RARE DISEASE
Propionic acidemia
Propionic acidemia
Propionic acidemia
Synonyms: Ketotic hyperglycinemia, Propionic aciduria, Propionyl-CoA carboxylase deficiency
Synonyms: Ketotic hyperglycinemia, Propionic aciduria, Propionyl-CoA carboxylase deficiency
Synonyms: Ketotic hyperglycinemia, Propionic aciduria, Propionyl-CoA carboxylase deficiency
Drug discovery
9
drugs
With orphan designations
Overview
Propionic acidemia (PA) is an autosomal recessive disorder caused by deficient propionyl-CoA carboxylase activity due to PCCA or PCCB gene mutations, impairing breakdown of branched-chain amino acids and odd-chain fats. This results in toxic metabolite accumulation, leading to metabolic acidosis, hyperammonemia, and multiorgan dysfunction. Neonatal onset manifests with vomiting, lethargy, and hypotonia, progressing to seizures or coma without prompt intervention. Late-onset forms present with episodic decompensation triggered by catabolic stressors. Management focuses on dietary protein restriction, metabolic stabilization, and crisis prevention [1][2][4].
Therapies
Acute: IV glucose, bicarbonate for acidosis, carnitine (100 mg/kg/day), and hemodialysis for hyperammonemia [6][11][16].
Chronic: Protein-restricted diet, medical formulas, biotin/carnitine supplements, and antibiotics to reduce gut propionate [2][9][16]. Liver transplantation and gene therapy (AAV vector trials) are investigational [3][12][13].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
380 drug discovery papers about Propionic acidemia, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
380 drug discovery papers about Propionic acidemia, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-03 | Real world experience of carglumic acid for methylmalonic and propionic acidurias: the second interim analysis of the multicentre observational PROTECT study
Abstract Introduction Propionic aciduria (PA) and methylmalonic aciduria (MMA) are rare inherited metabolic disorders marked by recurrent metabolic decompensation and hyperammonaemia, resulting in neurological morbidity, chronic complications, and substantial healthcare burden. Although carglumic acid (Carbaglu®) is established for acute hyperammonaemic crises, evidence for its long-term use is limited. This study reports the 18-month interim analysis of PROTECT, a large prospective observational study evaluating chronic Carbaglu® therapy in PA and MMA. Methods PROTECT is a prospective, longitudinal, observational study conducted across 34 centres in seven European countries. Patients with PA or MMA receiving long-term Carbaglu® for at least six months were eligible. Clinical data were extracted from medical records and analysed descriptively. Annualised pre- and post-treatment comparisons were performed in patients with at least six months of life without long-term Carbaglu® prior to initiation. Outcomes included metabolic decompensation events, ammonia control, healthcare utilisation, and growth parameters. Results Fifty-eight patients were included in this interim analysis. Among 39 evaluable patients, long-term Carbaglu® treatment was associated with reduced annualised metabolic decompensation events, including hyperammonaemic episodes. Mean peak ammonia levels during decompensations and background ammonia concentrations were significantly lower following treatment initiation. Healthcare utilisation decreased substantially, with significant reductions in inpatient admissions, inpatient days, and emergency room visits. Growth parameters remained stable in patients initiating treatment later in life, while patients treated from birth demonstrated sustained metabolic stability and favourable growth profiles. Discussion Despite heterogeneity and limitations inherent to real-world observational data, these findings indicate clinically meaningful improvements in metabolic control and healthcare burden with long-term Carbaglu® therapy. Reductions in both acute and background ammonia exposure suggest potential cumulative neuroprotective benefits. Conclusions This 18-month interim analysis supports Carbaglu® as a beneficial long-term treatment option for patients with PA and MMA, with particular promise when initiated early in life. Ongoing follow-up will further clarify long-term outcomes and inform optimisation of chronic management strategies. Clinical trial statement Findings based on clinical trial NCT04176523 titled the PRospective Observational study of long-TErm Carbaglu® for the Treatment of PA & MMA (PROTECT), registered retrospectively at ClinicalTrials.gov on 25th November 2019, available at https://clinicaltrials.gov/study/NCT04176523.
2026-07-17 | Liver Cancer in Methylmalonic and Propionic Acidemias: A Rare Complication? A Clinico-Pathological Study of 24 Livers.
