RARE DISEASE
Pyruvate carboxylase deficiency
Pyruvate carboxylase deficiency
Pyruvate carboxylase deficiency
Synonyms: Ataxia with lactic acidosis type 2, Ataxia with lactic acidosis type II, Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency, Leigh syndrome due to PC deficiency, Leigh syndrome due to pyruvate carboxylase deficiency
Synonyms: Ataxia with lactic acidosis type 2, Ataxia with lactic acidosis type II, Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency, Leigh syndrome due to PC deficiency, Leigh syndrome due to pyruvate carboxylase deficiency
Synonyms: Ataxia with lactic acidosis type 2, Ataxia with lactic acidosis type II, Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency, Leigh syndrome due to PC deficiency, Leigh syndrome due to pyruvate carboxylase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Pyruvate carboxylase deficiency is an autosomal recessive disorder caused by PC gene mutations, disrupting mitochondrial energy metabolism and gluconeogenesis. It manifests with lactic acidosis, hyperammonemia, and progressive neurological impairment (developmental delay, seizures, hypotonia). Three phenotypes exist: Type A (infantile-onset, North American prevalence), Type B (neonatal-onset, severe European cases), and Type C (intermittent/milder symptoms). Mortality is high in Types A/B, with multisystem organ failure and neurological decline [1][4][6][13].
Burden
Mortality: Type B mortality >90% by age 3 months; Type A survival rarely exceeds early childhood [1][4][8].
Morbidity: Neurodegeneration, intellectual disability, and treatment-resistant seizures necessitate lifelong care [6][13].
Resource impact: Frequent hospitalizations for metabolic crises and specialized dietary regimens [6][12].
Therapies
Anaplerotic therapy: High-carbohydrate/protein diets, citrate/aspartate supplementation [3][6].
Acute management: Triheptanoin (acetyl-CoA source), IV glucose, acidosis correction [3][6][8].
Supportive care: Anticonvulsants, ketogenic diets (limited efficacy), and liver failure monitoring [6][8][13].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
45 drug discovery papers about Pyruvate carboxylase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
45 drug discovery papers about Pyruvate carboxylase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-21 | Benefits and adverse effects of ketogenic diet treatment in pediatric patients with inborn errors of metabolism.
The ketogenic diet (KD) is an established therapeutic option for epilepsy and selected inborn errors of metabolism (IEMs), particularly glucose transporter type 1 deficiency (GLUT1D) and pyruvate dehydrogenase complex deficiency (PDCD). Increasing evidence suggests broader applications of KD in pediatric metabolic disorders; however, data on its safety and efficacy in heterogeneous IEM populations remain limited. To evaluate the efficacy, clinical benefits, and adverse effects (AEs) of KD in pediatric patients with various IEMs. A retrospective analysis was conducted in pediatric patients with IEMs receiving KD treatment. Patients were categorized into 3 groups: 1) other IEMs (n = 7), 2) mitochondrial diseases (MD) (n = 17), and 3) GLUT1D and PDCD (n = 20). The median age at initiation of KD was 37, 53, and 53 months, respectively, and the median duration of KD treatment was 5, 11, and 55 months in groups 1, 2, and 3. The KD was associated with clinical benefits in 84% of patients. Among children with epilepsy (n = 23), a seizure reduction of >50% was observed in 73.9% of patients, including complete seizure freedom in 4 individuals. Improvements were also noted in muscle tone (27.6%), exercise tolerance (51.2%), ataxia (83.3%), and involuntary movements (60%). Lactate levels decreased in 84.6% of patients with mitochondrial disease and in all patients with PDCD. The KD was discontinued in 12 patients due to insufficient efficacy (n = 5) or AEs (AEs; n = 7). The most common AEs included gastrointestinal (GI) symptoms, dyslipidemia, hyperuricemia, metabolic acidosis, and decreased free carnitine; most were transient. No significant association was found between median β-hydroxybutyrate (BHB) levels and clinical outcomes. The KD is an effective and generally well-tolerated therapeutic option in pediatric IEMs, with benefits extending beyond seizure control. Adverse effects are typically manageable, although GI intolerance may limit long-term use. Ketogenic diet should be considered not only for refractory epilepsy but also for selected metabolic indications.
