Journal of Inherited Metabolic Disease最新文献

Cobalamin (vitamin B12) is an essential cofactor for two human enzymes, methionine synthase and methylmalonyl-CoA mutase. Inborn errors of cobalamin metabolism (IECMs) are inherited genetic defects resulting in improper transport, modification, or utilization of cobalamin and include inherited methylmalonic acidurias, a group of IECMs most frequently caused by a defect in the methylmalonyl-CoA mutase enzyme. Here, we performed genome-scale modeling of IECMs to gain insight into their metabolic perturbations. First, we simulated deficiencies in 11 IECM-related genes and demonstrated that they cluster based on impaired metabolic pathways. Next, we leveraged RNA sequencing data from fibroblasts of 202 individuals with methylmalonic aciduria and 19 unaffected controls to construct and interrogate personalized metabolic models. Finally, we analyzed fluxes differing between patients depending on reported symptom presentation. Our findings reveal that (i) metabolic pathways including fatty acid metabolism and heme biosynthesis have reduced flux in IECMs, (ii) in personalized simulations, succinate and fumarate production and heme biosynthesis are impaired, especially in methylmalonyl-CoA mutase deficiency, (iii) one-carbon metabolism reactions such as serine hydroxymethyltransferase and folylglutamate synthase have reduced flux in all individuals with methylmalonic aciduria, and (iv) specific metabolic pathways are up- or down-regulated according to symptoms, including failure to thrive and hematological abnormalities, and treatments, such as antibiotics and protein restriction. Overall, our study delineates metabolic pathways perturbed in IECMs. In future applications, our modeling framework could be applied to other rare genetic diseases or used to predict personalized therapeutic or dietary interventions.

Pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency is an ultrarare inherited neurometabolic disease, characterized by primarily neonatal-onset B6-responsive epileptic encephalopathies. Treatment often requires sustainable access to high-quality pyridoxal-5′-phosphate (PLP, i.e., active vitamin B6), although some patients (also) respond to pyridoxine (PN). While PN is authorized as a medicinal product, PLP is not, and this forces reliance on lesser-regulated food supplements, which risks dosing inaccuracies. This systematic review evaluates the effectiveness and safety of PLP in PNPO deficiency (PROSPERO, CRD42024542199). A systematic search was conducted in PubMed, Embase, and ClinicalTrials.gov, with risk of bias assessed and observational evidence summarized using a narrative synthesis approach. A total of 30 studies were included reporting on 49 patients treated with PLP. Clinical seizure responsiveness following PLP therapy was observed in the majority of patients (n = 38, 77.6%) and PLP treatment significantly improved survival (p < 0.001) compared with untreated siblings with a similar phenotype. The majority of PLP-responsive patients responded exclusively to PLP, with PN being attempted but ineffective in most of them (n = 30/33, 90.9%) Liver toxicity was the most frequently observed adverse event (n = 10, 20.4%) and although the underlying pathophysiological mechanism remains unclear, it may be associated with high-dose PLP. Therefore, regular liver disease screening is recommended during PLP therapy. This means that PLP remains the only effective therapy for achieving and maintaining seizure control in the majority of PNPO deficient patients, but the therapeutic window for optimal management is narrow. Thus, it is essential to ensure patient access to high-quality and appropriate forms of PLP.

