RARE DISEASE
Glutaryl-CoA dehydrogenase deficiency
Glutaryl-CoA dehydrogenase deficiency
Glutaryl-CoA dehydrogenase deficiency
Synonyms: GA1, GCDHD, Glutaric acidemia type 1, Glutaric aciduria type 1, Glutaryl-coenzyme A dehydrogenase deficiency
Synonyms: GA1, GCDHD, Glutaric acidemia type 1, Glutaric aciduria type 1, Glutaryl-coenzyme A dehydrogenase deficiency
Synonyms: GA1, GCDHD, Glutaric acidemia type 1, Glutaric aciduria type 1, Glutaryl-coenzyme A dehydrogenase deficiency
Drug discovery
2
drugs
With orphan designations
Overview
Glutaryl-CoA dehydrogenase deficiency (GCDHD) is an autosomal recessive neurometabolic disorder disrupting lysine and tryptophan metabolism, causing toxic accumulation of glutaric acid and 3-hydroxyglutaric acid. This leads to acute encephalopathic crises (triggered by metabolic stressors) with striatal damage, severe dystonia, and macrocephaly [1][4][13]. Early diagnosis through newborn screening and prompt metabolic management can mitigate neurological sequelae [6][11].
Therapies
Dietary control: Protein-restricted diet with lysine/tryptophan reduction + lysine-free amino acid supplements [8][11]
Pharmacotherapy: L-carnitine supplementation (100-200 mg/kg/day); riboflavin for responsive cases [3][11]
Emergency protocols: High glucose infusion + temporary protein withdrawal during illness to prevent catabolism [4][8]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
162 drug discovery papers about Glutaryl-CoA dehydrogenase deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
162 drug discovery papers about Glutaryl-CoA dehydrogenase deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-25 | Mitochondria-targeted reactive species scavenger JP4-039 protects against disturbances of redox homeostasis, mitochondrial quality control, and glucose metabolism in brains of glutaryl-CoA dehydrogenase-deficient mice: A potential new therapeutic strategy for glutaric acidemia type 1.
Glutaric aciduria type 1 (GA1) is a cerebral organic aciduria caused by deficient activity of glutaryl-CoA dehydrogenase (GCDH). Patients present with acute striatal degeneration and develop progressive cortical leukodystrophy whose pathophysiology is only partially known. As treatment for GA1 is limited, we evaluated the impact of JP4-039, a mitochondria-targeted reactive oxygen species (ROS) and electron scavenger, on redox homeostasis, mitochondrial quality control, and glucose metabolism in the cortical and striatal brain tissues of GCDH-deficient (Gcdh-/-) mice. Both tissues exhibited increases in lipid peroxidation, ROS levels, and the activities of superoxide dismutase, catalase, and glutathione S-transferase. Furthermore, glutathione reductase activity was increased, and glutathione peroxidase was reduced in the striatum, while Nrf2 mRNA levels were elevated in the cortex. Notably, most of these altered endpoints of redox homeostasis were prevented by treatment with JP4-039. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression was reduced in the cortex of Gcdh-/- mice, whereas voltage-dependent anion channel (VDAC) and dynamin-related protein 1 (DRP1) expression were increased in the striatum, signaling a disturbance of mitochondrial quality control. JP4-039 mitigated the DRP1 change. The cerebral cortex displayed reduced glucose metabolism, increased lactate levels, and elevated activities of hexokinase, pyruvate kinase, and lactate dehydrogenase (LDH), which JP4-039 mitigated. GLUT3 expression was reduced in the cerebral cortex, but JP4-039 did not change this effect. Our data suggest that redox imbalance and dysregulated mitochondrial quality control and of the glycolytic pathway contribute to the pathophysiology of GA1, and that JP4-039 may offer therapeutic benefit.
2026-07-01 | Total intravenous anesthesia with propofol and remifentanil followed by planned sedation with propofol alone in Intensive care for a patient with glutaric acidemia type-1 undergoing complex thoracolumbar scoliosis surgery
ABSTRACT A 15-year-old boy with a severe phenotype of Glutaric Acidemia Type 1 (GA-1) presented for planned major thoracolumbar scoliosis correction under general anesthesia. Propofol is relatively contraindicated in patients with GA-1 according to latest guidance because of the risk of propofol infusion syndrome. Because of previous use of propofol in the patient when admitted to intensive care and the potential benefits as a sleep agent we decided to use propofol for his surgery and postoperative sedation. We report the successful use of propofol for general anesthesia and postoperative sedation on intensive care.
