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:
categories:
Small molecules
small molecules
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.
2026-06-30 | 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.
2026-05-14 | [N-carbamylglutamate in the treatment of neonatal organic acidemia crisis: a report of five cases].
Five neonates with organic acidemia complicated by severe hyperammonemia were reported, including one case of isovaleric acidemia (IVA), three cases of methylmalonic acidemia (MMA), and one case of propionic acidemia (PA). The neonates were 3 to 19 days old. All presented with nonspecific symptoms such as poor feeding and decreased responsiveness, some with vomiting. All had dyspnea, and one had seizures. All cases were genetically confirmed: the IVA case carried a homozygous IVD variant, the three MMA cases carried compound heterozygous MMUT variants, and the PA case carried a homozygous PCCA variant. During the acute hyperammonemic phase, all five received N-carbamylglutamate (NCG). Two critically ill infants with peak ammonia >1 500 μmol/L underwent continuous veno-venous hemodialysis first and were started on oral NCG after ammonia fell below 200 μmol/L; the other three received oral NCG directly. Blood ammonia levels declined markedly in all cases, feeding was resumed successfully, and protein intake was gradually increased. In the chronic phase, all were maintained on oral NCG. One MMA infant died at 6 days of age due to treatment withdrawal by the family; the remaining four maintained ammonia <80 μmol/L. Over more than 12 months of follow-up, all four survivors had growth parameters (length, weight, and head circumference) within normal ranges, with two exhibiting mild delays in gross motor and language comprehension. NCG shows good safety and effectiveness for both acute rescue and long-term management of organic-acidemia-related hyperammonemia, and provides a reference strategy for clinical care.
2026-05-08 | Loss of pyruvate carboxylase suppresses lethality in propionic acidemia.
Inborn errors in propionyl-CoA carboxylase cause life-threatening propionic acidemia. To understand the contribution of propionyl-CoA metabolism to cellular and systemic metabolic dysfunction, we generated inducible and tissue-specific Pcca knockout mouse models. The inducible whole-body loss of Pcca results in acute metabolic decompensation like the inborn error. The liver-specific loss of Pcca recapitulates these adverse effects, demonstrating the centrality of the liver to systemic disease. Propionate and pyruvate converge in the TCA cycle as major anaplerotic substrates. Strikingly, the lethality of Pcca knockout (KO) mice is reversed by simultaneously inhibiting pyruvate carboxylase (Pcx). Most metabolites suspected as deleterious in propionic acidemia are exacerbated in liver-specific Pcca;Pcx double KO mice with the exception of methylcitrate, suggesting a role of this metabolite in systemic toxicity. These data clarify relevant toxic biomarkers and suggest that rebalancing hepatic TCA cycle metabolism is critical to mitigate the adverse effects from alternative propionyl-CoA metabolic pathways.
2026-04-28 | Oxidative Stress and Inflammation in Methylmalonic and Propionic Acidemias: A Review.
Methylmalonic acidemia and propionic acidemia are inherited organic acidemias resulting from deficiencies in the enzymes methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. Impaired activity of these enzymes leads to the accumulation of propionyl-CoA and methylmalonyl-CoA metabolites in tissues and biological fluids. The two disorders share similar clinical features, most notably severe neurological involvement. In the absence of early diagnosis and appropriate treatment, affected individuals may develop irreversible neurological injury, progress to coma, and, in severe cases, death. In this scenario, this review presents some findings from studies in patients, cells and animal models, evidencing that oxidative stress and inflammation plays a crucial role in the pathophysiology of methylmalonic acidemia and propionic acidemia. Furthermore, it allows us to understand the profile of oxidative stress and new perspectives for the treatment of these diseases. Decreased antioxidant defenses, as well as increased levels of markers of inflammation, oxidative damage to lipids, proteins and DNA were observed in animal models, cells and patients, possibly due to the increase in the production of reactive species caused by the accumulated metabolites. The literature also indicates that the use of specific antioxidants may provide benefits by improving the oxidative profile. Based on this evidence, it is widely accepted that oxidative stress and inflammation contribute to severe neurological damage in patients with methylmalonic acidemia and propionic acidemia.
cell therapies
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.
2026-06-26 | 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.
2026-03-01 | 1343: CASE SERIES OF CONTINUOUS RENAL REPLACEMENT THERAPY IN ORGANIC ACIDEMIAS
Introduction: As critical care advances, technologies and life support systems that were selectively applied gain expanded use. However, it is important to carefully evaluate how these therapies interact with underlying chronic diseases. This is especially important in diseases that previously had shorter life expectancies. Propionic acidemia (PA) and methylmalonic acidemia (MMA) are two similar, autosomal recessive, inborn errors of metabolism. Severe metabolic crises can develop from dietary non-compliance, infectious triggers, or stress. Here, we report a single center experience with the use of continuous renal replacement therapy (CRRT) in this patient population. Description: During a 5-year period, at a tertiary academic pediatric hospital, there were 5 cases of initiation of CRRT for metabolic crisis in children with PA or MMA. Of these 5 cases, one patient with MMA had undergone a liver transplant but developed graft failure leading to a hyperammonemia crisis and acute kidney injury requiring CRRT. This patient tolerated CRRT until repeat liver transplant but ultimately died due to complications from her transplant. The other four cases were patients experiencing metabolic crisis from their underlying inborn error of metabolism. CRRT was offered to help correct the severe refractory metabolic acidosis. One family declined CRRT and redirected care. For the other three cases of CRRT use in metabolic crisis for PA/MMA, data including presenting symptoms, metabolic support, initial labs, VIS, PELOD-2, and pSOFA scores are reported as well as these same values at the initiation of CRRT and after 24 hours of CRRT. Discussion: Unfortunately, although all patients met criteria for initiation of CRRT due to severe refractory metabolic acidosis, all patients died. This raises the question on whether the application of CRRT is a useful therapy to help abort or manage a metabolic crisis in patients with PA/MMA. Perhaps, once multi-organ dysfunction develops in the PA/MMA patient population, CRRT is insufficient to reverse the ongoing metabolic injury. This is a small case series and raises the need for a future multi-institutional registry to evaluate the optimal treatment and management for severe refractory acidosis in patients with PA/MMA.
2026-01-17 | Heart and heart-liver transplantation in Amish patients with propionic acidemia.
Propionic acidemia (PA) is a genetic metabolic disorder caused by deficient activity of the enzyme propionyl-CoA carboxylase, resulting in accumulation of toxic metabolites during catabolism of odd-chain fatty acids and branched-chain amino acids. Most PA occurs in compound heterozygotes, typically presenting with metabolic acidosis and seizures in infancy. A milder phenotype of PA is prevalent in the Amish population due to a founder missense variant in PCCB (c.1606 A > G; p.Asn536Asp) and is frequently present as an isolated dilated cardiomyopathy in adolescence. Here we report our experience with three Amish patients with genetically confirmed PA and end-stage heart failure. While one patient underwent successful heart transplantation with no complications, another developed recurrent cardiogenic shock after transplant due to metabolic decompensation. Based on this experience, a subsequent patient was treated with combined heart/liver transplantation. These cases highlight unique challenges in managing patients with metabolic cardiomyopathies and emphasize the importance of a multidisciplinary approach to achieve the best possible outcomes.
2026-01-16 | Liver transplantation for propionic acidemia: Survival and metabolic outcomes.
