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:
categories:
Small molecules
small molecules
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.
2026-04-01 | 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.
2026-01-01 | Validating Novel Targets for Substrate Reduction Therapy in Glutaric Aciduria Type I
Glutaric aciduria type 1 (GA1) (OMIM #231670) is a rare autosomal recessive neurometabolic disorder caused by pathogenic variants in the GCDH gene (19p13.13). Deficiency of glutaryl-CoA dehydrogenase (GCDH) results in accumulation of neurotoxic glutaryl-CoA, glutaric acid, and 3-hydroxyglutaric acid. Clinically, GA1 features acute or insidious striatal damage causing variable movement disorders in infancy. Despite early diagnosis and treatment, current therapies remain suboptimal, and many patients develop dystonia, white-matter changes, intellectual impairment, and chronic kidney disease. This study aimed to identify a target for substrate reduction therapy (SRT) focusing on lysine-degradation enzymes upstream of GCDH and to develop a human iPSC-based GA1 model. In vivo experiments used a Gcdh KO mouse combined with Aass or Aadat knockouts. All groups experienced metabolic stress using a high-lysine diet (HLD) to provoke the GA1 phenotype. Behavioral, histological, and biochemical assessments evaluated neuropathological and systemic alterations. Analysis of Gcdh/Aadat KO and Gcdh/Aass KO mice showed that Aadat deletion did not ameliorate disease symptoms. Although neurotoxin reductions were seen in Gcdh/Aadat KO brains, this improvement was tissue-restricted, suggesting limited therapeutic coverage. Consistently, pharmacological AADAT inhibition with PF-04859989 had no benefit, demonstrating that AADAT is not a suitable monotherapy target. In contrast, Aass deletion provided systemic protection: Gcdh/Aass KO mice exhibited markedly reduced neurotoxins, attenuated neurological impairment, and improved overall condition under HLD stress. These findings indicate that blocking lysine metabolism effectively prevents neurotoxic metabolite formation. Taken together, the findings support AASS inhibition or knockout as a promising SRT strategy for GA1, demonstrating metabolic and phenotypic benefits in preclinical models and providing a foundation for more effective therapies.
cell therapies
2024-08-02 | Generation of hiPSC lines from four glutaric aciduria type I (GA1) patients carrying pathogenic biallelic variants in GCDH.
GCDH encodes for the enzyme catalyzing the sixth step of the lysine degradation pathway. Autosomal recessive variants in GCDH are associated with glutaric aciduria type I (GA1), of which a wide genotypic spectrum of pathogenic variants have been described. In this study, hiPSC lines derived from four GA1 patients with different genotypes were generated and fully characterized. Two patients carry compound heterozygous variants in GCDH, while the other two patients carry a variant in homozygosis. These hiPSC lines can significantly contribute to better understand the molecular mechanism underlying GA1 and provide excellent models for the development of new therapeutic strategies.
2019-11-07 | Organic acidurias in adults: late complications and management.
Organic acidurias (synonym, organic acid disorders, OADs) are a heterogenous group of inherited metabolic diseases delineated with the implementation of gas chromatography/mass spectrometry in metabolic laboratories starting in the 1960s and 1970s. Biochemically, OADs are characterized by accumulation of mono-, di- and/or tricarboxylic acids ("organic acids") and corresponding coenzyme A, carnitine and/or glycine esters, some of which are considered toxic at high concentrations. Clinically, disease onset is variable, however, affected individuals may already present during the newborn period with life-threatening acute metabolic crises and acute multi-organ failure. Tandem mass spectrometry-based newborn screening programmes, in particular for isovaleric aciduria and glutaric aciduria type 1, have significantly reduced diagnostic delay. Dietary treatment with low protein intake or reduced intake of the precursor amino acid(s), carnitine supplementation, cofactor treatment (in responsive patients) and nonadsorbable antibiotics is commonly used for maintenance treatment. Emergency treatment options with high carbohydrate/glucose intake, pharmacological and extracorporeal detoxification of accumulating toxic metabolites for intensified therapy during threatening episodes exist. Diagnostic and therapeutic measures have improved survival and overall outcome in individuals with OADs. However, it has become increasingly evident that the manifestation of late disease complications cannot be reliably predicted and prevented. Conventional metabolic treatment often fails to prevent irreversible organ dysfunction with increasing age, even if patients are considered to be "metabolically stable". This has challenged our understanding of OADs and has elicited the discussion on optimized therapy, including (early) organ transplantation, and long-term care.