2024-10-08 | Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.
Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management.
2023-12-28 | Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
Abstract Pyruvate carboxylase is a mitochondrial enzyme essential for the tricarboxylic acid cycle (TCA), gluconeogenesis and fatty‐acid synthesis. Pyruvate carboxylase deficiency (PCD) mostly presents with life‐limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis. Therapies remain essentially supportive. Triheptanoin is an odd‐chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood–brain‐barrier. Outcomes of triheptanoin treatment in PCD types A/B have been disappointing, but have not been reported in type C. Here, we present two new patients with PCD type C, and report the response to treatment with triheptanoin in one. Patient 1 (P1) presented with neonatal‐onset lactic acidosis and recurrent symptomatic lactic acidosis following exercise and during illnesses, with frequent hospitalisations. Speech development was delayed. MRI‐brain showed delayed cerebral myelination. Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain. Treatment with triheptanoin was commenced in P1 at 3 years of age with up‐titration to 35 mL/day (25% of daily energy intake) over 6 months, due to transient diarrhoea. Dietary long‐chain triglycerides were restricted, with fat‐soluble vitamin supplementation. Subsequently, hospitalisations during intercurrent illnesses decreased, post‐exertional hyperlactataemia resolved and exercise tolerance improved. Continued developmental progress was observed, and repeat MRI 18 months after initiation showed improved myelination. Triheptanoin was well‐tolerated and appeared efficacious during 2 years' follow‐up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C.
2023-06-19 | Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin.
Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive mitochondrial neurometabolic disorder of energy deficit resulting in high morbidity and mortality, with limited therapeutic options. The PC homotetramer has a critical role in gluconeogenesis, anaplerosis, neurotransmitter synthesis, and lipogenesis. The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction. Use of the anaplerotic agent triheptanoin on a limited number of individuals with PCD has had mixed results. We expand on the potential utility of triheptanoin in PCD by examining the clinical, biochemical, molecular, and health-related quality-of-life (HRQoL) findings in a cohort of 12 individuals with PCD (eight with Type A and two each with Types B and C) treated with triheptanoin ranging for 6 days to about 7 years. The main endpoints were changes in blood lactate and HRQoL scores, but collection of useful data was limited to about half of subjects. An overall trend of lactate reduction with time on triheptanoin was noted, but with significant variability among subjects and only one subject reaching close to statistical significance for this endpoint. Parent reported HRQoL assessments with treatment showed mixed results, with some subjects showing no change, some improvement, and some worsening of overall scores. Subjects with buried amino acids in the pyruvate carboxyltransferase domain of PC that undergo destabilizing replacements may be more likely to respond (with lactate reduction or HRQoL improvement) to triheptanoin compared to those with replacements that disrupt tetramerization or subunit-subunit interface contacts. The reason for this difference is unclear and requires further validation. We observed significant variability but an overall trend of lactate reduction with time on triheptanoin and mixed parent reported outcome changes by HRQoL assessments for subjects with PCD on long-term triheptanoin. The mixed results noted with triheptanoin therapy in this study could be due to endpoint data limitation, variability of disease severity between subjects, limitation of the parent reported HRQoL tool, or subject genotype variability. Alternative designed trials and more study subjects with PCD will be needed to validate important observations from this work.
2021-03-05 | Challenges in the management of an ignored cause of hyperammonemic encephalopathy: pyruvate carboxylase deficiency.
Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive disease and provides clinics in three essential phenotypes. Type B PC deficiency is characterized by lactic acidosis and hyperammonemia. We report a Turkish patient who was diagnosed with type B PC deficiency. Despite the application of anaplerotic treatment with biotin, citrate and arginine-aspartate, continuous veno-venous hemodialysis (CVVHD) treatments were applied due to the failure to keep hyperammonemia and lactic acidosis under control. Ammonia values increasing to 860 μmol/L were observed. A homozygous novel variant was detected in PC gene analyses containing a 12-base pair deletion on exon 8. Although the mutation found was not reported previously, it was accepted as a pathogenic variant due to its presence in a functional region of the protein. In type B PC deficiency, although a high level of ammonia is expected, it rarely exceeds 200 μmol/L. As far as we know, the present case has the highest ammonia values in the literature. This paper has been shared to highlight to keep PC deficiency in mind regarding the differential diagnosis of hyperammonemia, particularly in the presence of lactic acidosis, and to serve as a model for the use of different modalities in the management process of PC deficiency.
cell therapies
2023-01-23 | Generation of an induced pluripotent stem cell line (SHCDNi007-A) from a patient with pyruvate carboxylase deficiency carrying compound heterozygous (c.182 T > C/ c.2581G > A) variants in PC.
Pyruvate carboxylase (PC) deficiency (PCD), due to biallelic PC variants, is a rare inherited metabolic disease, which is characterized by seizures, global developmental delay, as well as lactic acidosis, and elevated plasma pyruvate and alanine levels in affected individuals. In the present study, a new induced pluripotent stem cell line (SHCDNi007-A) was generated from the peripheral blood mononuclear cells of a 2-month-old male infant with biallelic PC mutations c.(182 T > C;2581G > A), i.e. p.(Ile61Thr;Val861Met). This cell line is expected to facilitate the in vitro modeling of the disease pathophysiology and the development of future therapeutics for PCD.
2012-03-15 | Catabolite repression of phosphoenolpyruvate carboxykinase by a zinc finger protein under biotin- and pyruvate carboxylase-deficient conditions in Pichia pastoris.
We have identified a methanol- and biotin-starvation-inducible zinc finger protein named ROP [repressor of phosphoenolpyruvate carboxykinase (PEPCK)] in the methylotrophic yeast Pichia pastoris. When P. pastoris strain GS115 (wild-type, WT) is cultured in biotin-deficient, glucose-ammonium (Bio(-)) medium, growth is suppressed due to the inhibition of anaplerotic synthesis of oxaloacetate, catalysed by the biotin-dependent enzyme pyruvate carboxylase (PC). Deletion of ROP results in a strain (ΔROP) that can grow under biotin-deficient conditions due to derepression of a biotin- and PC-independent pathway of anaplerotic synthesis of oxaloacetate. Northern analysis as well as microarray expression profiling of RNA isolated from WT and ΔROP strains cultured in Bio(-) medium indicate that expression of the phosphoenolpyruvate carboxykinase gene (PEPCK) is induced in ΔROP during biotin- or PC-deficiency even under glucose-abundant conditions. There is an excellent correlation between PEPCK expression and growth of ΔROP in Bio(-) medium, suggesting that ROP-mediated regulation of PEPCK may have a crucial role in the biotin- and PC-independent growth of the ΔROP strain. To our knowledge, ROP is the first example of a zinc finger transcription factor involved in the catabolite repression of PEPCK in yeast cells cultured under biotin- or PC-deficient and glucose-abundant conditions.
2002-09-01 | Pyruvate carboxylase deficiency—insights from liver transplantation
Pyruvate carboxylase deficiency, complex form, presents in early infancy with lethal metabolic acidosis, resulting from ketoacidosis and lactic acidemia. Renal tubular acidosis, hyperammonemia, and citrullinemia complete the picture. In an infant with this disease, large amounts of glucose ameliorated the ketoacidosis, but worsened the lactic acidosis. Orthotopic hepatic transplantation completely reversed the ketoacidosis and the renal tubular abnormality and ameliorated the lactic acidemia. Concentrations of glutamine in cerebrospinal fluid were low and did not improve with liver transplantation.
