プロピオン酸血症

OBJECTIVE: Artificial intelligence (AI)-based large language models (LLMs) are increasingly used to support nutrition-related decision-making; however, their ability to generate clinically appropriate dietary plans for inherited protein metabolism disorders remains largely unexplored. This study aimed to perform an exploratory simulation-based benchmarking analysis of AI-generated dietary plans for phenylketonuria (PKU), maple syrup urine disease (MSUD), and propionic acidemia (PPA) using disease-specific metabolic nutrition guidelines. METHODS: Standardized pediatric case scenarios were developed for PKU, MSUD, and PPA. Using identical English-language prompts, ChatGPT-5.3 Pro and Gemini 3 Pro Advanced each generated 3-day dietary plans. Nutrient composition was analyzed using the BeBiS Nutrition Information System and evaluated against Dietary Reference Intakes (DRIs). Disease-specific nutritional targets, including amino acid intake, protein distribution, and energy provision, were benchmarked against recommendations from Genetic Metabolic Dietitians International (GMDI). Nutritional characteristics of the dietary plans generated by the two AI models were compared using exploratory statistical analyses. RESULTS: Both LLMs generated structured dietary plans with generally acceptable overall nutritional characteristics; however, clinically relevant deviations from disease-specific nutritional targets were identified across all three disorders. In the PKU case, both models achieved the recommended phenylalanine range, but neither simultaneously met protein and tyrosine recommendations. In the MSUD case, differences were primarily related to energy provision and branched-chain amino acid targets, while in the PPA case neither model achieved the recommended balance between intact protein and total protein. These findings demonstrated that conventional measures of nutritional adequacy alone were insufficient to determine the clinical appropriateness of AI-generated dietary plans for inherited protein metabolism disorders. CONCLUSION: General-purpose LLMs can generate structured dietary plans for inherited protein metabolism disorders; however, disease-specific metabolic targets are not consistently achieved. Evaluation of AI-generated dietary plans should therefore extend beyond conventional nutritional assessment and incorporate disease-specific benchmarking against established metabolic nutrition guidelines. This study provides a disease-specific benchmarking framework for evaluating AI-generated dietary plans in inherited protein metabolism disorders.

OBJECTIVES: The coexistence of multisystemic involvement in a young adult raises the need to consider rare metabolic and mitochondrial disorders. We report a case of late-onset propionic acidemia (PPA) that may have contributed to unmasking Leber hereditary optic neuropathy (LHON), an extremely infrequent association. CASE PRESENTATION: A 43-year-old woman presented with acute biventricular heart failure following a viral infection. Evaluation revealed severe dilated cardiomyopathy, newly diagnosed type 2 diabetes mellitus, and bilateral sensorineural hearing loss. Genetic testing for cardiomyopathy was unremarkable. Two months later, she developed sudden bilateral blindness due to optic neuropathy. Extended genetic analysis identified a pathogenic RDH12 variant consistent with LHON and two POLG variants. Progressive renal dysfunction and long QTc interval prompted metabolic investigation. Urine organic acids showed marked accumulation of propionate-related metabolites, and plasma acylcarnitines revealed elevated C3 and low free carnitine, confirming late-onset PPA. The pattern of cardiac dysfunction, renal impairment, and hearing loss was consistent with chronic multisystem toxicity of PPA. CONCLUSIONS: In this patient, mitochondrial dysfunction from PPA may have precipitated the clinical expression of LHON, a condition with incomplete penetrance. This exceptional coexistence highlights that rare diseases may overlap and that unexplained multisystem findings warrant comprehensive metabolic and genetic evaluation.