1995-06-01 | Bilateral arachnoid cysts of the sylvian region in female siblings with glutaric aciduria type I
✓ Two sisters, aged 6 and 2 1/2 years, presented with macrocephaly and delayed motor development and were found on computerized tomography to have bilateral arachnoid cysts of the sylvian region. Cystoperitoneal shunting of the larger cysts resulted in considerable neurological improvement in both children. Subsequent screening of the patients' urine for organic acids showed that the two sisters were suffering from glutaric aciduria type I (GA-I). To the best of the authors' knowledge, this is the first report to provide clear radiological and surgical evidence of the association between GA-I and bilateral arachnoid cysts of the sylvian region. The role of the shunting procedure used in these cases is discussed.
proteins
2024-07-26 | Role of Botulinum Toxin in Treatment of Secondary Dystonia: A Case Series and Overview of Literature.
Dystonia can present in primary and secondary forms, depending on co-occurring symptoms and syndromic associations. In contrast to primary dystonia, secondary forms of dystonia are often associated with lesions in the putamen or globus pallidus. Such disorders are commonly neurodegenerative or neurometabolic conditions which produce varied neurologic as well as systemic manifestations other than dystonia. Chemo-denervation with botulinum toxin has been successfully used for focal or segmental dystonia. However, studies evaluating the effect of BoNT therapy on patients with secondary dystonia are sparse, given the heterogeneity in etiology and presentation. We present a series of patients with secondary dystonia who were managed with botulinum toxin therapy. Patients included in this series had a confirmed neurometabolic cause of dystonia. A total of 14 patients, with ages ranging from 17 to 36 years, with disorders including Wilson's disease, pantothenate kinase-associated neurodegeneration (PKAN), Niemann-Pick disease type C (NPC), glutaric aciduria type 1, Sanfilippo syndrome (Mucopolysaccharidosis Type IIIb), and GM2 gangliosidosis (Sandhoff disease) are presented. Most patients experienced a mild to moderate improvement in treated dystonia with benefits ranging from 6 to 12 weeks, with the median length of the benefits lasting approximately eight weeks, without any significant adverse effects. Although the secondary causes of dystonia are complex and diverse, our presented data and the available reports of the use of botulinum toxin support the conclusion that chemo-denervation plays an important role in symptom alleviation.
2019-09-03 | Potential complementation effects of two disease-associated mutations in tetrameric glutaryl-CoA dehydrogenase is due to inter subunit stability-activity counterbalance
Glutaric Aciduria Type I (GA-I), is an autosomal recessive neurometabolic disease caused by mutations in the GCDH gene that encodes for glutaryl-CoA dehydrogenase (GCDH), a flavoprotein involved in the metabolism of tryptophan, lysine and hydroxylysine. Although over 200 disease mutations have been reported a clear correlation between genotype and phenotype has been difficult to establish. To contribute to a better molecular understanding of GA-I we undertook a detailed molecular study on two GCDH disease-related variants, GCDH-p.Arg227Pro and GCDH-p.Val400Met. Heterozygous patients harbouring these two mutations have increased residual enzymatic activity in relation to homozygous patients with only one of the mutations, suggesting a complementation effect between the two. Combining biochemical, biophysical and structural methods we here establish the effects of these mutations on protein folding, stability and catalytic activity. We show that both variants retain the overall protein fold, but with compromised enzymatic activities. Detailed enzyme kinetic studies reveal that GCDH-p.Arg227Pro has impaired function due to deficient substrate affinity as evidenced by its higher Km, and that the lower activity in GCDH-p.Val400Met results from weaker interactions with its physiological redox partner (electron transfer flavoprotein). Moreover, the GCDH-p.Val400Met variant has a significantly lower thermal stability (ΔTm ≈ 9 °C), and impaired binding of the FAD cofactor in relation to wild-type protein. On these grounds, we provide a rational for the possible interallelic complementation observed in heterozygous patients based on the fact that in GCDH, the low active p.Arg227Pro variant contributes to stabilize the tetramer while the structurally unstable p.Val400Met variant compensates for enzyme activity.
gene therapies
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.