1999-01-01 | Improvement of the primary metabolism of cell cultures by introducing a new cytoplasmic pyruvate carboxylase reaction
Continuous mammalian cell lines are important hosts for the production of biological pharmaceuticals. However, these cell lines show some severe disorders in primary metabolism, which they have in common with many cancer cells. This leads to a high throughput of substrates giving a low energy yield and ample toxic side products such as lactate and ammonia. Because the enzymatic connection between glycolysis and the tricarboxylic acid cycle (TCA) is very poor, glucose is mainly degraded via oxidative glycolysis. It will be shown that introducing a pyruvate carboxylase gene expressed in the cytoplasma into a continuous BHK-21 cell line, and thus reconstituting the missing link between glycolysis and TCA, can reduce this problem. Thus, glucose consumption could be reduced by a factor of four and glutamine utilization up to a factor of two, compared with control. Moreover, a 1.4-fold-higher adenosine triphosphate (ATP) content was achieved. The flux of labeled [(14)C]-glucose into the TCA is shown to be enhanced, indicating a higher rate of oxidative glucose degradation. Host cell lines with an improved energy metabolism will therefore result in better exploitation of substrates, an increasing yield by the more efficient use of carbon source, and higher product integrity combined with lower production costs.
gene therapies
2025-05-01 | Pyruvate Carboxylase Deficiency Induces Pulmonary Fibrosis via Mitochondrial Damage Though Slc25a4/AMPK/Nrf2 Pathway
Abstract Background The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear and is mainly related to the damage of type II alveolar epithelial cells (ATII). Persistent damage to ATII leads to oxidative stress, mitochondrial damage, which in turn trigger excessive apoptosis and epithelial – mesenchymal transition (EMT). Pyruvate carboxylase (PC), which involved in adenosine triphosphate (ATP) production, has long been thought to be associated with mitochondrial functional homeostasis and oxidative stress. However, the role of PC and its correlation with mitochondrial function in PF remain unknown. Methods The aim of this study was to evaluate the expression of PC in lung tissues of patients with IPF, employ a mouse model with ATIIs specific knockout of PC, manipulate PC expression in murine lung epithelial-12 (MLE-12) cells. Results The study findings revealed that compared to the control group, the expression of PC in the lungs of IPF patients and bleomycin (BLM)-induced mice, and also in MLE-12 cells stimulated by transforming growth factor (TGF)-β1 and BLM was downregulated. In BLM-injured mice, the knockout of PC led to severe fibrosis, mitochondrial damage, oxidative stress response and apoptosis. In vitro, silencing PC enhanced the epithelial-mesenchymal transition (EMT) induced by TGF-β1, as well as increased mitochondrial damage, oxidative stress and apoptosis. Immunoprecipitation combined with mass spectrometry showed that PC could interact with solute carrier family 25 member 4 (Slc25a4) in mitochondrial, and then reduced the ubiquitination-mediated degradation of Slc25a4. In ATII-specific PC-knockout mice, we observed the expressions of Slc25a4, Nrf2 and the phosphorylation of AMPKα were decreased and oxidative stress was exacerbated after BLM injury. When Slc25a4 was overexpressed using adeno-associated virus (AAV) in ATII-specific PC-knockout mice, the phosphorylation of AMPKα and the expression of Nrf2 were restored, mitochondrial damage was recovery, thereby alleviating PF. Conclusion Enhancing PC signaling could represent a viable strategy for the treatment of PF.
small molecules
2026-04-21 | Benefits and adverse effects of ketogenic diet treatment in pediatric patients with inborn errors of metabolism.