In methylmalonic (MMA) and propionic acidemias (PA), liver or liver-kidney transplantation (Tx) is indicated for metabolic decompensations, kidney failure (MMA), and to improve quality of life. Liver cancer was reported in five patients with MMA. We characterized the pathology of 23 explanted livers and one cancer to investigate for pre-cancerous changes. We included seven patients with PA, 16 with MMA, and a patient with cancer after kidney Tx for MMA. Liver function tests, alpha-foetoprotein, and liver ultrasound were collected. Routine and special stains were performed. Abnormalities were observed in liver tests or ultrasound in half of the patients. Two had cirrhosis (one MMA, one PA). The maximum alpha-foetoprotein was 28 ng/mL. The key lesion was clusters and nodules of clear cells in 83%: distended hepatocytes with central nuclei, sharply demarcated from the parenchyma, in the periportal area. These cells contained less glycogen than the surrounding liver; macro-vacuolar steatosis was observed in 20%. Fibrosis was present in all but two, mostly stage 1 (67%), and mild lymphocytic inflammation in the portal tracts. Large-cell dysplasia was observed in the three oldest patients (one PA, two MMA). The phenotype of the clusters and nodules highlighted mitochondrial and LFABP loss. Abnormal labelling of glutamine synthetase was seen at distance from the nodules. The liver cancer was a hepatocellular carcinoma. Liver abnormalities were observed in all patients. The clusters and nodules of clear cells likely originate from propionyl-CoA accumulation and mitochondrial dysfunction. This abnormal pathology pleads for early liver Tx. Regular liver monitoring is recommended with alpha-foetoprotein and ultrasound.
2026-07-01 | Immune Dysregulation in Branched Chain Organic Acidemias.
Organic acidemias (OAs) are a group of inherited disorders, most commonly caused by defects in mitochondrial enzymes involved in amino acid and fatty acid metabolism. While they characteristically present with metabolic and neurological crises, growing evidence reveals a significant burden of chronic immune dysregulation in some disorders and patients. This review provides a synthesis of clinical and mechanistic evidence discussing immune dysregulation in OAs. Cytopenia can occur in OAs and predispose patients to recurrent and severe infections. Adaptive immune deficits, such as hypogammaglobulinemia, reduced B and T cell populations, and impaired vaccine-specific antibody responses, including to diphtheria and tetanus in MSUD and to the inactivated COVID-19 vaccine in propionic acidemia, have also been reported. Additionally, some case series note hyperinflammatory conditions, such as hemophagocytic lymphohistiocytosis. Mechanistic studies indicate that accumulated metabolites disrupt innate and adaptive hematopoietic progenitor function, mitochondrial homeostasis, and inflammatory signaling. Emerging therapeutic avenues, such as gene and mRNA-based therapies, hold the potential to improve or normalize the biochemical phenotype in OAs. While their impact on immune abnormalities remains largely unexplored, future clinical trials offer an opportunity to systematically assess potential effects on immune parameters. OAs are increasingly recognized as disorders with intrinsic immune dysregulation, extending beyond their well-characterized metabolic and neurological manifestations. Future clinical trials will benefit from including immunological endpoints to evaluate immunological recovery for novel therapies.
2026-06-30 | Protective in vitro effects of antioxidants against DNA damage induced by metabolites accumulated in propionic and methylmalonic acidemias.
Methylmalonic acidemia and propionic acidemia are inborn errors of metabolism caused by genetic mutations in mitochondrial enzymes involved in propionate metabolism. When these enzymes fail to function properly, organic acids accumulate in tissues and biological fluids. The brain is the primary tissue affected in these disorders, particularly due to the accumulation of organic acids. Oxidative stress and DNA damage play an important role in the pathophysiology of these diseases and may contribute to neurological impairment. In this context, the present study aimed to evaluate the in vitro effects of L-carnitine, N-acetylcysteine, and coenzyme Q10 on DNA damage induced by metabolites accumulated in methylmalonic and propionic acidemias. Leukocytes isolated from whole blood were used, and DNA damage was assessed using the comet assay. Our results demonstrated that metabolites accumulated in these disorders were responsible for inducing DNA damage, individually and in combination. In addition, all tested antioxidants exhibited protective effects against DNA damage. This study is the first to demonstrate the genotoxic effects of other metabolites beyond methylmalonic and propionic acids and to show the protective potential effect of different antioxidants in mitigate DNA damage. Taken together, these findings reinforce the need for clinical trials evaluating antioxidant-based therapies to improve prognosis and clinical outcomes in patients with methylmalonic acidemia and propionic acidemia.