2025-09-30 | Application of Combined PGT-A and PGT-M for Reproductive Management in a Couple Carrying GCDH Mutations with Prior Affected Offspring: A Rare Case Report
Case A 31-year-old woman with secondary subfertility, four recurrent pregnancy losses, and one previous live-born child affected with glutaric acidemia type I (GA-I) was evaluated. Genetic testing confirmed that both partners were heterozygous carriers of pathogenic GCDH variants (c.769C>T in exon 8 and c.1204C>T in exon 11, NM_000159.4). Given the high recurrence risk, the couple underwent in vitro fertilization with intracytoplasmic sperm injection, blastocyst culture, trophectoderm biopsy, and combined preimplantation genetic testing for aneuploidy (PGT-A) and monogenic disease (PGT-M). Outcome Three blastocysts were biopsied. One embryo exhibited segmental aneuploidy of chromosome 16 and was excluded. A second embryo was euploid and wild-type for both GCDH variants, classified as genetically normal. The third was euploid but heterozygous for c.769C>T, consistent with carrier status. The genetically normal embryo was selected for frozen embryo transfer, resulting in a singleton intrauterine pregnancy. Non-invasive prenatal testing at 12 weeks showed a normal chromosomal profile. At the time of report, the pregnancy is ongoing at 20 weeks without complications. Conclusion This case demonstrates that combined PGT-A and PGT-M can effectively prevent recurrence of GA-I, improve reproductive outcomes, and provide a valuable option for couples with monogenic disorders and recurrent pregnancy loss.
2025-07-19 | Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice.
Glutaric aciduria type I (GA1) is an inherited disorder caused by the enzymatic defect of glutaryl-coenzyme A dehydrogenase in the lysine degradation pathway, characterized by the accumulation of toxic metabolites in the central nervous system. We reasoned that substrate reduction therapy targeting the α-aminoadipic semialdehyde synthase (AASS), the first enzyme in the catabolism of lysine, could provide an attractive therapeutic alternative. We explored reducing the expression of AASS by an artificial microRNA with AASS target sequences embedded in a miR-16 backbone (miR_AASS). We analyzed several delivery routes and AAV serotypes and evaluated the therapeutic efficacy of a systemic neonatal delivery of AAV9_miR_AASS in the Gcdh-/- mouse model of GA1. We detected dose-dependent miR-AASS expression and AASS inhibition in liver and striatum, the main tissues affected in GA1. Treatment with AAV9_miR_AASS in lysine overload-challenged mice reduced the accumulation of neurotoxic metabolites up to 6 months post-treatment in the striatum, prevented the neuropathological alterations, and improved mouse survival. Our results show that AAV9_miR_AASS supports AASS lowering as a potential gene therapy strategy for GA1.
2024-07-10 | Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model.
Glutaric aciduria type 1 (GA1) is a rare inherited metabolic disorder caused by a deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), with accumulation of neurotoxic metabolites, resulting in a complex movement disorder, irreversible brain damage, and premature death in untreated individuals. While early diagnosis and a lysine restricted diet can extend survival, they do not prevent neurological damage in approximately one-third of treated patients, and more effective therapies are required. Here we report the efficacy of adeno-associated virus 9 (AAV9)-mediated systemic delivery of human GCDH at preventing a high lysine diet (HLD)-induced phenotype in Gcdh -/- mice. Neonatal treatment with AAV-GCDH restores GCDH expression and enzyme activity in liver and striatum. This treatment protects the mice from HLD-aggressive phenotype with all mice surviving this exposure; in stark contrast, a lack of treatment on an HLD triggers very high accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine in tissues, with about 60% death due to brain accumulation of toxic lysine metabolites. AAV-GCDH significantly ameliorates the striatal neuropathology, minimizing neuronal dysfunction, gliosis, and alterations in myelination. Magnetic resonance imaging findings show protection against striatal injury. Altogether, these results provide preclinical evidence to support AAV-GCDH gene therapy for GA1.
small molecules
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.