The ketogenic diet (KD) is an established therapeutic option for epilepsy and selected inborn errors of metabolism (IEMs), particularly glucose transporter type 1 deficiency (GLUT1D) and pyruvate dehydrogenase complex deficiency (PDCD). Increasing evidence suggests broader applications of KD in pediatric metabolic disorders; however, data on its safety and efficacy in heterogeneous IEM populations remain limited. To evaluate the efficacy, clinical benefits, and adverse effects (AEs) of KD in pediatric patients with various IEMs. A retrospective analysis was conducted in pediatric patients with IEMs receiving KD treatment. Patients were categorized into 3 groups: 1) other IEMs (n = 7), 2) mitochondrial diseases (MD) (n = 17), and 3) GLUT1D and PDCD (n = 20). The median age at initiation of KD was 37, 53, and 53 months, respectively, and the median duration of KD treatment was 5, 11, and 55 months in groups 1, 2, and 3. The KD was associated with clinical benefits in 84% of patients. Among children with epilepsy (n = 23), a seizure reduction of >50% was observed in 73.9% of patients, including complete seizure freedom in 4 individuals. Improvements were also noted in muscle tone (27.6%), exercise tolerance (51.2%), ataxia (83.3%), and involuntary movements (60%). Lactate levels decreased in 84.6% of patients with mitochondrial disease and in all patients with PDCD. The KD was discontinued in 12 patients due to insufficient efficacy (n = 5) or AEs (AEs; n = 7). The most common AEs included gastrointestinal (GI) symptoms, dyslipidemia, hyperuricemia, metabolic acidosis, and decreased free carnitine; most were transient. No significant association was found between median β-hydroxybutyrate (BHB) levels and clinical outcomes. The KD is an effective and generally well-tolerated therapeutic option in pediatric IEMs, with benefits extending beyond seizure control. Adverse effects are typically manageable, although GI intolerance may limit long-term use. Ketogenic diet should be considered not only for refractory epilepsy but also for selected metabolic indications.
2024-10-08 | Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.
Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management.
2023-12-28 | Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
Abstract Pyruvate carboxylase is a mitochondrial enzyme essential for the tricarboxylic acid cycle (TCA), gluconeogenesis and fatty‐acid synthesis. Pyruvate carboxylase deficiency (PCD) mostly presents with life‐limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis. Therapies remain essentially supportive. Triheptanoin is an odd‐chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood–brain‐barrier. Outcomes of triheptanoin treatment in PCD types A/B have been disappointing, but have not been reported in type C. Here, we present two new patients with PCD type C, and report the response to treatment with triheptanoin in one. Patient 1 (P1) presented with neonatal‐onset lactic acidosis and recurrent symptomatic lactic acidosis following exercise and during illnesses, with frequent hospitalisations. Speech development was delayed. MRI‐brain showed delayed cerebral myelination. Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain. Treatment with triheptanoin was commenced in P1 at 3 years of age with up‐titration to 35 mL/day (25% of daily energy intake) over 6 months, due to transient diarrhoea. Dietary long‐chain triglycerides were restricted, with fat‐soluble vitamin supplementation. Subsequently, hospitalisations during intercurrent illnesses decreased, post‐exertional hyperlactataemia resolved and exercise tolerance improved. Continued developmental progress was observed, and repeat MRI 18 months after initiation showed improved myelination. Triheptanoin was well‐tolerated and appeared efficacious during 2 years' follow‐up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C.
2023-06-19 | Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin.
Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive mitochondrial neurometabolic disorder of energy deficit resulting in high morbidity and mortality, with limited therapeutic options. The PC homotetramer has a critical role in gluconeogenesis, anaplerosis, neurotransmitter synthesis, and lipogenesis. The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction. Use of the anaplerotic agent triheptanoin on a limited number of individuals with PCD has had mixed results. We expand on the potential utility of triheptanoin in PCD by examining the clinical, biochemical, molecular, and health-related quality-of-life (HRQoL) findings in a cohort of 12 individuals with PCD (eight with Type A and two each with Types B and C) treated with triheptanoin ranging for 6 days to about 7 years. The main endpoints were changes in blood lactate and HRQoL scores, but collection of useful data was limited to about half of subjects. An overall trend of lactate reduction with time on triheptanoin was noted, but with significant variability among subjects and only one subject reaching close to statistical significance for this endpoint. Parent reported HRQoL assessments with treatment showed mixed results, with some subjects showing no change, some improvement, and some worsening of overall scores. Subjects with buried amino acids in the pyruvate carboxyltransferase domain of PC that undergo destabilizing replacements may be more likely to respond (with lactate reduction or HRQoL improvement) to triheptanoin compared to those with replacements that disrupt tetramerization or subunit-subunit interface contacts. The reason for this difference is unclear and requires further validation. We observed significant variability but an overall trend of lactate reduction with time on triheptanoin and mixed parent reported outcome changes by HRQoL assessments for subjects with PCD on long-term triheptanoin. The mixed results noted with triheptanoin therapy in this study could be due to endpoint data limitation, variability of disease severity between subjects, limitation of the parent reported HRQoL tool, or subject genotype variability. Alternative designed trials and more study subjects with PCD will be needed to validate important observations from this work.
