Pyruvate Carboxylase Deficiency: A Benign Variant with Normal Development

Coster, Rudy N. Van; Fernhoff, Paul M.; Vivo, Darryl C. De

doi:10.1203/00006450-199107000-00001

Cited by 53 publications

(34 citation statements)

References 33 publications

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“…These patients suffer episodes of lactic acidosis but do not display the neurological issues shown by Type A or Type B patients [127, 129, 130]. These cases are rare and the molecular basis is unknown [131]. The molecular bases of Type A and Type B PC deficiency are varied, with some overlap.…”

Section: Mitochondrial Pyruvate Metabolismmentioning

confidence: 99%

Regulation of pyruvate metabolism and human disease

Gray

Tompkins

Taylor

2013

Cell. Mol. Life Sci.

666

567

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Pyruvate is a keystone molecule critical for numerous aspects of eukaryotic and human metabolism. Pyruvate is the end-product of glycolysis, is derived from additional sources in the cellular cytoplasm, and is ultimately destined for transport into mitochondria as a master fuel input undergirding citric acid cycle carbon flux. In mitochondria, pyruvate drives ATP production by oxidative phosphorylation and multiple biosynthetic pathways intersecting the citric acid cycle. Mitochondrial pyruvate metabolism is regulated by many enzymes, including the recently discovered mitochondria pyruvate carrier, pyruvate dehydrogenase, and pyruvate carboxylase, to modulate overall pyruvate carbon flux. Mutations in any of the genes encoding for proteins regulating pyruvate metabolism may lead to disease. Numerous cases have been described. Aberrant pyruvate metabolism plays an especially prominent role in cancer, heart failure, and neurodegeneration. Because most major diseases involve aberrant metabolism, understanding and exploiting pyruvate carbon flux may yield novel treatments that enhance human health.

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Section: Mitochondrial Pyruvate Metabolismmentioning

confidence: 99%

Regulation of pyruvate metabolism and human disease

Gray

Tompkins

Taylor

2013

Cell. Mol. Life Sci.

666

567

View full text Add to dashboard Cite

show abstract

“…Fifteen of the 38 patients reported with PC deficiency had the severe form [Pineda et al, 1995;Pollock et al, 1986;Robinson, 1995;Rutledge et al, 1989]. A benign form of PC deficiency was described by Van Coster et al [1991] with no central nervous system (CNS) involvement.…”

Section: Introductionmentioning

confidence: 97%

“…PC deficiency occurs with high frequency in some Algonkian Amerindian tribes in Eastern Canada but otherwise is rare (1: 250,000); 38 patients have been described. Great variability in phenotypic expression is observed, varying from mild intermittent lactic acidemia with normal psychomotor development [Hamilton et al, 1997;Van Coster et al, 1991] to severe acidosis and neonatal death. Robinson et al [1984] defined two forms based on the severity of clinical and biochemical manifestations.…”

Section: Introductionmentioning

confidence: 99%

Pyruvate carboxylase deficiency: Prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form

et al. 1999

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Pyruvate carboxylase (PC) is a key enzyme in the gluconeogenesis and anaplerotic metabolic pathways. PC deficiency is a rare autosomal recessive disorder with three clinical presentations: an infantile form, a severe neonatal form, and a benign form. We report brother and sister sibs with the severe form of PC deficiency. Both had macrocephaly and severe ischemia-like brain lesions at birth and died in the first week of life with intractable lactic acidemia. In the girl, increased head circumference and periventricular leukomalacia (PVL) were detected on fetal ultrasonography at 29.4 weeks of gestation. PC activity in cultured skin fibroblasts was <2% of control. This is the first reported case of ischemia-like brain lesions documented prenatally in PC deficiency. The lesions were detected at a time of maximal periventricular metabolic demand. We postulate that energy deprivation induced by PC deficiency impairs astrocytic buffering capacity against excitotoxic insult and compromises normal microvascular morphogenesis and autoregulation, both mechanisms leading to cystic degeneration of the periventricular white matter. Discovery of cystic PVL on cerebral ultrasound at birth in a newborn infant presenting with primary lactic acidemia is highly suggestive of PC deficiency. Moreover, PC deficiency should also be considered when ischemia-like brain lesions are documented by fetal ultrasonography.

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“…In form B or ''French'' phenotype, patients present with severe neonatal lactic acidosis, elevated lactate-to-pyruvate ratio, hyperammonemia, hyperlysinemia, and hypercitrullinemia, leading to death in the first weeks of life [Robinson et al, 1984]. A third uncommon phenotype is characterized by mild lactic acidemia with normal psychomotor development [Hamilton et al, 1997;Van Coster et al, 1991].…”

Section: Introductionmentioning

confidence: 99%

Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency

et al. 2009

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Pyruvate carboxylase (PC), a key enzyme for gluconeogenesis and anaplerotic pathways, consists of four domains, namely, biotin carboxylase (BC), carboxyltransferase (CT), pyruvate carboxylase tetramerization (PT), and biotin carboxyl carrier protein (BCCP). PC deficiency is a rare metabolic disorder inherited in an autosomal recessive way. The most severe form (form B) is characterized by neonatal lethal lactic acidosis, whereas patients with form A suffer chronic lactic acidosis with psychomotor retardation. Diagnosis of PC deficiency relies on enzymatic assay and identification of the PC gene mutations. To date, six mutations of the PC gene have been identified. We report nine novel mutations of the PC gene, in five unrelated patients: three being affected with form B, and the others with form A. Three of them were frameshift mutations predicted to introduce a premature termination codon, the remaining ones being five nucleotide substitutions and one in frame deletion. Impact of these mutations on mRNA was assessed by RT-PCR. Evidence for a deleterious effect of the missense mutations was achieved using protein alignments and three-dimensional structural prediction, thanks to our modeling of the human PC structure. Altogether, our data and those previously reported indicate that form B is consistently associated with at least one truncating mutation, mostly lying in CT (C-terminal part) or BCCP domains, whereas form A always results from association of two missense mutations located in BC or CT (N-terminal part) domains. Finally, although most PC mutations are suggested to interfere with biotin metabolism, none of the PC-deficient patients was biotin-responsive.

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Pyruvate Carboxylase Deficiency: A Benign Variant with Normal Development

Cited by 53 publications

References 33 publications

Regulation of pyruvate metabolism and human disease

Regulation of pyruvate metabolism and human disease

Pyruvate carboxylase deficiency: Prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form

Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency

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