2026-06-26 | Systemic AAV-hGCDH Gene Therapy Alleviates Glutaric Acid Accumulation and Attenuates Chronic Brain Vacuolation in a Novel Mouse Model of Glutaric Aciduria Type I.
Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder caused by glutaryl-CoA dehydrogenase (GCDH) deficiency, leading to the accumulation of neurotoxic metabolites that can cause both acute encephalopathic crises and progressive, insidious brain injury. Current management primarily relies on a protein-restricted diet, which remains therapeutically insufficient and burdensome for patients, highlighting the need for disease-modifying therapies. In this study, we established a novel GA1 mouse model using CRISPR/Cas9 technology and evaluated the preclinical efficacy of systemic recombinant adeno-associated virus (rAAV)-mediated gene therapy. Under standard dietary conditions without high-lysine challenge, our GA1 model exhibited sustained cerebral and hepatic glutaric acid (GA) accumulation and distinct chronic vacuolation in the hippocampus and cerebellum, mirroring the insidious-onset GA1 phenotype. Five-week-old mice received a single intravenous injection of rAAV-hGCDH using either rAAV2/8 or rAAV2/9 serotypes. Systemic rAAV-mediated gene therapy significantly reduced GA accumulation and attenuated chronic neuropathological changes in this GA1 mouse model for both serotypes. Our findings support the hypothesis that peripheral metabolic correction may play an important role in preventing the chronic neuropathological changes associated with GCDH deficiency. However, further investigation using tissue-specific expression systems is required to definitively delineate the relative contributions of hepatic versus central GCDH restoration to the observed neuroprotection.
2026-04-01 | Aminoadipate-semialdehyde synthase, a potential target for substrate reduction therapy in glutaric aciduria type 1.
Glutaric aciduria type 1 is caused by inherited deficiency of glutaryl-CoA dehydrogenase and subsequent accumulation of neurotoxic metabolites. Clinically, the disease is characterized by striatal damage and dystonic movement disorder in untreated infants. Despite newborn screening and pre-symptomatic therapy start, about one-third of patients still develop neurological symptoms. Furthermore, progressive white matter changes and chronic kidney disease highlights the need for improved therapies. To elucidate the potential of substrate reduction therapy for GA1 we investigated whether aminoadipate-semialdehyde synthetase, the first enzyme of the lysine oxidation pathway, could serve as therapeutic target. Therefore, we studied whether Gcdh knockout (KO) mice, a known animal model for GA1, were rescued by additional knockout of Aass. Gcdh/Aass KO mice were clinically indistinguishable from wild-type mice and showed a marked reduction of glutaric acid in brain (20.9 µg/mg protein vs. 59.2 µg/mg protein; p = 0.001), liver (23.5 µg/mg protein vs. 104.8 µg/mg protein; p = 0.001), and urine (11.9 mol/mol creatinine vs. 166.5 mol/mol creatinine; p = 0.001). The effect was less pronounced for 3-hydroxyglutaric acid. Unlike Gcdh KO mice, Gcdh/Aass KO mice did not develop a severe phenotype under high-lysine diet. In conclusion, knockout of Aass partially rescues the severe phenotype of Gcdh KO mice, providing a potential therapeutic target.
2026-02-11 | The neuropathological mechanisms underlying the inborn errors of lysine metabolism.
Optimal lysine catabolism is essential for the proper growth and development of mammals. Lysine is degraded through either the saccharopine or pipecolate pathway, processes characterized by distinct tissue specificity and subcellular compartmentalization. Although controversy persists, accumulating evidence suggests that the saccharopine pathway serves as the predominant route for lysine degradation in the mammalian brain. Pathogenic variants of genes encoding the enzymes involved in lysine catabolism lead to severe inborn errors of metabolism, including hyperlysinemia-II, pyridoxine-dependent epilepsy-ALDH7A1, and glutaric aciduria type I, which are biochemically characterized by the systemic accumulation of neurotoxic metabolites. Patients with the aforementioned disorders exhibit apparent neurological symptoms, ranging from cognitive impairment to severe encephalopathy, indicating that the dysregulation of lysine metabolism has deteriorative impacts on brain development and function. It is worth noting that a subset of patients still suffers from developmental delay and chronic neurological dysfunction, despite the amelioration of acute seizures or encephalopathic crises resulting from a combination of a lysine-restricted diet and pharmacotherapy. This elusive neuropathology has prompted increasing research aimed at identifying the pivotal regulatory roles of enzymes in neural functions and the neurotoxic effects of lysine metabolites in the brain. Here, we summarize current insights into the pathogenic mechanisms underlying the neurological manifestations of lysine metabolism disorders. A comprehensive understanding of the association between biochemical abnormalities and neurometabolic deficiencies has profound implications for refining therapeutic strategies to improve neurodevelopmental outcomes in affected patients.
