Metabolic and muscle-derived serum biomarkers define CHCHD10-linked late-onset spinal muscular atrophy
Metabolic and muscle-derived serum biomarkers define CHCHD10-linked late-onset spinal muscular atrophy
ABSTRACT ObjectiveTo characterize serum biomarkers in mitochondrial CHCHD10-linked spinal muscular atrophy Jokela type (SMAJ) for disease monitoring and for understanding of pathogenic mechanisms. MethodsWe collected serum samples from a cohort of 49 SMAJ patients, all carriers of the heterozygous c.197G>T p.G66V variant in CHCHD10. As controls, we used age- and sex-matched serum samples obtained from Helsinki Biobank. Neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were measured with Single molecule array (Simoa), and fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) with enzyme-linked immunosorbent assay. For nontargeted serum metabolite profiling, samples were analyzed with liquid chromatography–high resolution mass spectrometry. Disease severity was evaluated retrospectively by calculating a symptom-based score. ResultsAxon degeneration marker NfL was unexpectedly not altered in the serum of SMAJ patients, whereas astrocytic activation marker GFAP was slightly decreased. Creatine kinase was elevated in most patients, in particular males. We identified six metabolites that were significantly altered in SMAJ patients’ serum compared to controls: increased creatine and pyruvate, and decreased creatinine, taurine, N-acetyl-carnosine and succinate. Creatine correlated with disease severity. Altered pyruvate and succinate indicated a metabolic response to mitochondrial dysfunction, however, lactate or mitochondrial myopathy markers FGF-21 or GDF-15 were not changed. ConclusionsBiomarkers of muscle mass and damage are altered in SMAJ serum, indicating a role for skeletal muscle in disease pathogenesis in addition to neurogenic damage. Despite the minimal mitochondrial pathology in skeletal muscle, signs of a metabolic shift can be detected in the serum of SMAJ patients.
Palu Edouard、Kvist Jouni、Tyynismaa Henna、Zetterberg Henrik、Auranen Mari、Lehtonen Marko、Koskivuori Johanna、Harjuhaahto Sandra、Ylikallio Emil、J?rvilehto Julius、Saukkonen Anna Maija、Jokela Manu
Clinical Neurosciences, Neurology, Helsinki University HospitalStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki||Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki||Department of Medical and Clinical Genetics, University of HelsinkiClinical Neurochemistry Laboratory, Sahlgrenska University Hospital||Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg||Department of Neurodegenerative Disease, UCL Institute of Neurology||UK Dementia Research Institute at UCLClinical Neurosciences, Neurology, Helsinki University HospitalSchool of Pharmacy, University of Eastern FinlandSchool of Pharmacy, University of Eastern FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki||Clinical Neurosciences, Neurology, Helsinki University HospitalStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiDepartment of Neurology, Central Hospital of Northern KareliaDivision of Clinical Neurosciences, Turku University Hospital and University of Turku||Department of Neurology, Neuromuscular Research Center, Tampere University Hospital and Tampere University
神经病学、精神病学基础医学生物科学研究方法、生物科学研究技术
Palu Edouard,Kvist Jouni,Tyynismaa Henna,Zetterberg Henrik,Auranen Mari,Lehtonen Marko,Koskivuori Johanna,Harjuhaahto Sandra,Ylikallio Emil,J?rvilehto Julius,Saukkonen Anna Maija,Jokela Manu.Metabolic and muscle-derived serum biomarkers define CHCHD10-linked late-onset spinal muscular atrophy[EB/OL].(2025-03-28)[2025-05-09].https://www.medrxiv.org/content/10.1101/2021.04.07.21254960.点此复制
评论