Journal of Inherited Metabolic Disease最新文献

Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inherited metabolic disorders affecting valine and isoleucine catabolism. Long-term therapy mainly involves dietary protein restriction. An amino acid mixture (AAM, medical food) free of the precursor amino acids is frequently used, especially when protein intake does not reach World Health Organization (WHO) recommendations. However, its clinical impact on disease control and patient outcomes remains unclear. Our study aimed to retrospectively review the dietary prescriptions in a cohort of vitamin B12-unresponsive MMA and PA patients and to analyze their impact on clinical and laboratory parameters. Clinical data, anthropometric measurements and dietary prescriptions were collected from the patients' medical and dietary files. We included 71 patients (38 MMA and 33 PA). Fifty-nine percent of the patients' dietary prescriptions did not reach the safe WHO-recommended daily total protein intake. Among these, 28% included AAM supplementation versus 62% in the group of patients that met the WHO recommendations (p < 0.001). AAM was associated with a decrease in mean plasma concentrations of isoleucine and valine. These plasma amino acid concentrations were corrected by isoleucine and valine supplementation; however, leucine/isoleucine and leucine/valine ratios remained elevated in comparison to patients without AAM. Nutritional and clinical scores were worsened by AAM supplementation. We found that MMA/PA patients receiving AAM tend to have altered plasma amino acid concentrations, raising concerns about potential long-term deleterious consequences of AAM. We recommend prioritizing natural protein intake over AAM when possible, and if not, to carefully monitor and moderately supplement valine and isoleucine to prevent deficiencies.

Inherited metabolic disorders (IMDs) encompass a diverse and expanding group of rare diseases caused by genetic disruptions mainly in metabolic enzymes and transporters. Clinical diagnosis of IMDs presents significant challenges due to phenotypic heterogeneity, nonspecific symptoms, and the limited scope of current targeted biochemical assays typically available. Recent advances in mass spectrometry-based untargeted metabolomics offer promising solutions to several of these challenges by simultaneous detection and relative quantification of thousands of metabolites, not relying on any prior hypotheses. With the expansion of genetic diagnostics via whole-exome and whole-genome sequencing, metabolic insights are often crucial for understanding the pathogenicity of genetic variants of unknown significance, often enabling a clear diagnosis for patients. This review details current applications of untargeted metabolomics in IMDs, including biomarker discovery and elucidation of previously unknown pathophysiological mechanisms. Successful examples of biomarker identification in well-studied IMDs, such as pyridoxine-dependent epilepsy and phenylketonuria, are highlighted to provide novel disease insights. Additionally, we address technical and interpretation challenges inherent to this methodology, particularly concerning metabolite identification, high-dimensional data complexity, and limited patient numbers. Emerging analytical technologies and data analysis approaches are highlighted that are poised to mitigate these challenges in the upcoming years. Finally, we provide an outlook on future directions, emphasizing the complementary roles of targeted and untargeted metabolomics and the prospects for the identification of new therapeutic targets as well as therapy monitoring for the clinical management of IMDs.

Our research aimed to model primary hyperoxaluria type 1 in vitro using a stem cell model and assess the potential of adenine base editors in correcting the most common pathogenic AGXT genetic variant, c.508G>A (Gly170Arg), which leads to oxalate accumulation due to alanine-glyoxylate aminotransferase mislocalization. Patient-derived fibroblasts were induced to pluripotent stem cells, genetically corrected with adenine base editing, and subsequently differentiated into hepatocyte-like cells in parallel with their non-corrected isogenic counterparts. Enzyme localization was assessed through immunocytochemistry and confocal microscopy. The key metabolites associated with the disease were analyzed using liquid chromatography-mass spectrometry to evaluate the metabolic phenotype. Finally, lipid nanoparticle formulations were designed and tested as an in vivo-applicable delivery method for base editors. All induced pluripotent stem cell lines successfully differentiated into hepatocyte-like cells and expressed essential hepatocyte markers, including ALB, HNF1A, and AGXT. Adenine base editor-mediated genetic correction of the pathogenic AGXT mutation restored enzyme localization into peroxisomes and diminished oxalate accumulation without significant off-target effects. Base editor mRNA and AGXT variant targeting single guide RNA encapsulated within lipid nanoparticles mediated gene correction in the hepatocyte-like cell model. Using an in vitro model of primary hyperoxaluria type 1, we showed that base editor-mediated genetic correction of the most common hyperoxaluria-causing variant corrects enzyme mislocalization from mitochondria to peroxisomes and improves metabolic function. These results propose gene correction as a potential therapeutic approach to hyperoxaluria.

