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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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.
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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.
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