Propionic and methylmalonic acidemias are inborn errors of metabolism in which chronic kidney disease is a well-recognized long-term complication. The early detection of kidney involvement is essential, given that renal tubular dysfunction may develop and persist despite appropriate treatment. However, conventional renal biomarkers usually become altered only after renal impairment has become advanced, limiting their usefulness for identifying early renal damage. In the present study, we evaluated renal function in patients with propionic and methylmalonic acidemias at diagnosis and throughout clinical follow-up. We also evaluated the performance of β2-microglobulin (β2M) as an early biomarker of tubular injury in comparison with conventional markers of kidney function and investigated its correlation with the pro-inflammatory cytokine interleukin-1β (IL-1β). Plasma samples from 31 patients were analyzed and categorized into three groups according to follow-up duration (diagnosis, follow-up until 2 years, and follow-up after 2 years) and compared with healthy age-matched controls. β2M levels were significantly elevated at diagnosis compared with controls and increased progressively during follow-up. Among the conventional markers, creatinine and estimated glomerular filtration rate became significantly altered only during long-term follow-up, while uric acid levels increased progressively throughout the clinical follow-up. β2M was positively correlated with urea, uric acid, and interleukin-1β, suggesting an association between tubular dysfunction, renal impairment and inflammation. These findings demonstrate that β2M becomes altered earlier than conventional renal biomarkers, supporting its potential as a sensitive biomarker of early tubular injury and renal involvement. Moreover, its association with interleukin-1β suggests that β2M may also reflect inflammatory processes involved in the pathophysiology of tubular renal dysfunction in patients with propionic and methylmalonic acidemias.

Histone propionylation-the transfer of a three-carbon propionyl group from propionyl-CoA to lysine residues-is an emerging post-translational modification (PTM) with potential effects on gene expression. Interest in this PTM has grown because propionyl-CoA is at the interface between valine, isoleucine, methionine, and threonine catabolism, odd-chain fatty acid oxidation, gut-derived propionate assimilation, and anaplerotic entry into the tricarboxylic acid cycle. An informative context for studying the influence of disturbed propionyl-CoA metabolism on chromatin state and phenotype is propionic acidemia (PA), where loss-of-function mutations in genes coding propionyl-CoA carboxylase (PCC) lead to the accumulation of propiogenic substrates and propionyl-CoA. At least some of the clinical manifestations of PA (cardiomyopathy, arrhythmia, and neurological injury) may relate to altered histone propionylation, and a challenge is to distinguish these responses from metabolic toxicity. To that end, mouse models of PA are promising tools for connecting molecular-level histone changes to systems-level phenotypes. In this review, we describe recent advances in propionyl-CoA biology in the context of histone modifications and gene regulation. We present milestone studies that identified histone PTMs and described their association with phenotype. We also highlight emerging questions related to propionyl-CoA handling, its compartmentalization, and tissue specificity of actions, and discuss the relative contribution of histone propionylation versus other forms of acylation and broader metabolic stress. On balance, the literature supports a model in which propionyl-CoA exerts regulatory actions on chromatin state, but how this might be targeted therapeutically in PA and the implications for other metabolic disturbances remain important areas for further investigation.

Mitochondrial mechanisms are increasingly implicated in complex neurological conditions, including Autism Spectrum Disorder (ASD). Propionic acid (PPA) is widely used to study mitochondrial dysfunction in preclinical models of ASD. However, the molecular mechanisms that drive PPA-induced neurotoxicity are unresolved. Here, we examined mitochondrial remodeling under PPA-induced stress in neuroblastoma SH-SY5Y cells. PPA systemically altered the transcriptional regulation of mitochondrial dynamics and disrupted canonical proteins involved in mitochondrial fusion (L-OPA1, MFN2), fission (DRP1) and quality control (LC3-II). Confocal microscopy revealed an upregulation of both fission and fusion events and impairments to mitochondrial integrity, connectivity and turnover. Live-cell respirometry demonstrated consequent deficits in both oxidative and glycolytic energy production, while respiratory chain electron flow assays illustrated a shift in TCA cycle flux driven by a remodeling of mitochondrial substrate utilization. This work describes a molecular signature of metabolic stress in the SH-SY5Y system, providing novel insights into the mechanisms and manifestations of PPA-induced neurotoxicity.