プロピオン酸血症

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.

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.

Drug development in rare metabolic diseases is frequently limited by the lack of validated clinical trial endpoints, particularly for chronic disease modification. Propionic acidemia (PA) is an intoxication-type inherited metabolic disorder with significant morbidity and mortality that begins in early life, for which there are no approved disease-modifying therapies. While regulatory pathways such as accelerated approval permit the use of surrogate endpoints that are reasonably likely to predict clinical benefit, their acceptance requires strong biological rationale and evidence linking biomarker change to meaningful clinical outcomes. This review builds on prior work describing candidate biomarkers in PA by critically evaluating their suitability for use as surrogate- or response endpoints. We assess biomarkers derived from disrupted propionate metabolism, including methylcitric acid, propionylcarnitine, ammonia, and 13C-propionate oxidation, as well as biomarkers reflecting secondary mitochondrial dysfunction such as fibroblast growth factor 21. For each biomarker, we examine biological plausibility, empirical and clinical evidence, durability of response, and limitations relevant to regulatory decision making. Although several biomarkers are routinely used in clinical practice, most lack sufficient specificity, stability, or demonstrated linkage to clinically meaningful outcomes to support use as surrogate endpoints for chronic disease modification. Among those reviewed, fibroblast growth factor 21 and 13C-propionate oxidation show the strongest potential as response biomarkers within defined contexts of use, particularly for therapies that restore or augment enzymatic activity. However, substantial gaps remain, including prospective validation, standardized measurement, and direct correlation with clinical outcomes. This review outlines a framework for evaluating biomarker readiness in PA and defines the evidence required to advance selected biomarkers toward surrogate endpoint qualification for future clinical trials.

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.

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.