that affect tissues with high-energy requirements are often caused by defects in mitochondrial function (1). Pyruvate dehydrogenase (PDH) deficiency is a rare metabolic disorder that severely affects the central nervous system due to the high-energy demand of neurons and often results in developmental delay, feeding difficulties, lethargy, ataxia, blindness, and early death (2-4). PDH is a nuclear-encoded mitochondrial matrix multienzyme complex that provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the irreversible conversion of pyruvate into acetyl-CoA (5). Defects in PDH result in decreased acetyl-CoA synthesis and the accumulation of pyruvate and lactate, causing reduced energy production and metabolic acidosis, respectively.Current treatments for PDH deficiency, which include the activation of residual PDH with dichloroacetate (6), the administration of cofactors (lipoic acid and thiamine) (7,8), and the provision of ketogenic diets (9, 10), have yielded only limited or variable success (see Fig. 1). The technical challenges of working with small numbers of human patients has made it difficult to include all of the necessary controls and to systematically evaluate therapeutic agents and diets with varying proportions of calories from fat, carbohydrate, and protein (9, 11). Furthermore, preexisting neurological disorders compound the difficulty of evaluating treatments. A therapy that bypasses the entire complex would potentially be of greatest benefit, because it could be used to treat patients with defects in any of the PDH subunits and varying degrees of deficiency.An animal model for PDH deficiency would be of great value to improve current treatments and to allow the development of novel therapies. This model should exhibit phenotypic characteristics similar to those seen in human ...

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“…The majority of patients with PDH complex deficiency have a defect in the E~ component of the enzyme (Robinson et al 1987b(Robinson et al , 1990bRobinson 1993Robinson , 1995aWexler et al 1988), with a lesser number of defects occurring in the E2, E3. and X components (Robinson et al 1990a;Robinson 1993).…”

Section: Structure Of the Pdh Complexmentioning

confidence: 99%

Disorders of pyruvate carboxylase and the pyruvate dehydrogenase complex

Robinson

MacKay

Chun

et al. 1996

J of Inher Metab Disea

133

160

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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.

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Defects in the E2 lipoyl transacetylase and the X-lipoyl containing component of the pyruvate dehydrogenase complex in patients with lactic acidemia.

Cited by 62 publications

References 11 publications

Enhanced apoptosis during early neuronal differentiation in mouse ES cells with autosomal imbalance

Enhanced apoptosis during early neuronal differentiation in mouse ES cells with autosomal imbalance

A zebrafish model for pyruvate dehydrogenase deficiency: Rescue of neurological dysfunction and embryonic lethality using a ketogenic diet

Disorders of pyruvate carboxylase and the pyruvate dehydrogenase complex

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