Propionic acidemia (PA) is a severe metabolic disorder that leads to multiorgan damage despite comprehensive management. Liver transplantation (LT), particularly living donor liver transplantation, has been proposed as an effective treatment, but evidence from large-scale studies is limited. This retrospective study analyzed clinical outcomes of 39 children with PA who underwent LT at Shanghai Ren Ji Hospital between September 2017 and October 2023. The data included demographics, surgical details, biochemical/metabolic markers, and progression of symptoms. Patients were grouped based on the Diagnosis-to-Transplant Interval (<20 vs. ≥20 mo) for comparative analysis. Among 39 patients, 38 (97.4%) underwent living donor liver transplantation, and 1 received split LT. At 6 months after transplant, significant reductions were observed in propionylcarnitine/acetylcarnitine ratio (1.4 to 0.8, p=0.01), urinary methylcitrate (35.4 to 15.2, p=0.03), and 3-hydroxypropionic acid (198.8 to 6.8, p=0.02). Symptoms such as gross motor delay, metabolic acidosis, hyperammonemia, and feeding difficulties significantly improved (all p<0.001). The 5-year patient and graft survival rates were 97.4%. Short Diagnosis-to-Transplant Interval time (<20 mo) and long Diagnosis-to-Transplant Interval time (≥20 mo) also affected the results of specific PA clinical problems before and after transplantation. This single-center study on PA transplantation suggests that LT, especially living donor liver transplantation, effectively reduces metabolic waste, promotes metabolic stability, and enhances quality of life in pediatric patients with PA. LT represents an effective therapeutic option for patients with metabolic instability.
oligonucleotides
2026-04-24 | From N-of-1 to versatility in propionic acidemia: Antisense oligonucleotide-mediated skipping of a constitutive PCCA pseudoexon.
Propionic acidemia is a rare autosomal recessive disorder caused by mutations in the PCCA or PCCB gene, resulting in deficient propionyl-CoA carboxylase activity. We identified a unique homozygous deep-intronic PCCA variant, NM_000282.4:c.1285-1358C>G, in an individual with neonate-onset propionic acidemia. Fibroblasts from this individual expressed only PCCA mRNA containing an 84-bp pseudoexon, which is present at low levels in healthy controls, leading to the loss of PCCA and PCCB proteins and severely reduced propionyl-CoA carboxylase activity. Transfection of fibroblasts with chemically synthesized antisense oligonucleotides (ASOs) designed to skip the pseudoexon restored productive PCCA splicing, rescued PCCA protein expression, and markedly increased propionyl-CoA carboxylase activity above wild-type levels. The efficacy of the ASOs was further evaluated in fibroblasts from 7 additional individuals with propionic acidemia carrying mutations in PCCA or PCCB. ASO treatment successfully restored enzymatic activity, particularly in fibroblast lines, with residual activity exceeding 1% of normal. These findings suggest that ASO-mediated splicing correction targeting the 84-bp pseudoexon can restore mRNA, protein, and enzymatic function in individuals with deep intronic mutations, as well as in other individuals with propionic acidemia, indicating the feasibility of ASO therapy as a molecular treatment strategy for a subset of individuals with propionic acidemia.
2026-03-09 | Industry Insights: Early 2026 brings clinical progress, regulatory designations, and strategic partnerships in nucleic acid therapeutics
Across January and early February 2026, activity in the nucleic acid therapeutics field spanned early clinical readouts, regulatory designations, preclinical advances, and new strategic partnerships. ProQR reported initial Phase 1 data for its editing oligonucleotide AX-0810 in cholestatic diseases, while Providence Therapeutics supported the launch of a multi-site paediatric trial evaluating personalized mRNA cancer vaccines in Australia. Regulatory momentum continued, with the US FDA granting Fast Track designation to BioNTech’s mRNA immunotherapy BNT113 for HPV16-positive head and neck cancer, and Japan awarding Orphan Drug designation to Dyne’s antisense candidate DYNE-101 for myotonic dystrophy type 1. Preclinical studies highlighted mRNA and antisense approaches in infertility and metabolic disease, alongside new collaborations to expand access to individualized antisense therapies and advance mRNA treatment for propionic acidemia.
2023-12-13 | Regulating PCCA gene expression by modulation of pseudoexon splicing patterns to rescue enzyme activity in propionic acidemia
Pseudoexons are nonfunctional intronic sequences that can be activated by deep-intronic sequence variation. Activation increases pseudoexon inclusion in mRNA and interferes with normal gene expression. The PCCA c.1285-1416A>G variation activates a pseudoexon and causes the severe metabolic disorder propionic acidemia by deficiency of the propionyl-CoA carboxylase enzyme encoded by PCCA and PCCB. We characterized this pathogenic pseudoexon activation event in detail and identified hnRNP A1 to be important for normal repression. The PCCA c.1285-1416A>G variation disrupts an hnRNP A1-binding splicing silencer and simultaneously creates a splicing enhancer. We demonstrate that blocking this region of regulation with splice-switching antisense oligonucleotides restores normal splicing and rescues enzyme activity in patient fibroblasts and in a cellular model created by CRISPR gene editing. Interestingly, the PCCA pseudoexon offers an unexploited potential to upregulate gene expression because healthy tissues show relatively high inclusion levels. By blocking inclusion of the nonactivated wild-type pseudoexon, we can increase both PCCA and PCCB protein levels, which increases the activity of the heterododecameric enzyme. Surprisingly, we can increase enzyme activity from residual levels in not only patient fibroblasts harboring PCCA missense variants but also those harboring PCCB missense variants. This is a potential treatment strategy for propionic acidemia.
2023-07-05 | RegulatingPCCAgene expression by modulation of pseudoexon splicing patterns to rescue enzyme activity in propionic acidemia
Abstract Pseudoexons are nonfunctional intronic sequences that can be activated by deep intronic sequence variation. Activation increases pseudoexon inclusion in mRNA and interferes with normal gene expression. The PCCA c.1285-1416A>G variation activates a pseudoexon and causes the severe metabolic disorder, propionic acidemia, by deficiency of the propionyl-CoA carboxylase enzyme encoded by PCCA and PCCB . We characterized this pathogenic pseudoexon activation event in detail and identified hnRNP A1 to be important for normal repression. The PCCA c.1285-1416A>G variation disrupts an hnRNP A1-binding splicing silencer and simultaneously creates a splicing enhancer. We demonstrate that blocking this region of regulation with splice-switching antisense oligonucleotides restores normal splicing and rescues enzyme activity in patient fibroblasts and in a cellular model created by CRISPR gene editing. The PCCA pseudoexon can be exploited as a gene-regulatory switch, as healthy tissues show relatively high levels of inclusion. By blocking inclusion of the non-activated wild type pseudoexon, we increase both PCCA and PCCB protein levels, which increases the activity of the heterododecameric enzyme. Surprisingly, we can increase enzyme activity from residual levels not only in patient fibroblasts harboring PCCA missense variants, but also those harboring PCCB missense variants. This could be a potential treatment strategy for propionic acidemia.
2023-02-14 | Dysregulated Cell Homeostasis and miRNAs in Human iPSC-Derived Cardiomyocytes from a Propionic Acidemia Patient with Cardiomyopathy.