2021-03-05 | Challenges in the management of an ignored cause of hyperammonemic encephalopathy: pyruvate carboxylase deficiency.
Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive disease and provides clinics in three essential phenotypes. Type B PC deficiency is characterized by lactic acidosis and hyperammonemia. We report a Turkish patient who was diagnosed with type B PC deficiency. Despite the application of anaplerotic treatment with biotin, citrate and arginine-aspartate, continuous veno-venous hemodialysis (CVVHD) treatments were applied due to the failure to keep hyperammonemia and lactic acidosis under control. Ammonia values increasing to 860 μmol/L were observed. A homozygous novel variant was detected in PC gene analyses containing a 12-base pair deletion on exon 8. Although the mutation found was not reported previously, it was accepted as a pathogenic variant due to its presence in a functional region of the protein. In type B PC deficiency, although a high level of ammonia is expected, it rarely exceeds 200 μmol/L. As far as we know, the present case has the highest ammonia values in the literature. This paper has been shared to highlight to keep PC deficiency in mind regarding the differential diagnosis of hyperammonemia, particularly in the presence of lactic acidosis, and to serve as a model for the use of different modalities in the management process of PC deficiency.
cell therapies
2023-01-23 | Generation of an induced pluripotent stem cell line (SHCDNi007-A) from a patient with pyruvate carboxylase deficiency carrying compound heterozygous (c.182 T > C/ c.2581G > A) variants in PC.
Pyruvate carboxylase (PC) deficiency (PCD), due to biallelic PC variants, is a rare inherited metabolic disease, which is characterized by seizures, global developmental delay, as well as lactic acidosis, and elevated plasma pyruvate and alanine levels in affected individuals. In the present study, a new induced pluripotent stem cell line (SHCDNi007-A) was generated from the peripheral blood mononuclear cells of a 2-month-old male infant with biallelic PC mutations c.(182 T > C;2581G > A), i.e. p.(Ile61Thr;Val861Met). This cell line is expected to facilitate the in vitro modeling of the disease pathophysiology and the development of future therapeutics for PCD.
2012-03-15 | Catabolite repression of phosphoenolpyruvate carboxykinase by a zinc finger protein under biotin- and pyruvate carboxylase-deficient conditions in Pichia pastoris.
We have identified a methanol- and biotin-starvation-inducible zinc finger protein named ROP [repressor of phosphoenolpyruvate carboxykinase (PEPCK)] in the methylotrophic yeast Pichia pastoris. When P. pastoris strain GS115 (wild-type, WT) is cultured in biotin-deficient, glucose-ammonium (Bio(-)) medium, growth is suppressed due to the inhibition of anaplerotic synthesis of oxaloacetate, catalysed by the biotin-dependent enzyme pyruvate carboxylase (PC). Deletion of ROP results in a strain (ΔROP) that can grow under biotin-deficient conditions due to derepression of a biotin- and PC-independent pathway of anaplerotic synthesis of oxaloacetate. Northern analysis as well as microarray expression profiling of RNA isolated from WT and ΔROP strains cultured in Bio(-) medium indicate that expression of the phosphoenolpyruvate carboxykinase gene (PEPCK) is induced in ΔROP during biotin- or PC-deficiency even under glucose-abundant conditions. There is an excellent correlation between PEPCK expression and growth of ΔROP in Bio(-) medium, suggesting that ROP-mediated regulation of PEPCK may have a crucial role in the biotin- and PC-independent growth of the ΔROP strain. To our knowledge, ROP is the first example of a zinc finger transcription factor involved in the catabolite repression of PEPCK in yeast cells cultured under biotin- or PC-deficient and glucose-abundant conditions.