2026-07-25 | Mitochondria-targeted reactive species scavenger JP4-039 protects against disturbances of redox homeostasis, mitochondrial quality control, and glucose metabolism in brains of glutaryl-CoA dehydrogenase-deficient mice: A potential new therapeutic strategy for glutaric acidemia type 1.
Glutaric aciduria type 1 (GA1) is a cerebral organic aciduria caused by deficient activity of glutaryl-CoA dehydrogenase (GCDH). Patients present with acute striatal degeneration and develop progressive cortical leukodystrophy whose pathophysiology is only partially known. As treatment for GA1 is limited, we evaluated the impact of JP4-039, a mitochondria-targeted reactive oxygen species (ROS) and electron scavenger, on redox homeostasis, mitochondrial quality control, and glucose metabolism in the cortical and striatal brain tissues of GCDH-deficient (Gcdh-/-) mice. Both tissues exhibited increases in lipid peroxidation, ROS levels, and the activities of superoxide dismutase, catalase, and glutathione S-transferase. Furthermore, glutathione reductase activity was increased, and glutathione peroxidase was reduced in the striatum, while Nrf2 mRNA levels were elevated in the cortex. Notably, most of these altered endpoints of redox homeostasis were prevented by treatment with JP4-039. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression was reduced in the cortex of Gcdh-/- mice, whereas voltage-dependent anion channel (VDAC) and dynamin-related protein 1 (DRP1) expression were increased in the striatum, signaling a disturbance of mitochondrial quality control. JP4-039 mitigated the DRP1 change. The cerebral cortex displayed reduced glucose metabolism, increased lactate levels, and elevated activities of hexokinase, pyruvate kinase, and lactate dehydrogenase (LDH), which JP4-039 mitigated. GLUT3 expression was reduced in the cerebral cortex, but JP4-039 did not change this effect. Our data suggest that redox imbalance and dysregulated mitochondrial quality control and of the glycolytic pathway contribute to the pathophysiology of GA1, and that JP4-039 may offer therapeutic benefit.
2026-07-01 | Total intravenous anesthesia with propofol and remifentanil followed by planned sedation with propofol alone in Intensive care for a patient with glutaric acidemia type-1 undergoing complex thoracolumbar scoliosis surgery
ABSTRACT A 15-year-old boy with a severe phenotype of Glutaric Acidemia Type 1 (GA-1) presented for planned major thoracolumbar scoliosis correction under general anesthesia. Propofol is relatively contraindicated in patients with GA-1 according to latest guidance because of the risk of propofol infusion syndrome. Because of previous use of propofol in the patient when admitted to intensive care and the potential benefits as a sleep agent we decided to use propofol for his surgery and postoperative sedation. We report the successful use of propofol for general anesthesia and postoperative sedation on intensive care.
2026-06-26 | Systemic AAV-hGCDH Gene Therapy Alleviates Glutaric Acid Accumulation and Attenuates Chronic Brain Vacuolation in a Novel Mouse Model of Glutaric Aciduria Type I.
Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder caused by glutaryl-CoA dehydrogenase (GCDH) deficiency, leading to the accumulation of neurotoxic metabolites that can cause both acute encephalopathic crises and progressive, insidious brain injury. Current management primarily relies on a protein-restricted diet, which remains therapeutically insufficient and burdensome for patients, highlighting the need for disease-modifying therapies. In this study, we established a novel GA1 mouse model using CRISPR/Cas9 technology and evaluated the preclinical efficacy of systemic recombinant adeno-associated virus (rAAV)-mediated gene therapy. Under standard dietary conditions without high-lysine challenge, our GA1 model exhibited sustained cerebral and hepatic glutaric acid (GA) accumulation and distinct chronic vacuolation in the hippocampus and cerebellum, mirroring the insidious-onset GA1 phenotype. Five-week-old mice received a single intravenous injection of rAAV-hGCDH using either rAAV2/8 or rAAV2/9 serotypes. Systemic rAAV-mediated gene therapy significantly reduced GA accumulation and attenuated chronic neuropathological changes in this GA1 mouse model for both serotypes. Our findings support the hypothesis that peripheral metabolic correction may play an important role in preventing the chronic neuropathological changes associated with GCDH deficiency. However, further investigation using tissue-specific expression systems is required to definitively delineate the relative contributions of hepatic versus central GCDH restoration to the observed neuroprotection.