Propionic acidemia (PA) disorder shows major involvement of the heart, among other alterations. A significant number of PA patients develop cardiac complications, and available evidence suggests that this cardiac dysfunction is driven mainly by the accumulation of toxic metabolites. To contribute to the elucidation of the mechanistic basis underlying this dysfunction, we have successfully generated cardiomyocytes through the differentiation of induced pluripotent stem cells (iPSCs) from a PCCB patient and its isogenic control. In this human cellular model, we aimed to examine microRNAs (miRNAs) profiles and analyze several cellular pathways to determine miRNAs activity patterns associated with PA cardiac phenotypes. We have identified a series of upregulated cardiac-enriched miRNAs and alterations in some of their regulated signaling pathways, including an increase in the expression of cardiac damage markers and cardiac channels, an increase in oxidative stress, a decrease in mitochondrial respiration and autophagy; and lipid accumulation. Our findings indicate that miRNA activity patterns from PA iPSC-derived cardiomyocytes are biologically informative and advance the understanding of the molecular mechanisms of this rare disease, providing a basis for identifying new therapeutic targets for intervention strategies.
gene therapies
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.
2026-06-17 | Targeted gene editing of PCCA pseudoexon using CRISPR-Cas12a for potential therapy in propionic acidemia
Deep-intronic variants activating pseudoexons (PEs) are a common cause for monogenic diseases. Removal of the PE region predictably corrects the splicing defect, offering a potential therapeutic strategy. Previous studies, including our own, have identified an 84-bp PE in intron 14 of the gene PCCA that is included in the mature mRNA at relatively high basal levels across all tissues. When activated by the c.1285-1416A>G variant, this PE becomes fully included, ultimately causing the potentially lethal neurometabolic disorder propionic acidemia due to the deficiency of propionyl-CoA carboxylase (PCC) enzyme. In this study, we explored, through a CRISPR-Cas12-assisted non-homologous end joining (NHEJ)-mediated approach, whether PE removal or abrogation of the splice enhancer strengthened by the variant could efficiently restore normal transcript and functional PCCA protein. Both in wild-type hepatoma cells and in an edited cellular model homozygous for the activating variant, we show that the CRISPR-Cas12a approach increases PCC activity, with the highest values obtained with a guide RNA (gRNA) targeting the enhancer region in the PEs. The results provide proof-of-concept of its therapeutic potential for patients with PE activation and those with hypomorphic missense variants in whom residual activity levels may be effectively raised.
2026-03-07 | AAV-Mediated Dual-Gene Therapy Restores Metabolic Function in Mice with Propionic Acidemia
Abstract Background and Aims Propionic acidemia (PA) is a rare autosomal recessive disorder caused by mutations in PCCA or PCCB , which encode the two subunits of propionyl-CoA carboxylase (PCC). PCC deficiency causes toxic metabolite accumulation and multi-organ damage. Current management, including dietary restriction, pharmacological support, and liver transplantation, does not restore enzymatic activity. We developed a dual-gene adeno-associated virus (AAV) therapy that delivers both PCC subunits to treat both PA subtypes. Methods We generated a clinically relevant PCCA -R73W knock-in mouse model and administered AAV8 vectors encoding native human PCCA and PCCB under the control of a liver-specific thyroxine-binding globulin promoter (AAV8-TBG-h PCCA -P2A-h PCCB ). Metabolite levels and organ safety were longitudinally assessed. Results Dual-gene therapy produced dose-dependent reductions in plasma C3/C2 ratio, 3-hydroxypropionic acid, 2-methylcitric acid, and propionylglycine, and significantly outperformed single-gene ( PCCA -only) therapy. Neonatal facial-vein injection achieved metabolic correction comparable to or better than adult treatment. The longitudinal follow-up revealed sustained efficacy over a 16-week period, with no signs of hepatotoxicity or adverse effects. Conclusions Single-dose, dual-gene AAV therapy achieves sustained metabolic correction and demonstrates long-term safety in a clinically relevant PA model, supporting its translational potential for both type I and type II propionic acidemia.
2026-01-01 | P033: Integrating clinical data, biomarkers and in vivo propionate oxidation to inform genotype-based phenotype prediction in propionic acidemia
Introduction: Propionic acidemia (PA), a deficiency of propionyl-CoA carboxylase, is caused by biallelic pathogenic variants in PCCA or PCCB.The genotypic heterogeneity and compound heterozygosity make genotype-based phenotype severity predictions challenging, particularly when individuals do not harbor two loss-of-function (LOF) alleles.Improved understanding of the genotype-phenotype associations may help improve prognostication and guide selections of patients who could benefit from emerging liver-directed therapies.Methods: We are conducting a prospective natural history study of PA in the NIH Clinical Center (ClinicalTrials.govIdentifier: NCT02890342).Protocol visits were accomplished via outpatient visits or hospital admissions and included specialty evaluations, nutritional assessments, imaging studies, laboratory testing, biobanking of research.Cardiac, renal, hematological, hepatic, ophthalmologic, neurological and metabolic parameters were systematically evaluated.Patients underwent a 1-13 C-propionate oxidation breath test (POBT), a non-invasive whole-body measurement that largely reflects residual hepatic propionyl-CoA carboxylase activity, expressed as cumulative percent isotope dose metabolized at 120 min.Results: Fifty-nine individuals with PA were enrolled, including 52 evaluated in person and 7 virtually.Variants in PCCA were present in 20 individuals (34%) and in PCCB in 39 individuals (66%).The most frequent PCCB variant was c.1218_1228delinsTAGAGCACAGGA (p.Gly407fs), identified in 18/39 participants (46%).Seven individuals have undergone organ transplantation: five isolated liver transplants (median age 1.5 years; range 1-20), one isolated kidney transplant (age 42), and one combined liver-kidney transplant (age 21.5 years).Among non-transplanted participants, individuals harboring two LOF alleles had significantly lower propionate oxidation compared to those with other genotypes (p<0.001).This group also demonstrated lower full-scale IQ (p=0.006),lower composite Vineland scores (p=0.014),higher 3-hydroxypropionic acid levels (p=0.021), and higher C3 levels (p=0.028).In contrast, 2-methylcitric acid levels were not significantly different between groups (p=0.242).The PCCA missense variant c.782A>G (p.Glu261Gly) was associated with a severe clinical phenotype when present in trans with a LOF allele; two of three individuals harboring this variant underwent liver transplantation.In contrast, the PCCB missense variant c.683C>T (p.Pro228Leu), identified in two individuals, both of whom carried this variant in trans with the common LOF allele c.1218_1228delinsTAGAGCACAGGA (p.Gly407fs), correlated with a milder phenotype, higher propionate oxidation (mean POBT 120 min: 26.6%), and relatively lower metabolite levels (mean 3-hydroxypropionic acid 31.1
2025-03-06 | Novel CRISPR-Cas9 iPSC knockouts for PCCA and PCCB genes: advancing propionic acidemia research.
Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by mutations in the PCCA and PCCB genes, which encode subunits of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). This enzyme deficiency leads to the accumulation of toxic metabolites, resulting in severe metabolic dysfunction. To create ideal in vitro disease models of PA with isogenic controls and provide a robust platform for therapeutic research, we generated two induced pluripotent stem cell (iPSC) lines with knockout (KO) mutations in the PCCA and PCCB genes using CRISPR-Cas9 gene editing in a healthy control iPSC line. The KO iPS cells were successfully established and characterized, confirming the presence of frameshift insertions and deletions in each target gene, as well as the loss of the corresponding transcript, protein expression, and activity. Additionally, the generated iPSC lines exhibit hallmark characteristics of pluripotency, including the potential to differentiate into all three germ layers. Our PCCA and PCCB KO iPSC models provide a valuable tool for studying the molecular mechanisms underlying PA and hold potential for advancing new therapeutic approaches.
other
2026-06-25 | Precision metabolic therapy for propionic acidemia.
Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by a deficiency of mitochondrial propionyl-CoA carboxylase, leading to the accumulation of propionyl-CoA and toxic metabolites that disrupt TCA cycle flux and ammonia detoxification. Propionyl-CoA is generated from gut microbiome-derived propionate, propiogenic amino acids, odd-chain fatty acids, and cholesterol side chains. Its accumulation produces downstream metabolites such as propionylcarnitine and methylcitrate and promotes histone propionylation. These alterations collectively contribute to mitochondrial dysfunction, oxidative stress, and multi-organ pathology. Current clinical management focuses on reducing propionyl-CoA burden through dietary restriction and supportive therapies, but long-term outcomes remain suboptimal due to poor tolerability and progressive complications. Although liver transplantation improves hepatic metabolism, it does not fully correct extrahepatic disease. Gene-based approaches, including mRNA-based enzyme replacement and viral vector-mediated gene delivery, show promise but face challenges related to delivery efficiency, durability of expression, and immune responses. Emerging small-molecule strategies aim to reprogram metabolism by restoring the balance between propionyl-CoA and acetyl-CoA while replenishing cellular CoA pools. Precision metabolic therapy may combine acetate supplementation and NRF2 activation to enhance acetyl-CoA production and mitochondrial resilience, while suppressing propionyl-CoA formation through ACSS3 inhibition and propiogenic amino acid restriction. In parallel, CoA availability may be increased through activation of PANK1-3, inhibition of PANK4, and supplementation with CoA precursor compounds. We propose that rational combination therapy targeting multiple nodes of short-chain fatty-acid metabolism and CoA homeostasis will provide a more effective strategy than single-agent approaches for correcting metabolic imbalance in PA.
2025-12-22 | When Metabolism Meets Immunity: Inborn Errors of Metabolism Mimicking Primary Immunodeficiencies—A Case Series
Several inborn errors of metabolism (IEMs) are known to affect immune function; the latter may arise from disruptions in metabolic pathways critical to immune cell development or from accumulation of toxic metabolites that impair immunity. This overlap can complicate diagnosis and management. We present seven patients with IEMs initially suspected of having inborn errors of immunity (IEIs) to highlight the phenotypic intersections between these disorders. All patients were referred for immunological evaluation due to recurrent infections, cytopenias, or abnormal immune profiles. Each was ultimately diagnosed with an IEM known to affect immune function. Results • Purine nucleoside phosphorylase deficiency: A 4-year-old female with CMV infection, seizures, and lymphopenia was diagnosed with this T cell defect associated with purine metabolism. Good clinical response with intravenous immunoglobulin, oral prednisolone, folic acid, vitamin B, and antiviral. • Propionic acidemia: Three patients presented with early-onset sepsis or viral infections. Immunologic findings included hypogammaglobulinemia, lymphopenia (particularly affecting B and natural killer cells), and neutropenia. Treated with carglumic acid, levocarnitine, protein-rich diet, and replacement immunoglobulin. • Transcobalamin II deficiency: Two patients had recurrent infections, cytopenias, and global lymphopenia. One showed hypogammaglobulinemia. Good response with intramuscular B12 vitamin and folic acid. • Thymidine phosphorylase deficiency: A 17-year-old male presented with ophthalmoparesis, severe abdominal pain, and angiographic images resembling vasculitis, with negative autoantibodies and poor response to immunosuppression. He died a few weeks after liver transplantation. Conclusion This series underscores the immunologic manifestations of IEMs, which can mimic IEIs and complicate diagnosis. Recognizing the bidirectional overlap is crucial: immune evaluation may uncover an underlying metabolic disorder, while persistent infections or immune alterations in IEMs warrant thorough immunological assessment. Immunologic interventions like immunoglobulins, antibiotic prophylaxis, vaccines, etc. may help to reduce the infectious burden in IEMs and improve quality of life. Timely diagnosis and comprehensive management are crucial for both groups of diseases.
2025-11-07 | Nanoscale conformational dynamics of human propionyl-CoA carboxylase.
Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme responsible for propionyl-CoA catabolism. Deficiencies in human PCC (hPCC) cause propionic acidemia, a severe metabolic disorder driven by toxic metabolite accumulation. Despite its therapeutic relevance, the structural basis of hPCC's catalytic function remains unresolved. Here, we present high-resolution cryo-EM structures of hPCC in four distinct states, unliganded, ADP-, AMPPNP-, and ATP-bound/substrate-bound, capturing the full trajectory of the biotin carboxyl carrier protein (BCCP) domain as it translocates between active sites. Our results reinforce the crucial role of nucleotide-gated B-lid subdomain in synchronizing catalysis through coupling with BCCP movement. Structural and biochemical analysis of 10 disease-associated variants reveals how mutations disrupt key domain interfaces and dynamic motions required for activity. These new insights define the mechanistic principles governing hPCC functions, establish a structural framework for understanding PCC-related disorders, and lay the groundwork for future efforts to engineer functional replacements or modulators for metabolic therapy.
2018-01-24 | Import of TAT-Conjugated Propionyl Coenzyme A Carboxylase Using Models of Propionic Acidemia
Propionic acidemia is caused by a deficiency of the enzyme propionyl coenzyme A carboxylase (PCC) located in the mitochondrial matrix. Cell-penetrating peptides, including transactivator of transcription (TAT), offer a potential to deliver a cargo into the mitochondrion. Here, we investigated the delivery of an α6β6 PCC enzyme into mitochondria using the HIV TAT peptide at several levels: into isolated mitochondria, in patient fibroblast cells, and in a mouse model. Results from Western blots and enzyme activity assays confirmed the import of TAT-PCC into mitochondria, as well as into patient fibroblasts, where the colocalization of imported TAT-PCC and mitochondria was also confirmed by confocal fluorescence microscopy. Furthermore, a single-dose intraperitoneal injection into PCC-deficient mice decreased the propionylcarnitine/acetylcarnitine (C3/C2) ratio toward the normal level. These results show that a cell-penetrating peptide can deliver active multimeric enzyme into mitochondria in vitro, in situ, and in vivo and push the size limit of intracellular delivery achieved so far. Our results are promising for other mitochondrion-specific deficiencies.
2016-11-17 | Molecular cloning of rat acss3 and characterization of mammalian propionyl-CoA synthetase in the liver mitochondrial matrix.
Among the three acyl-CoA synthetase short-chain family members (ACSS), ACSS3 is poorly characterized. To characterize ACSS3, we performed molecular cloning and protein expression of rat acss3 and determined its intracellular localization, tissue distribution, and substrate specificity. Transient expression of rat ACSS3 in HeLa cells resulted in a 10-fold increase of acetyl-CoA synthetase activity compared with that in control cells. The acss3 transcripts are expressed in a wide range of tissues, with the highest levels observed in liver tissue followed by kidney tissue. Subcellular fractionation using liver tissue showed that ACSS3 is localized into the mitochondrial matrix. Among the short-chain fatty acids examined, recombinant ACSS3, purified from Escherichia coli cells transformed with the plasmid containing rat acss3, preferentially utilized propionate with a KM value of 0.19 mM. Knockdown of acss3 in HepG2 cells resulted in a significant decrease of ACSS3 expression level and propionyl-CoA synthetase activity in cell lysates. Levels of ACSS3 in the liver and the activity of propionyl-CoA synthetase in the mitochondria were significantly increased by fasting. These results suggested that ACSS3 is a liver mitochondrial matrix enzyme with high affinity to propionic acid, and its expression level is upregulated under ketogenic conditions.
small molecules
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.