2002-09-01 | Pyruvate carboxylase deficiency—insights from liver transplantation
Pyruvate carboxylase deficiency, complex form, presents in early infancy with lethal metabolic acidosis, resulting from ketoacidosis and lactic acidemia. Renal tubular acidosis, hyperammonemia, and citrullinemia complete the picture. In an infant with this disease, large amounts of glucose ameliorated the ketoacidosis, but worsened the lactic acidosis. Orthotopic hepatic transplantation completely reversed the ketoacidosis and the renal tubular abnormality and ameliorated the lactic acidemia. Concentrations of glutamine in cerebrospinal fluid were low and did not improve with liver transplantation.
1999-01-01 | Improvement of the primary metabolism of cell cultures by introducing a new cytoplasmic pyruvate carboxylase reaction
Continuous mammalian cell lines are important hosts for the production of biological pharmaceuticals. However, these cell lines show some severe disorders in primary metabolism, which they have in common with many cancer cells. This leads to a high throughput of substrates giving a low energy yield and ample toxic side products such as lactate and ammonia. Because the enzymatic connection between glycolysis and the tricarboxylic acid cycle (TCA) is very poor, glucose is mainly degraded via oxidative glycolysis. It will be shown that introducing a pyruvate carboxylase gene expressed in the cytoplasma into a continuous BHK-21 cell line, and thus reconstituting the missing link between glycolysis and TCA, can reduce this problem. Thus, glucose consumption could be reduced by a factor of four and glutamine utilization up to a factor of two, compared with control. Moreover, a 1.4-fold-higher adenosine triphosphate (ATP) content was achieved. The flux of labeled [(14)C]-glucose into the TCA is shown to be enhanced, indicating a higher rate of oxidative glucose degradation. Host cell lines with an improved energy metabolism will therefore result in better exploitation of substrates, an increasing yield by the more efficient use of carbon source, and higher product integrity combined with lower production costs.
gene therapies
2025-05-01 | Pyruvate Carboxylase Deficiency Induces Pulmonary Fibrosis via Mitochondrial Damage Though Slc25a4/AMPK/Nrf2 Pathway
Abstract Background The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear and is mainly related to the damage of type II alveolar epithelial cells (ATII). Persistent damage to ATII leads to oxidative stress, mitochondrial damage, which in turn trigger excessive apoptosis and epithelial – mesenchymal transition (EMT). Pyruvate carboxylase (PC), which involved in adenosine triphosphate (ATP) production, has long been thought to be associated with mitochondrial functional homeostasis and oxidative stress. However, the role of PC and its correlation with mitochondrial function in PF remain unknown. Methods The aim of this study was to evaluate the expression of PC in lung tissues of patients with IPF, employ a mouse model with ATIIs specific knockout of PC, manipulate PC expression in murine lung epithelial-12 (MLE-12) cells. Results The study findings revealed that compared to the control group, the expression of PC in the lungs of IPF patients and bleomycin (BLM)-induced mice, and also in MLE-12 cells stimulated by transforming growth factor (TGF)-β1 and BLM was downregulated. In BLM-injured mice, the knockout of PC led to severe fibrosis, mitochondrial damage, oxidative stress response and apoptosis. In vitro, silencing PC enhanced the epithelial-mesenchymal transition (EMT) induced by TGF-β1, as well as increased mitochondrial damage, oxidative stress and apoptosis. Immunoprecipitation combined with mass spectrometry showed that PC could interact with solute carrier family 25 member 4 (Slc25a4) in mitochondrial, and then reduced the ubiquitination-mediated degradation of Slc25a4. In ATII-specific PC-knockout mice, we observed the expressions of Slc25a4, Nrf2 and the phosphorylation of AMPKα were decreased and oxidative stress was exacerbated after BLM injury. When Slc25a4 was overexpressed using adeno-associated virus (AAV) in ATII-specific PC-knockout mice, the phosphorylation of AMPKα and the expression of Nrf2 were restored, mitochondrial damage was recovery, thereby alleviating PF. Conclusion Enhancing PC signaling could represent a viable strategy for the treatment of PF.
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