Patients with metachromatic leukodystrophy (MLD) show variable motor and cognitive decline. The ARSA variants c.256C>T, p.(Arg86Trp), c.257G>A, p.(Arg86Gln) and c.542T>G, p.(Ile181Ser) are associated with predominantly cognitive decline. This multinational study analyzed MLD onset type, presenting signs/symptoms, cognitive function, gross motor function, central motor tract involvement, MRI severity score, peripheral neuropathy, and survival of 47 patients (three homozygous for c.256C>T and five, twelve and 27 compound heterozygous for c.256C>T, c.257G>A, or c.542T>G and another ARSA variant, respectively). Eleven underwent hematopoietic stem cell transplantation (HSCT). Onset was late-juvenile (46.8%) or adult (44.7%) with predominantly cognitive decline (n = 40/41 symptomatic patients). At diagnosis, untreated patients typically retained independent walking (100%), sparing of central motor tracts (87.5%), and absence of demyelinating neuropathy (95.5%), which persisted in follow-up for most (76.5%, 71.4%, and 64.7%, respectively). Early-juvenile onset and rapid motor decline occurred only in patients compound heterozygous for c.256C>T and a severe second variant (n = 4), showing central motor tract involvement at diagnosis. One untreated and one treated patient died of disease progression, and another from HSCT complications. All other treated patients retained independent walking, and four of five tested normal cognitive function. Median MRI severity score remained lower in treated (13) than untreated patients (25). The phenotype of c.256C>T carriers depends on the severity of the second ARSA variant. Patients harboring c.257G>A or c.542T>G show late-juvenile or adult onset with cognitive decline and preserved motor function, usually associated with sparing of central motor tracts. In these patients, cognitive function and MRI severity score should be preferred treatment outcomes.

Extensive studies have examined the clinical manifestations, pathogenic mechanisms, and genetic variations of phenylketonuria (PKU) across different populations, resulting in a substantial collection of molecular genetic data on the phenylalanine hydroxylase (PAH) gene and its variants. However, many genotypes are associated with a range of clinical phenotypes, as well as variable responsiveness to sapropterin, presenting ongoing challenges for effective treatment. To address this, we enhanced the PAH activity landscapes method by incorporating high-throughput techniques, including automated pipetting, integrated data processing via Gaussian modeling of 3D surfaces, and bioinformatics analyses with robust quality control. Using PAH activity landscapes, we visualized PAH enzymatic function across 99 common PAH genotypes under varying metabolic and therapeutic conditions. This deep functional phenotyping approach enabled us to identify distinct genotype subpopulations by using consensus clustering, correlate them with clinical phenotypes, and propose subpopulation-specific treatment protocols. Our findings suggest that clinical phenotypes can be predicted and treatment regimens can be adjusted based on residual PAH function profiles. To further support personalized treatment strategies, we revised our publicly accessible PAH genotype & activity landscapes database to share the latest insights into PAH function and patient phenotypes—namely residual enzyme activity and responsiveness to sapropterin as conveyed by two alleles. This resource underscores the translational significance of functional research in PKU and offers a practical tool to support personalized treatment in clinical settings.

Long-chain fatty acid oxidation disorders are characterized by rhabdomyolysis, often provoked by physical exercise. For the newborn screening (NBS) cohort, it remains uncertain to what extent they will develop the myopathic phenotype. This study assesses physiological responses to exercise, muscle symptoms, and activity levels in 14 adolescent lcFAOD patients (VLCADD (n = 8), LCHADD (n = 4), CPT2D (n = 1) and LCKATD (n = 1); ages 9.9–17.8 years). Analyses of incremental and prolonged cardiopulmonary exercise tests, a symptom-based questionnaire, and the Short Questionnaire to Assess Health-enhancing physical activity were performed. The results revealed a decreased ventilatory anaerobic threshold compared to control data (z-score − 0.5 (0.8) [median (interquartile range (IQR))], p = 0.001) and, on average, a decreased relative peak oxygen uptake (z-score − 1.3 (2.8), p = 0.005) and relative peak work rate (z-score − 0.7 (1.3), p = 0.03). There were no adverse events during and following prolonged exercise under well-fed circumstances (based on symptoms and post-exercise creatine kinase). The symptom-based questionnaire revealed that the presence of provoking factors (e.g., infection, inadequate intake) increased the risk of rhabdomyolysis during/after exercise. Screening (n = 11) and symptomatically (n = 3) diagnosed patients showed normal levels of physical activity (medians: 3.5 h per week) compared to their healthy peers (3.2 h), despite debilitating muscle pain in 46% of the by screening and all of the symptomatically diagnosed patients. In conclusion, patients with seemingly normal exercise patterns reported debilitating muscle symptoms and rhabdomyolysis, especially when additional provoking factors were present. Exercise tests may provide a valuable tool to monitor and guide exercise potential in these new NBS cohorts.

