RARE DISEASE
Pyruvate carboxylase deficiency, benign type
Pyruvate carboxylase deficiency, benign type
Pyruvate carboxylase deficiency, benign type
Synonyms: Pyruvate carboxylase deficiency type C
Synonyms: Pyruvate carboxylase deficiency type C
Synonyms: Pyruvate carboxylase deficiency type C
Drug discovery
0
drugs
With orphan designations
Overview
Pyruvate carboxylase deficiency, benign type (Type C) is a rare autosomal recessive neurometabolic disorder characterized by episodic metabolic acidosis triggered by stress (e.g., illness, fasting) and normal/mildly delayed neurodevelopment. Biochemical findings include mild lactic acidemia (2–5 mmol/L) without severe neurological involvement, differentiating it from fatal Types A/B. Diagnosis requires enzyme activity assays in fibroblasts or genetic confirmation of PC gene variants [1][4][9][11].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
25 drug discovery papers about Pyruvate carboxylase deficiency, benign type, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
25 drug discovery papers about Pyruvate carboxylase deficiency, benign type, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
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.
2023-06-30 | The Presence of Pyruvate Carboxylase in the Human Brain and its Role in the Survival of Cultured Human Astrocytes
Pyruvate carboxylase (PC) is a mitochondrial, biotin-containing enzyme catalyzing the ATP-dependent synthesis of oxaloacetate from pyruvate and bicarbonate, with a critical anaplerotic role in sustaining the brain metabolism. Based on the studies performed on animal models, PC expression was assigned to be glia-specific. To study PC distribution among human neural cells, we probed the cultured human astrocytes and brain sections with antibodies against PC. Additionally, we tested the importance of PC for the viability of cultured human astrocytes by applying the PC inhibitor 3-chloropropane-1,2-diol (CPD). Our results establish the expression of PC in mitochondria of human astrocytes in culture and brain tissue and also into a subpopulation of the neurons in situ. CPD negatively affected the viability of astrocytes in culture, which could be partially reversed by supplementing media with malate, 2-oxoglutarate, citrate, or pyruvate. The provided data estimates PC expression in human astrocytes and neurons in human brain parenchyma. Furthermore, the enzymatic activity of PC is vital for sustaining the viability of cultured astrocytes.
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.
2023-01-31 | The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease
Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways in the liver in regulating hepatic and systemic energy metabolism and summarize the current state of targeting this pathway to treat diseases of the liver. Available evidence suggests that inhibiting the MPC in hepatocytes and other cells of the liver produces a variety of beneficial effects for treating type 2 diabetes and nonalcoholic steatohepatitis. We also highlight areas where our understanding is incomplete regarding the pleiotropic effects of MPC inhibition.
2022-11-02 | Phosphatidylethanolamine facilitates mitochondrial pyruvate entry to regulate metabolic flexibility
Abstract Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness by small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulates metabolic responses that occur in humans. Bioenergetic phenotyping of mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration ( J O 2 ) in absence of a change in palmitate-stimulated J O 2 . Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a novel mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility.
small molecules
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.
2023-06-30 | The Presence of Pyruvate Carboxylase in the Human Brain and its Role in the Survival of Cultured Human Astrocytes
Pyruvate carboxylase (PC) is a mitochondrial, biotin-containing enzyme catalyzing the ATP-dependent synthesis of oxaloacetate from pyruvate and bicarbonate, with a critical anaplerotic role in sustaining the brain metabolism. Based on the studies performed on animal models, PC expression was assigned to be glia-specific. To study PC distribution among human neural cells, we probed the cultured human astrocytes and brain sections with antibodies against PC. Additionally, we tested the importance of PC for the viability of cultured human astrocytes by applying the PC inhibitor 3-chloropropane-1,2-diol (CPD). Our results establish the expression of PC in mitochondria of human astrocytes in culture and brain tissue and also into a subpopulation of the neurons in situ. CPD negatively affected the viability of astrocytes in culture, which could be partially reversed by supplementing media with malate, 2-oxoglutarate, citrate, or pyruvate. The provided data estimates PC expression in human astrocytes and neurons in human brain parenchyma. Furthermore, the enzymatic activity of PC is vital for sustaining the viability of cultured astrocytes.
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.
2023-01-31 | The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease
Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways in the liver in regulating hepatic and systemic energy metabolism and summarize the current state of targeting this pathway to treat diseases of the liver. Available evidence suggests that inhibiting the MPC in hepatocytes and other cells of the liver produces a variety of beneficial effects for treating type 2 diabetes and nonalcoholic steatohepatitis. We also highlight areas where our understanding is incomplete regarding the pleiotropic effects of MPC inhibition.
2022-11-02 | Phosphatidylethanolamine facilitates mitochondrial pyruvate entry to regulate metabolic flexibility
Abstract Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness by small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulates metabolic responses that occur in humans. Bioenergetic phenotyping of mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration ( J O 2 ) in absence of a change in palmitate-stimulated J O 2 . Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a novel mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility.
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