2026-04-01 | Aminoadipate-semialdehyde synthase, a potential target for substrate reduction therapy in glutaric aciduria type 1.
Glutaric aciduria type 1 is caused by inherited deficiency of glutaryl-CoA dehydrogenase and subsequent accumulation of neurotoxic metabolites. Clinically, the disease is characterized by striatal damage and dystonic movement disorder in untreated infants. Despite newborn screening and pre-symptomatic therapy start, about one-third of patients still develop neurological symptoms. Furthermore, progressive white matter changes and chronic kidney disease highlights the need for improved therapies. To elucidate the potential of substrate reduction therapy for GA1 we investigated whether aminoadipate-semialdehyde synthetase, the first enzyme of the lysine oxidation pathway, could serve as therapeutic target. Therefore, we studied whether Gcdh knockout (KO) mice, a known animal model for GA1, were rescued by additional knockout of Aass. Gcdh/Aass KO mice were clinically indistinguishable from wild-type mice and showed a marked reduction of glutaric acid in brain (20.9 µg/mg protein vs. 59.2 µg/mg protein; p = 0.001), liver (23.5 µg/mg protein vs. 104.8 µg/mg protein; p = 0.001), and urine (11.9 mol/mol creatinine vs. 166.5 mol/mol creatinine; p = 0.001). The effect was less pronounced for 3-hydroxyglutaric acid. Unlike Gcdh KO mice, Gcdh/Aass KO mice did not develop a severe phenotype under high-lysine diet. In conclusion, knockout of Aass partially rescues the severe phenotype of Gcdh KO mice, providing a potential therapeutic target.
2026-02-11 | The neuropathological mechanisms underlying the inborn errors of lysine metabolism.
Optimal lysine catabolism is essential for the proper growth and development of mammals. Lysine is degraded through either the saccharopine or pipecolate pathway, processes characterized by distinct tissue specificity and subcellular compartmentalization. Although controversy persists, accumulating evidence suggests that the saccharopine pathway serves as the predominant route for lysine degradation in the mammalian brain. Pathogenic variants of genes encoding the enzymes involved in lysine catabolism lead to severe inborn errors of metabolism, including hyperlysinemia-II, pyridoxine-dependent epilepsy-ALDH7A1, and glutaric aciduria type I, which are biochemically characterized by the systemic accumulation of neurotoxic metabolites. Patients with the aforementioned disorders exhibit apparent neurological symptoms, ranging from cognitive impairment to severe encephalopathy, indicating that the dysregulation of lysine metabolism has deteriorative impacts on brain development and function. It is worth noting that a subset of patients still suffers from developmental delay and chronic neurological dysfunction, despite the amelioration of acute seizures or encephalopathic crises resulting from a combination of a lysine-restricted diet and pharmacotherapy. This elusive neuropathology has prompted increasing research aimed at identifying the pivotal regulatory roles of enzymes in neural functions and the neurotoxic effects of lysine metabolites in the brain. Here, we summarize current insights into the pathogenic mechanisms underlying the neurological manifestations of lysine metabolism disorders. A comprehensive understanding of the association between biochemical abnormalities and neurometabolic deficiencies has profound implications for refining therapeutic strategies to improve neurodevelopmental outcomes in affected patients.
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Drug Discovery Landscape
2 orphan drug designations for Glutaryl-CoA dehydrogenase deficiency.
2 orphan drug designations for Glutaryl-CoA dehydrogenase deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adeno-associated virus vector serotype 9 containing the human GCDH gene | gene therapies | EMA | 2024-08-21 | — | Consorcio Centro De Investigacion Biomedica En Red |
adeno-associated viral vector 9 delivering human Glutaryl-CoA Dehydrogenase (GCDH) gene | gene therapies | FDA | 2022-05-26 | — | Shanghai Vitalgen BioPharma Co., Ltd. |
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