2026-06-30 | 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.
2026-05-14 | [N-carbamylglutamate in the treatment of neonatal organic acidemia crisis: a report of five cases].
Five neonates with organic acidemia complicated by severe hyperammonemia were reported, including one case of isovaleric acidemia (IVA), three cases of methylmalonic acidemia (MMA), and one case of propionic acidemia (PA). The neonates were 3 to 19 days old. All presented with nonspecific symptoms such as poor feeding and decreased responsiveness, some with vomiting. All had dyspnea, and one had seizures. All cases were genetically confirmed: the IVA case carried a homozygous IVD variant, the three MMA cases carried compound heterozygous MMUT variants, and the PA case carried a homozygous PCCA variant. During the acute hyperammonemic phase, all five received N-carbamylglutamate (NCG). Two critically ill infants with peak ammonia >1 500 μmol/L underwent continuous veno-venous hemodialysis first and were started on oral NCG after ammonia fell below 200 μmol/L; the other three received oral NCG directly. Blood ammonia levels declined markedly in all cases, feeding was resumed successfully, and protein intake was gradually increased. In the chronic phase, all were maintained on oral NCG. One MMA infant died at 6 days of age due to treatment withdrawal by the family; the remaining four maintained ammonia <80 μmol/L. Over more than 12 months of follow-up, all four survivors had growth parameters (length, weight, and head circumference) within normal ranges, with two exhibiting mild delays in gross motor and language comprehension. NCG shows good safety and effectiveness for both acute rescue and long-term management of organic-acidemia-related hyperammonemia, and provides a reference strategy for clinical care.
2026-05-08 | Loss of pyruvate carboxylase suppresses lethality in propionic acidemia.
Inborn errors in propionyl-CoA carboxylase cause life-threatening propionic acidemia. To understand the contribution of propionyl-CoA metabolism to cellular and systemic metabolic dysfunction, we generated inducible and tissue-specific Pcca knockout mouse models. The inducible whole-body loss of Pcca results in acute metabolic decompensation like the inborn error. The liver-specific loss of Pcca recapitulates these adverse effects, demonstrating the centrality of the liver to systemic disease. Propionate and pyruvate converge in the TCA cycle as major anaplerotic substrates. Strikingly, the lethality of Pcca knockout (KO) mice is reversed by simultaneously inhibiting pyruvate carboxylase (Pcx). Most metabolites suspected as deleterious in propionic acidemia are exacerbated in liver-specific Pcca;Pcx double KO mice with the exception of methylcitrate, suggesting a role of this metabolite in systemic toxicity. These data clarify relevant toxic biomarkers and suggest that rebalancing hepatic TCA cycle metabolism is critical to mitigate the adverse effects from alternative propionyl-CoA metabolic pathways.
2026-04-28 | Oxidative Stress and Inflammation in Methylmalonic and Propionic Acidemias: A Review.
Methylmalonic acidemia and propionic acidemia are inherited organic acidemias resulting from deficiencies in the enzymes methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. Impaired activity of these enzymes leads to the accumulation of propionyl-CoA and methylmalonyl-CoA metabolites in tissues and biological fluids. The two disorders share similar clinical features, most notably severe neurological involvement. In the absence of early diagnosis and appropriate treatment, affected individuals may develop irreversible neurological injury, progress to coma, and, in severe cases, death. In this scenario, this review presents some findings from studies in patients, cells and animal models, evidencing that oxidative stress and inflammation plays a crucial role in the pathophysiology of methylmalonic acidemia and propionic acidemia. Furthermore, it allows us to understand the profile of oxidative stress and new perspectives for the treatment of these diseases. Decreased antioxidant defenses, as well as increased levels of markers of inflammation, oxidative damage to lipids, proteins and DNA were observed in animal models, cells and patients, possibly due to the increase in the production of reactive species caused by the accumulated metabolites. The literature also indicates that the use of specific antioxidants may provide benefits by improving the oxidative profile. Based on this evidence, it is widely accepted that oxidative stress and inflammation contribute to severe neurological damage in patients with methylmalonic acidemia and propionic acidemia.
cell therapies
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.
2026-06-26 | 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.
2026-03-01 | 1343: CASE SERIES OF CONTINUOUS RENAL REPLACEMENT THERAPY IN ORGANIC ACIDEMIAS
Introduction: As critical care advances, technologies and life support systems that were selectively applied gain expanded use. However, it is important to carefully evaluate how these therapies interact with underlying chronic diseases. This is especially important in diseases that previously had shorter life expectancies. Propionic acidemia (PA) and methylmalonic acidemia (MMA) are two similar, autosomal recessive, inborn errors of metabolism. Severe metabolic crises can develop from dietary non-compliance, infectious triggers, or stress. Here, we report a single center experience with the use of continuous renal replacement therapy (CRRT) in this patient population. Description: During a 5-year period, at a tertiary academic pediatric hospital, there were 5 cases of initiation of CRRT for metabolic crisis in children with PA or MMA. Of these 5 cases, one patient with MMA had undergone a liver transplant but developed graft failure leading to a hyperammonemia crisis and acute kidney injury requiring CRRT. This patient tolerated CRRT until repeat liver transplant but ultimately died due to complications from her transplant. The other four cases were patients experiencing metabolic crisis from their underlying inborn error of metabolism. CRRT was offered to help correct the severe refractory metabolic acidosis. One family declined CRRT and redirected care. For the other three cases of CRRT use in metabolic crisis for PA/MMA, data including presenting symptoms, metabolic support, initial labs, VIS, PELOD-2, and pSOFA scores are reported as well as these same values at the initiation of CRRT and after 24 hours of CRRT. Discussion: Unfortunately, although all patients met criteria for initiation of CRRT due to severe refractory metabolic acidosis, all patients died. This raises the question on whether the application of CRRT is a useful therapy to help abort or manage a metabolic crisis in patients with PA/MMA. Perhaps, once multi-organ dysfunction develops in the PA/MMA patient population, CRRT is insufficient to reverse the ongoing metabolic injury. This is a small case series and raises the need for a future multi-institutional registry to evaluate the optimal treatment and management for severe refractory acidosis in patients with PA/MMA.
2026-01-17 | Heart and heart-liver transplantation in Amish patients with propionic acidemia.
Propionic acidemia (PA) is a genetic metabolic disorder caused by deficient activity of the enzyme propionyl-CoA carboxylase, resulting in accumulation of toxic metabolites during catabolism of odd-chain fatty acids and branched-chain amino acids. Most PA occurs in compound heterozygotes, typically presenting with metabolic acidosis and seizures in infancy. A milder phenotype of PA is prevalent in the Amish population due to a founder missense variant in PCCB (c.1606 A > G; p.Asn536Asp) and is frequently present as an isolated dilated cardiomyopathy in adolescence. Here we report our experience with three Amish patients with genetically confirmed PA and end-stage heart failure. While one patient underwent successful heart transplantation with no complications, another developed recurrent cardiogenic shock after transplant due to metabolic decompensation. Based on this experience, a subsequent patient was treated with combined heart/liver transplantation. These cases highlight unique challenges in managing patients with metabolic cardiomyopathies and emphasize the importance of a multidisciplinary approach to achieve the best possible outcomes.
2026-01-16 | Liver transplantation for propionic acidemia: Survival and metabolic outcomes.