X-linked adrenoleukodystrophy (ALD) is a genetic disorder with neurological and endocrine manifestations, including myelopathy and hypergonadotropic hypogonadism. Many patients experience sexual dysfunction but the underlying cause has not been clarified. The aim of this study was to assess the prevalence of sexual dysfunction and its relationship with biochemical hypergonadotropic hypogonadism (i.e., low testosterone and high luteinizing hormone [LH] levels) and/or myelopathy. Male ALD patients from “the Dutch ALD cohort” at the Amsterdam University Medical Centers were questioned regarding sexual functioning, and underwent neurological examination to assess myelopathy. Testosterone, LH, and follicle-stimulating hormone (FSH) concentrations were analyzed from fasting blood samples. The prevalence of biochemical hypogonadism in the cohort was 4/36 patients (11%), of whom 3 were diagnosed prior to the initiation of this study. Eighteen out of 33 patients (55%), of whom clinical data were collected, experienced sexual dysfunction. Of these patients, 10 (55%) were biochemically eugonadal, 7 (39%) had biochemical subclinical hypogonadism, and 1 had biochemical hypogonadism. Neurological function differed significantly between patients with and without sexual dysfunction, with more severe myelopathy in patients with sexual dysfunction (Expanded Disability Status Scale: 4.8 [IQR 3–6] vs. 0.0 [IQR 0–2]; p < 0.001). In conclusion, we showed that half of all adult male ALD patients experienced sexual dysfunction and the majority of these patients had normal testosterone levels. Neurological impairment appears to play a more important role in these complaints than previously appreciated. We recommend discussing sexual dysfunction regularly, in order to start early and adequate treatment.

P. S. Kishnani, C. Rehder, K. Ozono, et al., “Revisiting the Genetics of Hypophosphatasia,” Journal of Inherited Metabolic Disease 48, no. 6 (2025): e70083, https://doi.org/10.1002/jimd.70083.

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North Sea-Progressive Myoclonus Epilepsy (NS-PME) is a progressive neurological disorder, initially only associated with the homozygous GOSR2 founder mutation (c.430G>T; p.Gly144Trp). Clinical symptoms include untreatable early-onset ataxia, cortical myoclonus and epilepsy. Recently, the spectrum of GOSR2 mutations and associated phenotypic variability has expanded. To improve care and to facilitate genotype–phenotype predictions for NS-PME patients, we systematically reviewed all reported GOSR2 mutations, clinical phenotypes, and pathophysiological findings. A narrative review literature search was conducted in PubMed, EMBASE, and Web of Science (1985—August 2024) using the keywords “GOSR2”, “GS27 protein”, “Bos1”, and “Membrin”. Only studies in English and specifically studies on GOSR2 function, pathogenic variants, clinical manifestations, and potential therapies were included. A total of 42 patients with 11 different GOSR2 mutations were identified. Three main phenotypes were observed: progressive myoclonus ataxia/epilepsy (PMA/PME), congenital muscular dystrophy, and hearing loss. Orthopedic abnormalities were frequently reported. Intercurrent infections or fever often led to a worsening of symptoms. Glycosylation defects were reported in several compound heterozygous GOSR2 variants. Molecularly, GOSR2 mutations result in (partial) loss of function of the GOSR2/SNARE complex, with mutation severity and the involvement of specific isoforms contributing to phenotypic variability. GOSR2 mutations lead to progressive neurological disorders, primarily characterized by myoclonus ataxia/epilepsy, muscular dystrophy, and hearing loss. The genotypic background of NS-PME has expanded with pathogenic biallelic GOSR2 variants beyond the original homozygous founder mutation. Understanding the clinical spectrum and molecular mechanisms of GOSR2-related diseases may facilitate more targeted treatment strategies as well as better-informed phenotype predictions.