2026-04-01 | 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.
2026-01-01 | Validating Novel Targets for Substrate Reduction Therapy in Glutaric Aciduria Type I
Glutaric aciduria type 1 (GA1) (OMIM #231670) is a rare autosomal recessive neurometabolic disorder caused by pathogenic variants in the GCDH gene (19p13.13). Deficiency of glutaryl-CoA dehydrogenase (GCDH) results in accumulation of neurotoxic glutaryl-CoA, glutaric acid, and 3-hydroxyglutaric acid. Clinically, GA1 features acute or insidious striatal damage causing variable movement disorders in infancy. Despite early diagnosis and treatment, current therapies remain suboptimal, and many patients develop dystonia, white-matter changes, intellectual impairment, and chronic kidney disease. This study aimed to identify a target for substrate reduction therapy (SRT) focusing on lysine-degradation enzymes upstream of GCDH and to develop a human iPSC-based GA1 model. In vivo experiments used a Gcdh KO mouse combined with Aass or Aadat knockouts. All groups experienced metabolic stress using a high-lysine diet (HLD) to provoke the GA1 phenotype. Behavioral, histological, and biochemical assessments evaluated neuropathological and systemic alterations. Analysis of Gcdh/Aadat KO and Gcdh/Aass KO mice showed that Aadat deletion did not ameliorate disease symptoms. Although neurotoxin reductions were seen in Gcdh/Aadat KO brains, this improvement was tissue-restricted, suggesting limited therapeutic coverage. Consistently, pharmacological AADAT inhibition with PF-04859989 had no benefit, demonstrating that AADAT is not a suitable monotherapy target. In contrast, Aass deletion provided systemic protection: Gcdh/Aass KO mice exhibited markedly reduced neurotoxins, attenuated neurological impairment, and improved overall condition under HLD stress. These findings indicate that blocking lysine metabolism effectively prevents neurotoxic metabolite formation. Taken together, the findings support AASS inhibition or knockout as a promising SRT strategy for GA1, demonstrating metabolic and phenotypic benefits in preclinical models and providing a foundation for more effective therapies.
cell therapies
2024-08-02 | Generation of hiPSC lines from four glutaric aciduria type I (GA1) patients carrying pathogenic biallelic variants in GCDH.
GCDH encodes for the enzyme catalyzing the sixth step of the lysine degradation pathway. Autosomal recessive variants in GCDH are associated with glutaric aciduria type I (GA1), of which a wide genotypic spectrum of pathogenic variants have been described. In this study, hiPSC lines derived from four GA1 patients with different genotypes were generated and fully characterized. Two patients carry compound heterozygous variants in GCDH, while the other two patients carry a variant in homozygosis. These hiPSC lines can significantly contribute to better understand the molecular mechanism underlying GA1 and provide excellent models for the development of new therapeutic strategies.
2019-11-07 | Organic acidurias in adults: late complications and management.
Organic acidurias (synonym, organic acid disorders, OADs) are a heterogenous group of inherited metabolic diseases delineated with the implementation of gas chromatography/mass spectrometry in metabolic laboratories starting in the 1960s and 1970s. Biochemically, OADs are characterized by accumulation of mono-, di- and/or tricarboxylic acids ("organic acids") and corresponding coenzyme A, carnitine and/or glycine esters, some of which are considered toxic at high concentrations. Clinically, disease onset is variable, however, affected individuals may already present during the newborn period with life-threatening acute metabolic crises and acute multi-organ failure. Tandem mass spectrometry-based newborn screening programmes, in particular for isovaleric aciduria and glutaric aciduria type 1, have significantly reduced diagnostic delay. Dietary treatment with low protein intake or reduced intake of the precursor amino acid(s), carnitine supplementation, cofactor treatment (in responsive patients) and nonadsorbable antibiotics is commonly used for maintenance treatment. Emergency treatment options with high carbohydrate/glucose intake, pharmacological and extracorporeal detoxification of accumulating toxic metabolites for intensified therapy during threatening episodes exist. Diagnostic and therapeutic measures have improved survival and overall outcome in individuals with OADs. However, it has become increasingly evident that the manifestation of late disease complications cannot be reliably predicted and prevented. Conventional metabolic treatment often fails to prevent irreversible organ dysfunction with increasing age, even if patients are considered to be "metabolically stable". This has challenged our understanding of OADs and has elicited the discussion on optimized therapy, including (early) organ transplantation, and long-term care.