2026-06-26 | Long Term Follow-Up After Transplantation in Propionic Acidemia: A Retrospective French Pediatric and Adult Cohort Study.
Propionic acidemia (PA) is a rare inherited metabolic disorder associated with recurrent metabolic decompensations and chronic multisystemic complications. Liver transplantation (LT) may improve metabolic stability, but its long-term impact on organ involvement remains debated. We retrospectively studied 20 patients with PA transplanted between 1993 and 2024 in three French reference centers. Clinical, biochemical, and organ-specific data were collected before and after transplantation. Eighteen isolated LT and two combined liver-kidney transplantations were performed. Median age at transplantation was 13.6 years; median follow-up was 4.5 years. Indications included frequent metabolic decompensation (70%) and cardiomyopathy (35%). Four patients died perioperatively, three from cardiac causes; crude survival was 75%. Transplantation markedly improved metabolic stability and allowed significant dietary liberalization, with reduced need for enteral feeding. Cardiac involvement, present in 15 patients pre-transplant, showed variable evolution: 10 improved initially, but three deteriorated later, and one required heart transplantation. New neurological manifestations occurred in eight patients, with acute episodes including CNI-related encephalopathy. Psychiatric disorders progressed from 40% to 59% of patients, requiring treatment in seven. Renal impairment worsened post-LT to 70%, with mean measured glomerular filtration rate declining from 72 to 60 mL/min/1.73 m2. LT improves metabolic and nutritional outcomes but does not consistently prevent chronic organ complications. In conclusion, early LT, before the onset of cardiac, neurologic, and psychiatric manifestations, should be considered on a case-by-case basis, as we could not demonstrate correlation between age at transplantation and organ involvement.
2026-08-03 | Real world experience of carglumic acid for methylmalonic and propionic acidurias: the second interim analysis of the multicentre observational PROTECT study
Abstract Introduction Propionic aciduria (PA) and methylmalonic aciduria (MMA) are rare inherited metabolic disorders marked by recurrent metabolic decompensation and hyperammonaemia, resulting in neurological morbidity, chronic complications, and substantial healthcare burden. Although carglumic acid (Carbaglu®) is established for acute hyperammonaemic crises, evidence for its long-term use is limited. This study reports the 18-month interim analysis of PROTECT, a large prospective observational study evaluating chronic Carbaglu® therapy in PA and MMA. Methods PROTECT is a prospective, longitudinal, observational study conducted across 34 centres in seven European countries. Patients with PA or MMA receiving long-term Carbaglu® for at least six months were eligible. Clinical data were extracted from medical records and analysed descriptively. Annualised pre- and post-treatment comparisons were performed in patients with at least six months of life without long-term Carbaglu® prior to initiation. Outcomes included metabolic decompensation events, ammonia control, healthcare utilisation, and growth parameters. Results Fifty-eight patients were included in this interim analysis. Among 39 evaluable patients, long-term Carbaglu® treatment was associated with reduced annualised metabolic decompensation events, including hyperammonaemic episodes. Mean peak ammonia levels during decompensations and background ammonia concentrations were significantly lower following treatment initiation. Healthcare utilisation decreased substantially, with significant reductions in inpatient admissions, inpatient days, and emergency room visits. Growth parameters remained stable in patients initiating treatment later in life, while patients treated from birth demonstrated sustained metabolic stability and favourable growth profiles. Discussion Despite heterogeneity and limitations inherent to real-world observational data, these findings indicate clinically meaningful improvements in metabolic control and healthcare burden with long-term Carbaglu® therapy. Reductions in both acute and background ammonia exposure suggest potential cumulative neuroprotective benefits. Conclusions This 18-month interim analysis supports Carbaglu® as a beneficial long-term treatment option for patients with PA and MMA, with particular promise when initiated early in life. Ongoing follow-up will further clarify long-term outcomes and inform optimisation of chronic management strategies. Clinical trial statement Findings based on clinical trial NCT04176523 titled the PRospective Observational study of long-TErm Carbaglu® for the Treatment of PA & MMA (PROTECT), registered retrospectively at ClinicalTrials.gov on 25th November 2019, available at https://clinicaltrials.gov/study/NCT04176523.
