A case of benign pyruvate carboxylase deficiency with normal development

Hamilton, Jennifer J.; Rae, Margaret; Logan, R. W.; Robinson, P.H.

doi:10.1023/a:1005350600278

Cited by 23 publications

(14 citation statements)

References 3 publications

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“…1 in 250 000 live births. PC deficiency ranges in severity from (1) the Benign (Type C) mild form causing only mild recurrent episodes of lacticacidosis with normal neurological development [14,15,16], through (2) the Simple (Type A) milder form in which the presenting features are lacticacidaemia and psychomotor retardation, to (3) the Severe (Type B) form in which neonatal lacticacidosis, hyperammonaemia and abnormal redox states result in death at less than 3 months of age [17][18][19][20]. To date, there have been four documented point mutations associated with Type A PC deficiency [21,22], two deletion mutations associated with Type B PC deficiency [23], and two point mutations associated with Type C PC deficiency (M. A. Carbone, S. Rahman, G. T. N. Besley, P. T. Clayton and B. H. Robinson, unpublished work).…”

Section: Introductionmentioning

confidence: 99%

Expression and characterization of a human pyruvate carboxylase variant by retroviral gene transfer

Carbone

Robinson

2003

Biochemical Journal

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Type A pyruvate carboxylase (PC) deficiency presents mainly in the Amerindian population, specifically the Ojibwa, Cree and Micmac tribes of the Algonquin-speaking peoples. The gene for PC contains a homozygous founder mutation (G1828-->A) that results in an Ala610-->Thr amino acid substitution in Ojibwa with Type A PC deficiency. The mutation is located in the highly conserved pyruvate-binding domain of PC. The present paper describes a retroviral expression system for human PC used to analyse the effects of this mutation. We show, through immunoblot analysis, PC enzyme activity assays, reverse-transcription PCR and mitochondrial-import experiments, that this mutation is disease-causing in the Ojibwa population owing to its decreased catalytic activity, decreased steady-state levels of expression and inefficient import into the mitochondria. Our data suggest that this mutation may affect the stability of the protein, resulting in decreased steady-state levels of expression, and that it may also affect the secondary structure of the protein during the import process, thereby inhibiting proper translocation into the mitochondria, where PC is active.

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Section: Introductionmentioning

confidence: 99%

Expression and characterization of a human pyruvate carboxylase variant by retroviral gene transfer

Carbone

Robinson

2003

Biochemical Journal

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“…As stated above, only six patients with the milder late‐onset type C PCD were reported before our study and the PCD causing variants were described in only two of them (Arnold et al, ; Hamilton et al, ; Schiff et al, ; Van Coster et al, ; Wang et al, ). Thus, our three type C patients significantly increase our ability to examine mutations in these mild patients.…”

Section: Discussionmentioning

confidence: 82%

“…PCD mutations were reported in only two cases (Wang et al, ). Enzymatic activity was reported as 1–10% (of healthy control) in skin fibroblasts or peripheral blood leukocytes in three patients (Arnold et al, ; Hamilton et al, ; Van Coster et al, ), below 1% in two patients (Schiff et al, ; Wang et al, ) and was unreported in one patient (Wang et al, ). Thus, the residual enzymatic activity does not appear to be a reliable prognostic parameter in this condition.…”

Section: Introductionmentioning

confidence: 99%

“…Only 38 inactivating mutations in the PC gene have been described in patients with type A and B PCD (Breen et al, 2014;Carbone et al, 1998Carbone et al, , 2002Monnot et al, 2009;Ortez et al, 2013;Wang et al, 2008;Wexler et al, 1998). Several other PCD patients have been reported based on biochemical stigmata of PCD and/or on reduction of pyruvate carboxylase activity, but without molecular confirmation of the diagnosis (Ahmad et al, 1999;Arnold, Griebel, Porterfield, & Brewster, 2001;Brun et al, 1999;Hamilton, Rae, Logan, & Robinson, 1997;Oizumi et al, 1983;Pineda et al, 1995;Robinson et al, 1987;Van Coster, Fernhoff, & De Vivo, 1991;Van Coster, Janssens, Misson, Verloes, & Leroy, 1998).…”

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confidence: 99%

“…The third form of PCD (type C or benign) is characterized by short episodes of ketoacidosis during infancy and childhood, typically associated with intercurrent illnesses, mild psychological delay and neurologic symptoms, and survival until late adolescence in the six reported patients (Arnold et al, 2001;Hamilton et al, 1997;Higgins, Glasgow, Lusk, & Kerr, 1994;Higgins, Ide, Oghalai, & Polymeropoulos, 1997;Schiff et al, 2006;Van Coster et al, 1991;Wang et al, 2008). PCD mutations were reported in only two cases (Wang et al, 2008).…”

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confidence: 99%

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Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants inPCand analysis of the genotype–phenotype correlation

Coci

Gapsys²,

Shur

et al. 2019

Human Mutation

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Pyruvate carboxylase deficiency (PCD) is caused by biallelic mutations of the PC gene. The reported clinical spectrum includes a neonatal form with early death (type B), an infantile fatal form (type A), and a late‐onset form with isolated mild intellectual delay (type C). Apart from homozygous stop‐codon mutations leading to type B PCD, a genotype–phenotype correlation has not otherwise been discernible. Indeed, patients harboring biallelic heterozygous variants leading to PC activity near zero can present either with a fatal infantile type A or with a benign late onset type C form. In this study, we analyzed six novel patients with type A (three) and type C (three) PCD, and compared them with previously reported cases. First, we observed that type C PCD is not associated to homozygous variants in PC. In silico modeling was used to map former and novel variants associated to type A and C PCD, and to predict their potential effects on the enzyme structure and function. We found that variants lead to type A or type C phenotype based on the destabilization between the two major enzyme conformers. In general, our study on novel and previously reported patients improves the overall understanding on type A and C PCD.

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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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A case of benign pyruvate carboxylase deficiency with normal development

Cited by 23 publications

References 3 publications

Expression and characterization of a human pyruvate carboxylase variant by retroviral gene transfer

Expression and characterization of a human pyruvate carboxylase variant by retroviral gene transfer

Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants inPCand analysis of the genotype–phenotype correlation

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

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