Journal of Inherited Metabolic Disease最新文献

McNutt, M., Rutsch, F., Russo, R.S., Gasperini, S., Batzios, S., Teles, E.L., Brassier, A., Ganesh, J., Schulze, A., Enns, G.M., Rudebeck, M., “Long-Term Efficacy and Tolerability of Pegzilarginase in Arginase 1 Deficiency: Results of Two International Multicentre Open-Label Extension Studies.” Journal of Inherited Metabolic Disease 48, no. 4 (2025): e70066. https://doi.org/10.1002/jimd.70066.

In the Abstract section of this article, the wording incorrectly stated that 6MWT and 2MWT “improved to” certain distances. The correct description should read “improved by,” as the values represent changes from baseline rather than final absolute distances. Similarly, in the Results section, walk test distances were changes from baseline, that is improvements, not final absolute distances. These wording changes do not alter the study's conclusions.

We apologize for this error.

Molybdenum cofactor deficiency (MoCD) is a rare differential diagnosis of neonatal hypoxic ischemic encephalopathy (HIE) with considerable variation in presentation and treatment outcomes. The temporospatial evolution of brain MRI appearances has not been well described. We systematically evaluated 35 MRI brain scans of 13 patients with neonatal MoCD (7 type A, 6 type B) to characterize brain abnormalities arising from exposure to toxicity related to sulfite accumulation and to evaluate changes in response to cPMP treatment in 6 children with MoCD type A. All cases showed evidence of chronic toxicity with developmental disruption. We identified a disease-specific pattern of acute and chronic brain injury, distinct from HIE. White matter edema, as the earliest sign of sulfite-related toxicity, indicates a reversible disease stage. The presence of restricted diffusion in the context of MoCD signifies irreversible brain injury and a poor neurological prognosis, irrespective of subsequent biochemical correction upon cPMP treatment. This is the largest neuroimaging study of children with MoCD and the first longitudinal study to examine MR imaging changes in MoCD type A under cPMP substitution. Neuroimaging can identify diagnostic and prognostic features with relevance for treatment decisions and for the evaluation of the effectiveness of treatment attempts.

Inherited metabolic disorders (IMD) can disrupt brain development and functioning, leading to cognitive and behavioral abnormalities. This systematic review aims to provide a comprehensive synthesis of the evidence regarding neurocognitive impairments in intoxication IMD due to the accumulation of small molecule disorders and energy-related IMD. A search was conducted in the PubMed database until August 2024, using the term “cognition” and up to 421 energy-related IMD and 196 intoxication IMD. Reviews, animal models, studies with non-standardized measures, and studies that focused on complex molecule disorders, small molecule deficiencies, and phenylketonuria were excluded. In total, 163 studies were included in the final analysis. The cognitive domains assessed were executive functions, attention, processing speed, language, speech, visual performance, fine motor dexterity, memory, behavioral and emotional regulation, and social cognition. Most available evidence focused on intoxication IMD (83%), which exhibited better global cognitive functioning than energy defects. The cognitive domains most frequently reported as impaired were fine motor dexterity (80.9%), behavioral and emotional regulation (80%), executive functions (73.3%), attention (72.4%), and social cognition (65.6%). After applying the chi-square test with a 95% confidence level, no statistically significant differences were found between intoxication and energy-related IMD. However, language impairments were slightly more pronounced in intoxication disorders, while visuospatial deficits were more common in energy disorders. Individuals with IMD are at a higher risk of neurodevelopmental disorders, which can persist despite early detection and treatment. Although the number of cognitive studies has increased in recent years, further research with standardized measures is necessary to understand the underlying pathophysiology of neurocognitive impairments.

Many inborn errors of metabolism affect pathways involved in the synthesis of a metabolite that has an important biochemical or physiological function, and adverse effects of the disorder can be attributed to the lack of this metabolite. Thus, there is the opportunity for treatment by ‘product replacement’. One of the disorders in the pathways for the synthesis of bile acids from cholesterol, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, causes cholestatic liver disease in infancy that can be treated very effectively with chenodeoxycholic acid (CDCA) and/or cholic acid (CA). There are several other enzyme deficiencies that can cause liver disease in infancy that improve with CDCA or CA or both (alongside a reduction of abnormal bile acids or alcohols); however, individuals with the same gene variant(s) may remain asymptomatic or have transient liver dysfunction that resolves spontaneously. In some disorders, the more usual presentation is with neurological disease later in childhood or in adolescence or adult life, for example, cerebrotendinous xanthomatosis (CTX), α-methylacyl-CoA racemase deficiency, and oxysterol 7α-hydroxylase deficiency. Treatment with CDCA has been dramatically effective in the neurological disease of CTX. In the disorders of peroxisome biogenesis, liver disease is a part of the clinical picture although neurological symptoms tend to be predominant. Treatment with CDCA and CA (or CA alone) leads to a reduction in the levels of C27 bile acids. Some trials suggest this treatment leads to significant improvement in clinical status and liver function tests; others do not. Defects in individual peroxisomal enzymes and transporters vary in their clinical presentations. Treatment of acyl-CoA oxidase 2 deficiency with ursodeoxycholic acid is discussed.

mRNA encapsulated in lipid nanoparticles (LNPs) provides a dual revolution in the field of gene therapy. mRNA brings fleeting efficacy and the possibility to adjust the therapy to clinical needs. LNP, as a non-viral vehicle with flexible organ-targeting, overcomes most immune complications of viral gene therapy. mRNA-LNP has rapidly progressed from preventive medicine and vaccine applications to therapeutic use, especially in inherited metabolic diseases (IMDs). Given their natural tropism for liver uptake, this platform has been utilised successfully in numerous preclinical programmes. Early phase clinical trials are recruiting to assess safety and efficacy in liver IMDs. Here, we provide the latest update on mRNA and LNP technologies, preclinical studies and clinical trials targeting IMDs, safety considerations with a spotlight on infusion-related reactions and safety modelling. We discuss the future directions of therapeutic mRNA-LNP in IMDs and the right clinical use of this adjustable therapy, still to be defined. The versatility of this technology is appealing, with multiple clinical applications as bridge, long-term cure, rescue, or adjuvant therapy. mRNA-LNP for gene editing/insertion is an alternative approach for one-off cure. Translating various successful preclinical programmes in patients remains an unsolved limitation. mRNA-LNP can be tuned according to the patient's needs and is the next step in personalised medicine and individualised gene therapy.

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.