2026-07-17 | Liver Cancer in Methylmalonic and Propionic Acidemias: A Rare Complication? A Clinico-Pathological Study of 24 Livers.
In methylmalonic (MMA) and propionic acidemias (PA), liver or liver-kidney transplantation (Tx) is indicated for metabolic decompensations, kidney failure (MMA), and to improve quality of life. Liver cancer was reported in five patients with MMA. We characterized the pathology of 23 explanted livers and one cancer to investigate for pre-cancerous changes. We included seven patients with PA, 16 with MMA, and a patient with cancer after kidney Tx for MMA. Liver function tests, alpha-foetoprotein, and liver ultrasound were collected. Routine and special stains were performed. Abnormalities were observed in liver tests or ultrasound in half of the patients. Two had cirrhosis (one MMA, one PA). The maximum alpha-foetoprotein was 28 ng/mL. The key lesion was clusters and nodules of clear cells in 83%: distended hepatocytes with central nuclei, sharply demarcated from the parenchyma, in the periportal area. These cells contained less glycogen than the surrounding liver; macro-vacuolar steatosis was observed in 20%. Fibrosis was present in all but two, mostly stage 1 (67%), and mild lymphocytic inflammation in the portal tracts. Large-cell dysplasia was observed in the three oldest patients (one PA, two MMA). The phenotype of the clusters and nodules highlighted mitochondrial and LFABP loss. Abnormal labelling of glutamine synthetase was seen at distance from the nodules. The liver cancer was a hepatocellular carcinoma. Liver abnormalities were observed in all patients. The clusters and nodules of clear cells likely originate from propionyl-CoA accumulation and mitochondrial dysfunction. This abnormal pathology pleads for early liver Tx. Regular liver monitoring is recommended with alpha-foetoprotein and ultrasound.
2026-07-01 | Immune Dysregulation in Branched Chain Organic Acidemias.
Organic acidemias (OAs) are a group of inherited disorders, most commonly caused by defects in mitochondrial enzymes involved in amino acid and fatty acid metabolism. While they characteristically present with metabolic and neurological crises, growing evidence reveals a significant burden of chronic immune dysregulation in some disorders and patients. This review provides a synthesis of clinical and mechanistic evidence discussing immune dysregulation in OAs. Cytopenia can occur in OAs and predispose patients to recurrent and severe infections. Adaptive immune deficits, such as hypogammaglobulinemia, reduced B and T cell populations, and impaired vaccine-specific antibody responses, including to diphtheria and tetanus in MSUD and to the inactivated COVID-19 vaccine in propionic acidemia, have also been reported. Additionally, some case series note hyperinflammatory conditions, such as hemophagocytic lymphohistiocytosis. Mechanistic studies indicate that accumulated metabolites disrupt innate and adaptive hematopoietic progenitor function, mitochondrial homeostasis, and inflammatory signaling. Emerging therapeutic avenues, such as gene and mRNA-based therapies, hold the potential to improve or normalize the biochemical phenotype in OAs. While their impact on immune abnormalities remains largely unexplored, future clinical trials offer an opportunity to systematically assess potential effects on immune parameters. OAs are increasingly recognized as disorders with intrinsic immune dysregulation, extending beyond their well-characterized metabolic and neurological manifestations. Future clinical trials will benefit from including immunological endpoints to evaluate immunological recovery for novel therapies.
2026-06-30 | Protective in vitro effects of antioxidants against DNA damage induced by metabolites accumulated in propionic and methylmalonic acidemias.
