Pyruvate dehydrogenase deficiency.

Brown, G. K.; Otero, Lucy J.; LeGris, M.; Brown, Ruth

doi:10.1136/jmg.31.11.875

Cited by 165 publications

(127 citation statements)

References 21 publications

(4 reference statements)

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…We speculate that the growth retardation of the Slc25a19 Ϫ/Ϫ embryos is caused by decreased flux through the PDH and KGDH complex reactions. The structural brain malformations of Slc25a19 Ϫ/Ϫ embryos support the hypothesis that the developing brain has a higher need for oxidative metabolism than other organs do (16). In addition to the reduction of energy produced by oxidative metabolism in the Slc25a19 Ϫ/Ϫ embryos and MCPHA patients caused by reduced PDH and KGDH complex activities, reduced Krebs cycle intermediates also could play a role in the phenotype of the mutants.…”

Section: Discussionsupporting

confidence: 54%

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

Lindhurst

Fiermonte

Song

et al. 2006

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

146

138

View full text Add to dashboard Cite

SLC25A19 mutations cause Amish lethal microcephaly (MCPHA), which markedly retards brain development and leads to ␣-ketoglutaric aciduria. Previous data suggested that SLC25A19, also called DNC, is a mitochondrial deoxyribonucleotide transporter. We generated a knockout mouse model of Slc25a19. These animals had 100% prenatal lethality by embryonic day 12. Affected embryos at embryonic day 10.5 have a neural-tube closure defect with ruffling of the neural fold ridges, a yolk sac erythropoietic failure, and elevated ␣-ketoglutarate in the amniotic fluid. We found that these animals have normal mitochondrial ribo-and deoxyribonucleoside triphosphate levels, suggesting that transport of these molecules is not the primary role of SLC25A19. We identified thiamine pyrophosphate (ThPP) transport as a candidate function of SLC25A19 through homology searching and confirmed it by using transport assays of the recombinant reconstituted protein.The mitochondria of Slc25a19 ؊/؊ and MCPHA cells have undetectable and markedly reduced ThPP content, respectively. The reduction of ThPP levels causes dysfunction of the ␣-ketoglutarate dehydrogenase complex, which explains the high levels of this organic acid in MCPHA and suggests that mitochondrial ThPP transport is important for CNS development.development ͉ mitochondrial transporter ͉ mouse model ͉ thiamine pyrophosphate deficiency ͉ neural tube defect

show abstract

Section: Discussionsupporting

confidence: 54%

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

Lindhurst

Fiermonte

Song

et al. 2006

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

146

138

View full text Add to dashboard Cite

show abstract

“…Patients with the metabolic form present with severe lactic acidosis, which is usually refractory to treatment, and often die early in the neonatal period. Surprisingly, patients with the metabolic form of the disease may show remarkably little neuropathology in comparison to patients with the neurological form of the disease (2,40). To determine whether noa exhibits neuropathology, we histologically examined the mutants for brain abnormalities at 8 dpf, but did not uncover any obvious defects.…”

Section: Resultsmentioning

confidence: 99%

“…Human patients with PDH deficiency most often exhibit developmental delay and growth retardation (2,41). To address this issue in noa, we raised larvae on the ketogenic diet and assessed their growth rates.…”

Section: Resultsmentioning

confidence: 99%

“…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)(3)(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).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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.

View full text Add to dashboard Cite

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 ...

show abstract

“…Pyruvate dehydrogenase (PDH) was significantly decreased at the protein level and showed a significant reduction at the transcript level for two subunits (DLAT, PDHa1) and an E3 binding protein (PDX1) (Table 1; Figure 2a). Deficiencies of PDH have been shown to result in increased lactate concentrations and cellular acidosis, 17 correlating with the detection of significantly raised lactate levels in schizophrenia brains by NMRbased metabolomics (Table 2). An increase in lactate and a decreased flux through the PDH complex implies a shift towards anaerobic respiration and could be in the context of hypoxia and/or mitochondrial dysfunction within the schizophrenia prefrontal cortex.…”

Section: D-digementioning

confidence: 97%

Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress

et al. 2004

View full text Add to dashboard Cite

The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

show abstract

Pyruvate dehydrogenase deficiency.

Cited by 165 publications

References 21 publications

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

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

Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress

Contact Info

Product

Resources

About