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disease. The most commonly affected organs are the spleen, the liver, and the lungs. Pulmonary involvement resembles interstitial lung disease and often leads to decreased diffusion capacity of the lungs for carbon monoxide (DLCO). An emerging technique in pulmonary research is the analysis of exhaled breath. The aim of this study was to investigate potential markers of pulmonary involvement in the exhaled breath of adult chronic visceral ASMD patients and to quantify findings on high-resolution computed tomography (HRCT) of the lungs in order to be able to correlate HRCT findings with (the potential) markers for pulmonary involvement. Fifteen adult, chronic visceral ASMD patients and 34 age-, sex-, and smoking habit-matched healthy controls were recruited and provided two different types of exhaled breath samples: exhaled air and exhaled condensate. Additionally, pulmonary function testing was performed for both patients and healthy controls, and HRCT of the lungs and biochemical markers were available for patients. Exhaled breath samples were analyzed using gas and liquid chromatography-mass spectrometry (GC–MS and LC–MS respectively). Fifteen compounds of interest were identified based on significant differences between ASMD patients and healthy controls, of which the most promising were 2-hydroperoxyhexane, 6-heptyn-2-one, and 4-pentenyl acetate. Other compounds have been described in the context of systemic sclerosis (i.e., acetophenone) or lung cancer (i.e., benzaldehyde and dodecane). Some markers were associated with the pathophysiological process of lipid peroxidation (i.e., decane, dodecane and 2-methylnonane). SPLSDA and AUROCC analyses showed that the model was better able to distinguish the patients with pulmonary involvement from their matched controls than all patients from all controls. Lastly, a quantitative HRCT score was performed and correlated with patients' DLCO (R = −0.74, p = 0.006). The most promising markers based on our analyses (i.e., 2-hydroperoxyhexane, 6-heptyn-2-one and 4-pentenyl acetate) have not been described in previous studies in the pulmonary field and might be ASMD-specific.

Arginase 1 deficiency (ARG1-D) is an autosomal recessive urea cycle disorder characterised by chronic hyperargininaemia, progressive spasticity, loss of mobility, and cognitive dysfunction. Standard of care (SOC), based on dietary protein restriction, rarely prevents progression. Pegzilarginase, a recombinant human enzyme, is the first approved disease-modifying therapy. We report outcomes from Study 102A (n = 14; up to 5 years) and the PEACE long-term extension (LTE) (n = 31; up to 3 years). Weekly pegzilarginase was administered with SOC. Outcomes included functional mobility (2-/6-minute walk tests [2MWT/6MWT], Gross Motor Function Measure [GMFM] D/E), spasticity (Modified Ashworth Scale [MAS]), plasma arginine, guanidino compounds, and safety. In PEACE, LTE arms were named according to initial 24-week double-blind treatment: placebo–pegzilarginase or pegzilarginase–pegzilarginase. Of 39 evaluable participants, 37 (95%) met composite response or achieved maximum score in ≥ 1 motor function domain. In 102A, mean 6MWT improved to 68.2 m (+19%; n = 12); GMFM-D/E increased by 2.7/3.7. In PEACE (pegzilarginase–pegzilarginase; placebo–pegzilarginase), 2MWT improved to 16.5 m (+25%; n = 6) and 13.5 m (+16%; n = 2); GMFM-D/E improved by 4.3/6.0 (n = 6) and 5.3/11.3 (n = 3). Spasticity improved in 21/25 (84%), with 12 reaching MAS 0 (no spasticity). Pegzilarginase sustained plasma arginine control: in 102A, means were 118 μmol/L at Week 192 (n = 9); in PEACE, < 115 μmol/L through Week 96 (n = 11). Guanidinoacetic acid normalised; N-acetylarginine approached normal; argininic acid and α-keto-δ-guanidinovaleric acid declined by > 50%. Most adverse events were mild/moderate; no treatment-related discontinuations or persistent antibodies occurred. Pegzilarginase produced sustained improvements in mobility, spasticity and biochemical control, supporting early intervention, long-term use and disease modification in ARG1-D.

Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre-molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA-based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.