Methylmalonic acidemia and propionic acidemia are inborn errors of metabolism caused by genetic mutations in mitochondrial enzymes involved in propionate metabolism. When these enzymes fail to function properly, organic acids accumulate in tissues and biological fluids. The brain is the primary tissue affected in these disorders, particularly due to the accumulation of organic acids. Oxidative stress and DNA damage play an important role in the pathophysiology of these diseases and may contribute to neurological impairment. In this context, the present study aimed to evaluate the in vitro effects of L-carnitine, N-acetylcysteine, and coenzyme Q10 on DNA damage induced by metabolites accumulated in methylmalonic and propionic acidemias. Leukocytes isolated from whole blood were used, and DNA damage was assessed using the comet assay. Our results demonstrated that metabolites accumulated in these disorders were responsible for inducing DNA damage, individually and in combination. In addition, all tested antioxidants exhibited protective effects against DNA damage. This study is the first to demonstrate the genotoxic effects of other metabolites beyond methylmalonic and propionic acids and to show the protective potential effect of different antioxidants in mitigate DNA damage. Taken together, these findings reinforce the need for clinical trials evaluating antioxidant-based therapies to improve prognosis and clinical outcomes in patients with methylmalonic acidemia and propionic acidemia.
2026-06-26 | Long Term Follow-Up After Transplantation in Propionic Acidemia: A Retrospective French Pediatric and Adult Cohort Study.
Propionic acidemia (PA) is a rare inherited metabolic disorder associated with recurrent metabolic decompensations and chronic multisystemic complications. Liver transplantation (LT) may improve metabolic stability, but its long-term impact on organ involvement remains debated. We retrospectively studied 20 patients with PA transplanted between 1993 and 2024 in three French reference centers. Clinical, biochemical, and organ-specific data were collected before and after transplantation. Eighteen isolated LT and two combined liver-kidney transplantations were performed. Median age at transplantation was 13.6 years; median follow-up was 4.5 years. Indications included frequent metabolic decompensation (70%) and cardiomyopathy (35%). Four patients died perioperatively, three from cardiac causes; crude survival was 75%. Transplantation markedly improved metabolic stability and allowed significant dietary liberalization, with reduced need for enteral feeding. Cardiac involvement, present in 15 patients pre-transplant, showed variable evolution: 10 improved initially, but three deteriorated later, and one required heart transplantation. New neurological manifestations occurred in eight patients, with acute episodes including CNI-related encephalopathy. Psychiatric disorders progressed from 40% to 59% of patients, requiring treatment in seven. Renal impairment worsened post-LT to 70%, with mean measured glomerular filtration rate declining from 72 to 60 mL/min/1.73 m2. LT improves metabolic and nutritional outcomes but does not consistently prevent chronic organ complications. In conclusion, early LT, before the onset of cardiac, neurologic, and psychiatric manifestations, should be considered on a case-by-case basis, as we could not demonstrate correlation between age at transplantation and organ involvement.
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Drug Discovery Landscape
9 orphan drug designations for Propionic acidemia.
9 orphan drug designations for Propionic acidemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adeno-Associated Virus 9 vector expressing a wild-type cDNA encoding human Propionyl-CoA Carboxylase, subunit beta (AAV9-hPCCB) | gene therapies | FDA | 2024-09-10 | — | National Institutes of Health (NIH), National Center for Advancing Translational Sciences (NCATS) |
Adeno-Associated Virus 9 human Propionyl-CoA Carboxylase, alpha subunit (AAV9-hPCCA) | gene therapies | FDA | 2021-09-27 | — | National Institutes of Health, National Center for Advancing Translational Sciences |
Claziprotamide | small molecules | EMA | 2021-07-19 | — | BridgeBio Europe B.V. |
2,2-dimethylbutanoic acid | small molecules | FDA | 2020-12-10 | — | HemoShear Therapeutics, LLC |
Adeno-Associated Viral Vector Expressing Codon-optimized Human PCCA cDNA | gene therapies | FDA | 2020-08-26 | — | Mayo Clinic |
Small molecule activator of pantothenate kinases | small molecules | FDA | 2020-08-14 | — | CoA Therapeutics |
Modified messenger ribonucleic acid encoding human propionyl-coenzyme A carboxylase alpha and beta subunits encapsulated into lipid nanoparticle | RNAs | EMA | 2019-04-24 | — | Moderna Biotech Spain S.L. |
messenger ribonucleic acid-based therapeutic agent encoding human propionyl-CoA carboxylase alpha and beta subunits | RNAs | FDA | 2018-12-05 | — | Moderna Therapeutics, Inc. |
Carglumic acid [Carbaglu] | small molecules | EMA | 2008-11-07 | — | Recordati Rare Diseases |
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