Propionic acidemia (PA) is a severe metabolic disorder that leads to multiorgan damage despite comprehensive management. Liver transplantation (LT), particularly living donor liver transplantation, has been proposed as an effective treatment, but evidence from large-scale studies is limited. This retrospective study analyzed clinical outcomes of 39 children with PA who underwent LT at Shanghai Ren Ji Hospital between September 2017 and October 2023. The data included demographics, surgical details, biochemical/metabolic markers, and progression of symptoms. Patients were grouped based on the Diagnosis-to-Transplant Interval (<20 vs. ≥20 mo) for comparative analysis. Among 39 patients, 38 (97.4%) underwent living donor liver transplantation, and 1 received split LT. At 6 months after transplant, significant reductions were observed in propionylcarnitine/acetylcarnitine ratio (1.4 to 0.8, p=0.01), urinary methylcitrate (35.4 to 15.2, p=0.03), and 3-hydroxypropionic acid (198.8 to 6.8, p=0.02). Symptoms such as gross motor delay, metabolic acidosis, hyperammonemia, and feeding difficulties significantly improved (all p<0.001). The 5-year patient and graft survival rates were 97.4%. Short Diagnosis-to-Transplant Interval time (<20 mo) and long Diagnosis-to-Transplant Interval time (≥20 mo) also affected the results of specific PA clinical problems before and after transplantation. This single-center study on PA transplantation suggests that LT, especially living donor liver transplantation, effectively reduces metabolic waste, promotes metabolic stability, and enhances quality of life in pediatric patients with PA. LT represents an effective therapeutic option for patients with metabolic instability.
oligonucleotides
2026-04-24 | From N-of-1 to versatility in propionic acidemia: Antisense oligonucleotide-mediated skipping of a constitutive PCCA pseudoexon.
Propionic acidemia is a rare autosomal recessive disorder caused by mutations in the PCCA or PCCB gene, resulting in deficient propionyl-CoA carboxylase activity. We identified a unique homozygous deep-intronic PCCA variant, NM_000282.4:c.1285-1358C>G, in an individual with neonate-onset propionic acidemia. Fibroblasts from this individual expressed only PCCA mRNA containing an 84-bp pseudoexon, which is present at low levels in healthy controls, leading to the loss of PCCA and PCCB proteins and severely reduced propionyl-CoA carboxylase activity. Transfection of fibroblasts with chemically synthesized antisense oligonucleotides (ASOs) designed to skip the pseudoexon restored productive PCCA splicing, rescued PCCA protein expression, and markedly increased propionyl-CoA carboxylase activity above wild-type levels. The efficacy of the ASOs was further evaluated in fibroblasts from 7 additional individuals with propionic acidemia carrying mutations in PCCA or PCCB. ASO treatment successfully restored enzymatic activity, particularly in fibroblast lines, with residual activity exceeding 1% of normal. These findings suggest that ASO-mediated splicing correction targeting the 84-bp pseudoexon can restore mRNA, protein, and enzymatic function in individuals with deep intronic mutations, as well as in other individuals with propionic acidemia, indicating the feasibility of ASO therapy as a molecular treatment strategy for a subset of individuals with propionic acidemia.
2026-03-09 | Industry Insights: Early 2026 brings clinical progress, regulatory designations, and strategic partnerships in nucleic acid therapeutics
Across January and early February 2026, activity in the nucleic acid therapeutics field spanned early clinical readouts, regulatory designations, preclinical advances, and new strategic partnerships. ProQR reported initial Phase 1 data for its editing oligonucleotide AX-0810 in cholestatic diseases, while Providence Therapeutics supported the launch of a multi-site paediatric trial evaluating personalized mRNA cancer vaccines in Australia. Regulatory momentum continued, with the US FDA granting Fast Track designation to BioNTech’s mRNA immunotherapy BNT113 for HPV16-positive head and neck cancer, and Japan awarding Orphan Drug designation to Dyne’s antisense candidate DYNE-101 for myotonic dystrophy type 1. Preclinical studies highlighted mRNA and antisense approaches in infertility and metabolic disease, alongside new collaborations to expand access to individualized antisense therapies and advance mRNA treatment for propionic acidemia.
2023-12-13 | Regulating PCCA gene expression by modulation of pseudoexon splicing patterns to rescue enzyme activity in propionic acidemia
Pseudoexons are nonfunctional intronic sequences that can be activated by deep-intronic sequence variation. Activation increases pseudoexon inclusion in mRNA and interferes with normal gene expression. The PCCA c.1285-1416A>G variation activates a pseudoexon and causes the severe metabolic disorder propionic acidemia by deficiency of the propionyl-CoA carboxylase enzyme encoded by PCCA and PCCB. We characterized this pathogenic pseudoexon activation event in detail and identified hnRNP A1 to be important for normal repression. The PCCA c.1285-1416A>G variation disrupts an hnRNP A1-binding splicing silencer and simultaneously creates a splicing enhancer. We demonstrate that blocking this region of regulation with splice-switching antisense oligonucleotides restores normal splicing and rescues enzyme activity in patient fibroblasts and in a cellular model created by CRISPR gene editing. Interestingly, the PCCA pseudoexon offers an unexploited potential to upregulate gene expression because healthy tissues show relatively high inclusion levels. By blocking inclusion of the nonactivated wild-type pseudoexon, we can increase both PCCA and PCCB protein levels, which increases the activity of the heterododecameric enzyme. Surprisingly, we can increase enzyme activity from residual levels in not only patient fibroblasts harboring PCCA missense variants but also those harboring PCCB missense variants. This is a potential treatment strategy for propionic acidemia.
2023-07-05 | RegulatingPCCAgene expression by modulation of pseudoexon splicing patterns to rescue enzyme activity in propionic acidemia
Abstract Pseudoexons are nonfunctional intronic sequences that can be activated by deep intronic sequence variation. Activation increases pseudoexon inclusion in mRNA and interferes with normal gene expression. The PCCA c.1285-1416A>G variation activates a pseudoexon and causes the severe metabolic disorder, propionic acidemia, by deficiency of the propionyl-CoA carboxylase enzyme encoded by PCCA and PCCB . We characterized this pathogenic pseudoexon activation event in detail and identified hnRNP A1 to be important for normal repression. The PCCA c.1285-1416A>G variation disrupts an hnRNP A1-binding splicing silencer and simultaneously creates a splicing enhancer. We demonstrate that blocking this region of regulation with splice-switching antisense oligonucleotides restores normal splicing and rescues enzyme activity in patient fibroblasts and in a cellular model created by CRISPR gene editing. The PCCA pseudoexon can be exploited as a gene-regulatory switch, as healthy tissues show relatively high levels of inclusion. By blocking inclusion of the non-activated wild type pseudoexon, we increase both PCCA and PCCB protein levels, which increases the activity of the heterododecameric enzyme. Surprisingly, we can increase enzyme activity from residual levels not only in patient fibroblasts harboring PCCA missense variants, but also those harboring PCCB missense variants. This could be a potential treatment strategy for propionic acidemia.
2023-02-14 | Dysregulated Cell Homeostasis and miRNAs in Human iPSC-Derived Cardiomyocytes from a Propionic Acidemia Patient with Cardiomyopathy.