1995-06-01 | Bilateral arachnoid cysts of the sylvian region in female siblings with glutaric aciduria type I
✓ Two sisters, aged 6 and 2 1/2 years, presented with macrocephaly and delayed motor development and were found on computerized tomography to have bilateral arachnoid cysts of the sylvian region. Cystoperitoneal shunting of the larger cysts resulted in considerable neurological improvement in both children. Subsequent screening of the patients' urine for organic acids showed that the two sisters were suffering from glutaric aciduria type I (GA-I). To the best of the authors' knowledge, this is the first report to provide clear radiological and surgical evidence of the association between GA-I and bilateral arachnoid cysts of the sylvian region. The role of the shunting procedure used in these cases is discussed.
proteins
2024-07-26 | Role of Botulinum Toxin in Treatment of Secondary Dystonia: A Case Series and Overview of Literature.
Dystonia can present in primary and secondary forms, depending on co-occurring symptoms and syndromic associations. In contrast to primary dystonia, secondary forms of dystonia are often associated with lesions in the putamen or globus pallidus. Such disorders are commonly neurodegenerative or neurometabolic conditions which produce varied neurologic as well as systemic manifestations other than dystonia. Chemo-denervation with botulinum toxin has been successfully used for focal or segmental dystonia. However, studies evaluating the effect of BoNT therapy on patients with secondary dystonia are sparse, given the heterogeneity in etiology and presentation. We present a series of patients with secondary dystonia who were managed with botulinum toxin therapy. Patients included in this series had a confirmed neurometabolic cause of dystonia. A total of 14 patients, with ages ranging from 17 to 36 years, with disorders including Wilson's disease, pantothenate kinase-associated neurodegeneration (PKAN), Niemann-Pick disease type C (NPC), glutaric aciduria type 1, Sanfilippo syndrome (Mucopolysaccharidosis Type IIIb), and GM2 gangliosidosis (Sandhoff disease) are presented. Most patients experienced a mild to moderate improvement in treated dystonia with benefits ranging from 6 to 12 weeks, with the median length of the benefits lasting approximately eight weeks, without any significant adverse effects. Although the secondary causes of dystonia are complex and diverse, our presented data and the available reports of the use of botulinum toxin support the conclusion that chemo-denervation plays an important role in symptom alleviation.
2019-09-03 | Potential complementation effects of two disease-associated mutations in tetrameric glutaryl-CoA dehydrogenase is due to inter subunit stability-activity counterbalance
Glutaric Aciduria Type I (GA-I), is an autosomal recessive neurometabolic disease caused by mutations in the GCDH gene that encodes for glutaryl-CoA dehydrogenase (GCDH), a flavoprotein involved in the metabolism of tryptophan, lysine and hydroxylysine. Although over 200 disease mutations have been reported a clear correlation between genotype and phenotype has been difficult to establish. To contribute to a better molecular understanding of GA-I we undertook a detailed molecular study on two GCDH disease-related variants, GCDH-p.Arg227Pro and GCDH-p.Val400Met. Heterozygous patients harbouring these two mutations have increased residual enzymatic activity in relation to homozygous patients with only one of the mutations, suggesting a complementation effect between the two. Combining biochemical, biophysical and structural methods we here establish the effects of these mutations on protein folding, stability and catalytic activity. We show that both variants retain the overall protein fold, but with compromised enzymatic activities. Detailed enzyme kinetic studies reveal that GCDH-p.Arg227Pro has impaired function due to deficient substrate affinity as evidenced by its higher Km, and that the lower activity in GCDH-p.Val400Met results from weaker interactions with its physiological redox partner (electron transfer flavoprotein). Moreover, the GCDH-p.Val400Met variant has a significantly lower thermal stability (ΔTm ≈ 9 °C), and impaired binding of the FAD cofactor in relation to wild-type protein. On these grounds, we provide a rational for the possible interallelic complementation observed in heterozygous patients based on the fact that in GCDH, the low active p.Arg227Pro variant contributes to stabilize the tetramer while the structurally unstable p.Val400Met variant compensates for enzyme activity.
gene therapies
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.
2025-09-30 | Application of Combined PGT-A and PGT-M for Reproductive Management in a Couple Carrying GCDH Mutations with Prior Affected Offspring: A Rare Case Report
Case A 31-year-old woman with secondary subfertility, four recurrent pregnancy losses, and one previous live-born child affected with glutaric acidemia type I (GA-I) was evaluated. Genetic testing confirmed that both partners were heterozygous carriers of pathogenic GCDH variants (c.769C>T in exon 8 and c.1204C>T in exon 11, NM_000159.4). Given the high recurrence risk, the couple underwent in vitro fertilization with intracytoplasmic sperm injection, blastocyst culture, trophectoderm biopsy, and combined preimplantation genetic testing for aneuploidy (PGT-A) and monogenic disease (PGT-M). Outcome Three blastocysts were biopsied. One embryo exhibited segmental aneuploidy of chromosome 16 and was excluded. A second embryo was euploid and wild-type for both GCDH variants, classified as genetically normal. The third was euploid but heterozygous for c.769C>T, consistent with carrier status. The genetically normal embryo was selected for frozen embryo transfer, resulting in a singleton intrauterine pregnancy. Non-invasive prenatal testing at 12 weeks showed a normal chromosomal profile. At the time of report, the pregnancy is ongoing at 20 weeks without complications. Conclusion This case demonstrates that combined PGT-A and PGT-M can effectively prevent recurrence of GA-I, improve reproductive outcomes, and provide a valuable option for couples with monogenic disorders and recurrent pregnancy loss.
2025-07-19 | Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice.
Glutaric aciduria type I (GA1) is an inherited disorder caused by the enzymatic defect of glutaryl-coenzyme A dehydrogenase in the lysine degradation pathway, characterized by the accumulation of toxic metabolites in the central nervous system. We reasoned that substrate reduction therapy targeting the α-aminoadipic semialdehyde synthase (AASS), the first enzyme in the catabolism of lysine, could provide an attractive therapeutic alternative. We explored reducing the expression of AASS by an artificial microRNA with AASS target sequences embedded in a miR-16 backbone (miR_AASS). We analyzed several delivery routes and AAV serotypes and evaluated the therapeutic efficacy of a systemic neonatal delivery of AAV9_miR_AASS in the Gcdh-/- mouse model of GA1. We detected dose-dependent miR-AASS expression and AASS inhibition in liver and striatum, the main tissues affected in GA1. Treatment with AAV9_miR_AASS in lysine overload-challenged mice reduced the accumulation of neurotoxic metabolites up to 6 months post-treatment in the striatum, prevented the neuropathological alterations, and improved mouse survival. Our results show that AAV9_miR_AASS supports AASS lowering as a potential gene therapy strategy for GA1.
2024-07-10 | Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model.
Glutaric aciduria type 1 (GA1) is a rare inherited metabolic disorder caused by a deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), with accumulation of neurotoxic metabolites, resulting in a complex movement disorder, irreversible brain damage, and premature death in untreated individuals. While early diagnosis and a lysine restricted diet can extend survival, they do not prevent neurological damage in approximately one-third of treated patients, and more effective therapies are required. Here we report the efficacy of adeno-associated virus 9 (AAV9)-mediated systemic delivery of human GCDH at preventing a high lysine diet (HLD)-induced phenotype in Gcdh -/- mice. Neonatal treatment with AAV-GCDH restores GCDH expression and enzyme activity in liver and striatum. This treatment protects the mice from HLD-aggressive phenotype with all mice surviving this exposure; in stark contrast, a lack of treatment on an HLD triggers very high accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine in tissues, with about 60% death due to brain accumulation of toxic lysine metabolites. AAV-GCDH significantly ameliorates the striatal neuropathology, minimizing neuronal dysfunction, gliosis, and alterations in myelination. Magnetic resonance imaging findings show protection against striatal injury. Altogether, these results provide preclinical evidence to support AAV-GCDH gene therapy for GA1.
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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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