Propionic acidemia (PA) disorder shows major involvement of the heart, among other alterations. A significant number of PA patients develop cardiac complications, and available evidence suggests that this cardiac dysfunction is driven mainly by the accumulation of toxic metabolites. To contribute to the elucidation of the mechanistic basis underlying this dysfunction, we have successfully generated cardiomyocytes through the differentiation of induced pluripotent stem cells (iPSCs) from a PCCB patient and its isogenic control. In this human cellular model, we aimed to examine microRNAs (miRNAs) profiles and analyze several cellular pathways to determine miRNAs activity patterns associated with PA cardiac phenotypes. We have identified a series of upregulated cardiac-enriched miRNAs and alterations in some of their regulated signaling pathways, including an increase in the expression of cardiac damage markers and cardiac channels, an increase in oxidative stress, a decrease in mitochondrial respiration and autophagy; and lipid accumulation. Our findings indicate that miRNA activity patterns from PA iPSC-derived cardiomyocytes are biologically informative and advance the understanding of the molecular mechanisms of this rare disease, providing a basis for identifying new therapeutic targets for intervention strategies.
gene therapies
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.
2026-06-17 | Targeted gene editing of PCCA pseudoexon using CRISPR-Cas12a for potential therapy in propionic acidemia
Deep-intronic variants activating pseudoexons (PEs) are a common cause for monogenic diseases. Removal of the PE region predictably corrects the splicing defect, offering a potential therapeutic strategy. Previous studies, including our own, have identified an 84-bp PE in intron 14 of the gene PCCA that is included in the mature mRNA at relatively high basal levels across all tissues. When activated by the c.1285-1416A>G variant, this PE becomes fully included, ultimately causing the potentially lethal neurometabolic disorder propionic acidemia due to the deficiency of propionyl-CoA carboxylase (PCC) enzyme. In this study, we explored, through a CRISPR-Cas12-assisted non-homologous end joining (NHEJ)-mediated approach, whether PE removal or abrogation of the splice enhancer strengthened by the variant could efficiently restore normal transcript and functional PCCA protein. Both in wild-type hepatoma cells and in an edited cellular model homozygous for the activating variant, we show that the CRISPR-Cas12a approach increases PCC activity, with the highest values obtained with a guide RNA (gRNA) targeting the enhancer region in the PEs. The results provide proof-of-concept of its therapeutic potential for patients with PE activation and those with hypomorphic missense variants in whom residual activity levels may be effectively raised.
2026-03-07 | AAV-Mediated Dual-Gene Therapy Restores Metabolic Function in Mice with Propionic Acidemia
Abstract Background and Aims Propionic acidemia (PA) is a rare autosomal recessive disorder caused by mutations in PCCA or PCCB , which encode the two subunits of propionyl-CoA carboxylase (PCC). PCC deficiency causes toxic metabolite accumulation and multi-organ damage. Current management, including dietary restriction, pharmacological support, and liver transplantation, does not restore enzymatic activity. We developed a dual-gene adeno-associated virus (AAV) therapy that delivers both PCC subunits to treat both PA subtypes. Methods We generated a clinically relevant PCCA -R73W knock-in mouse model and administered AAV8 vectors encoding native human PCCA and PCCB under the control of a liver-specific thyroxine-binding globulin promoter (AAV8-TBG-h PCCA -P2A-h PCCB ). Metabolite levels and organ safety were longitudinally assessed. Results Dual-gene therapy produced dose-dependent reductions in plasma C3/C2 ratio, 3-hydroxypropionic acid, 2-methylcitric acid, and propionylglycine, and significantly outperformed single-gene ( PCCA -only) therapy. Neonatal facial-vein injection achieved metabolic correction comparable to or better than adult treatment. The longitudinal follow-up revealed sustained efficacy over a 16-week period, with no signs of hepatotoxicity or adverse effects. Conclusions Single-dose, dual-gene AAV therapy achieves sustained metabolic correction and demonstrates long-term safety in a clinically relevant PA model, supporting its translational potential for both type I and type II propionic acidemia.
2026-01-01 | P033: Integrating clinical data, biomarkers and in vivo propionate oxidation to inform genotype-based phenotype prediction in propionic acidemia
Introduction: Propionic acidemia (PA), a deficiency of propionyl-CoA carboxylase, is caused by biallelic pathogenic variants in PCCA or PCCB.The genotypic heterogeneity and compound heterozygosity make genotype-based phenotype severity predictions challenging, particularly when individuals do not harbor two loss-of-function (LOF) alleles.Improved understanding of the genotype-phenotype associations may help improve prognostication and guide selections of patients who could benefit from emerging liver-directed therapies.Methods: We are conducting a prospective natural history study of PA in the NIH Clinical Center (ClinicalTrials.govIdentifier: NCT02890342).Protocol visits were accomplished via outpatient visits or hospital admissions and included specialty evaluations, nutritional assessments, imaging studies, laboratory testing, biobanking of research.Cardiac, renal, hematological, hepatic, ophthalmologic, neurological and metabolic parameters were systematically evaluated.Patients underwent a 1-13 C-propionate oxidation breath test (POBT), a non-invasive whole-body measurement that largely reflects residual hepatic propionyl-CoA carboxylase activity, expressed as cumulative percent isotope dose metabolized at 120 min.Results: Fifty-nine individuals with PA were enrolled, including 52 evaluated in person and 7 virtually.Variants in PCCA were present in 20 individuals (34%) and in PCCB in 39 individuals (66%).The most frequent PCCB variant was c.1218_1228delinsTAGAGCACAGGA (p.Gly407fs), identified in 18/39 participants (46%).Seven individuals have undergone organ transplantation: five isolated liver transplants (median age 1.5 years; range 1-20), one isolated kidney transplant (age 42), and one combined liver-kidney transplant (age 21.5 years).Among non-transplanted participants, individuals harboring two LOF alleles had significantly lower propionate oxidation compared to those with other genotypes (p<0.001).This group also demonstrated lower full-scale IQ (p=0.006),lower composite Vineland scores (p=0.014),higher 3-hydroxypropionic acid levels (p=0.021), and higher C3 levels (p=0.028).In contrast, 2-methylcitric acid levels were not significantly different between groups (p=0.242).The PCCA missense variant c.782A>G (p.Glu261Gly) was associated with a severe clinical phenotype when present in trans with a LOF allele; two of three individuals harboring this variant underwent liver transplantation.In contrast, the PCCB missense variant c.683C>T (p.Pro228Leu), identified in two individuals, both of whom carried this variant in trans with the common LOF allele c.1218_1228delinsTAGAGCACAGGA (p.Gly407fs), correlated with a milder phenotype, higher propionate oxidation (mean POBT 120 min: 26.6%), and relatively lower metabolite levels (mean 3-hydroxypropionic acid 31.1
2025-03-06 | Novel CRISPR-Cas9 iPSC knockouts for PCCA and PCCB genes: advancing propionic acidemia research.
Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by mutations in the PCCA and PCCB genes, which encode subunits of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). This enzyme deficiency leads to the accumulation of toxic metabolites, resulting in severe metabolic dysfunction. To create ideal in vitro disease models of PA with isogenic controls and provide a robust platform for therapeutic research, we generated two induced pluripotent stem cell (iPSC) lines with knockout (KO) mutations in the PCCA and PCCB genes using CRISPR-Cas9 gene editing in a healthy control iPSC line. The KO iPS cells were successfully established and characterized, confirming the presence of frameshift insertions and deletions in each target gene, as well as the loss of the corresponding transcript, protein expression, and activity. Additionally, the generated iPSC lines exhibit hallmark characteristics of pluripotency, including the potential to differentiate into all three germ layers. Our PCCA and PCCB KO iPSC models provide a valuable tool for studying the molecular mechanisms underlying PA and hold potential for advancing new therapeutic approaches.
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2026-06-25 | Precision metabolic therapy for propionic acidemia.
Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by a deficiency of mitochondrial propionyl-CoA carboxylase, leading to the accumulation of propionyl-CoA and toxic metabolites that disrupt TCA cycle flux and ammonia detoxification. Propionyl-CoA is generated from gut microbiome-derived propionate, propiogenic amino acids, odd-chain fatty acids, and cholesterol side chains. Its accumulation produces downstream metabolites such as propionylcarnitine and methylcitrate and promotes histone propionylation. These alterations collectively contribute to mitochondrial dysfunction, oxidative stress, and multi-organ pathology. Current clinical management focuses on reducing propionyl-CoA burden through dietary restriction and supportive therapies, but long-term outcomes remain suboptimal due to poor tolerability and progressive complications. Although liver transplantation improves hepatic metabolism, it does not fully correct extrahepatic disease. Gene-based approaches, including mRNA-based enzyme replacement and viral vector-mediated gene delivery, show promise but face challenges related to delivery efficiency, durability of expression, and immune responses. Emerging small-molecule strategies aim to reprogram metabolism by restoring the balance between propionyl-CoA and acetyl-CoA while replenishing cellular CoA pools. Precision metabolic therapy may combine acetate supplementation and NRF2 activation to enhance acetyl-CoA production and mitochondrial resilience, while suppressing propionyl-CoA formation through ACSS3 inhibition and propiogenic amino acid restriction. In parallel, CoA availability may be increased through activation of PANK1-3, inhibition of PANK4, and supplementation with CoA precursor compounds. We propose that rational combination therapy targeting multiple nodes of short-chain fatty-acid metabolism and CoA homeostasis will provide a more effective strategy than single-agent approaches for correcting metabolic imbalance in PA.
2025-12-22 | When Metabolism Meets Immunity: Inborn Errors of Metabolism Mimicking Primary Immunodeficiencies—A Case Series
Several inborn errors of metabolism (IEMs) are known to affect immune function; the latter may arise from disruptions in metabolic pathways critical to immune cell development or from accumulation of toxic metabolites that impair immunity. This overlap can complicate diagnosis and management. We present seven patients with IEMs initially suspected of having inborn errors of immunity (IEIs) to highlight the phenotypic intersections between these disorders. All patients were referred for immunological evaluation due to recurrent infections, cytopenias, or abnormal immune profiles. Each was ultimately diagnosed with an IEM known to affect immune function. Results • Purine nucleoside phosphorylase deficiency: A 4-year-old female with CMV infection, seizures, and lymphopenia was diagnosed with this T cell defect associated with purine metabolism. Good clinical response with intravenous immunoglobulin, oral prednisolone, folic acid, vitamin B, and antiviral. • Propionic acidemia: Three patients presented with early-onset sepsis or viral infections. Immunologic findings included hypogammaglobulinemia, lymphopenia (particularly affecting B and natural killer cells), and neutropenia. Treated with carglumic acid, levocarnitine, protein-rich diet, and replacement immunoglobulin. • Transcobalamin II deficiency: Two patients had recurrent infections, cytopenias, and global lymphopenia. One showed hypogammaglobulinemia. Good response with intramuscular B12 vitamin and folic acid. • Thymidine phosphorylase deficiency: A 17-year-old male presented with ophthalmoparesis, severe abdominal pain, and angiographic images resembling vasculitis, with negative autoantibodies and poor response to immunosuppression. He died a few weeks after liver transplantation. Conclusion This series underscores the immunologic manifestations of IEMs, which can mimic IEIs and complicate diagnosis. Recognizing the bidirectional overlap is crucial: immune evaluation may uncover an underlying metabolic disorder, while persistent infections or immune alterations in IEMs warrant thorough immunological assessment. Immunologic interventions like immunoglobulins, antibiotic prophylaxis, vaccines, etc. may help to reduce the infectious burden in IEMs and improve quality of life. Timely diagnosis and comprehensive management are crucial for both groups of diseases.
2025-11-07 | Nanoscale conformational dynamics of human propionyl-CoA carboxylase.
Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme responsible for propionyl-CoA catabolism. Deficiencies in human PCC (hPCC) cause propionic acidemia, a severe metabolic disorder driven by toxic metabolite accumulation. Despite its therapeutic relevance, the structural basis of hPCC's catalytic function remains unresolved. Here, we present high-resolution cryo-EM structures of hPCC in four distinct states, unliganded, ADP-, AMPPNP-, and ATP-bound/substrate-bound, capturing the full trajectory of the biotin carboxyl carrier protein (BCCP) domain as it translocates between active sites. Our results reinforce the crucial role of nucleotide-gated B-lid subdomain in synchronizing catalysis through coupling with BCCP movement. Structural and biochemical analysis of 10 disease-associated variants reveals how mutations disrupt key domain interfaces and dynamic motions required for activity. These new insights define the mechanistic principles governing hPCC functions, establish a structural framework for understanding PCC-related disorders, and lay the groundwork for future efforts to engineer functional replacements or modulators for metabolic therapy.
2018-01-24 | Import of TAT-Conjugated Propionyl Coenzyme A Carboxylase Using Models of Propionic Acidemia
Propionic acidemia is caused by a deficiency of the enzyme propionyl coenzyme A carboxylase (PCC) located in the mitochondrial matrix. Cell-penetrating peptides, including transactivator of transcription (TAT), offer a potential to deliver a cargo into the mitochondrion. Here, we investigated the delivery of an α6β6 PCC enzyme into mitochondria using the HIV TAT peptide at several levels: into isolated mitochondria, in patient fibroblast cells, and in a mouse model. Results from Western blots and enzyme activity assays confirmed the import of TAT-PCC into mitochondria, as well as into patient fibroblasts, where the colocalization of imported TAT-PCC and mitochondria was also confirmed by confocal fluorescence microscopy. Furthermore, a single-dose intraperitoneal injection into PCC-deficient mice decreased the propionylcarnitine/acetylcarnitine (C3/C2) ratio toward the normal level. These results show that a cell-penetrating peptide can deliver active multimeric enzyme into mitochondria in vitro, in situ, and in vivo and push the size limit of intracellular delivery achieved so far. Our results are promising for other mitochondrion-specific deficiencies.
2016-11-17 | Molecular cloning of rat acss3 and characterization of mammalian propionyl-CoA synthetase in the liver mitochondrial matrix.
Among the three acyl-CoA synthetase short-chain family members (ACSS), ACSS3 is poorly characterized. To characterize ACSS3, we performed molecular cloning and protein expression of rat acss3 and determined its intracellular localization, tissue distribution, and substrate specificity. Transient expression of rat ACSS3 in HeLa cells resulted in a 10-fold increase of acetyl-CoA synthetase activity compared with that in control cells. The acss3 transcripts are expressed in a wide range of tissues, with the highest levels observed in liver tissue followed by kidney tissue. Subcellular fractionation using liver tissue showed that ACSS3 is localized into the mitochondrial matrix. Among the short-chain fatty acids examined, recombinant ACSS3, purified from Escherichia coli cells transformed with the plasmid containing rat acss3, preferentially utilized propionate with a KM value of 0.19 mM. Knockdown of acss3 in HepG2 cells resulted in a significant decrease of ACSS3 expression level and propionyl-CoA synthetase activity in cell lysates. Levels of ACSS3 in the liver and the activity of propionyl-CoA synthetase in the mitochondria were significantly increased by fasting. These results suggested that ACSS3 is a liver mitochondrial matrix enzyme with high affinity to propionic acid, and its expression level is upregulated under ketogenic conditions.
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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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