Serum Creatine, Not Neurofilament Light, Is Elevated in CHCHD10-Linked Spinal Muscular Atrophy.

Autor:	Järvilehto J; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Harjuhaahto S; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Palu E; Clinical Neurosciences, Neurology, Helsinki University Hospital, Helsinki, Finland., Auranen M; Clinical Neurosciences, Neurology, Helsinki University Hospital, Helsinki, Finland., Kvist J; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Zetterberg H; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.; UK Dementia Research Institute at UCL, London, United Kingdom., Koskivuori J; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Lehtonen M; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Saukkonen AM; Department of Neurology, Central Hospital of Northern Karelia, Joensuu, Finland., Jokela M; Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland.; Department of Neurology, Neuromuscular Research Center, Tampere University Hospital and Tampere University, Tampere, Finland., Ylikallio E; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Clinical Neurosciences, Neurology, Helsinki University Hospital, Helsinki, Finland., Tyynismaa H; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
Jazyk:	angličtina
Zdroj:	Frontiers in neurology [Front Neurol] 2022 Feb 17; Vol. 13, pp. 793937. Date of Electronic Publication: 2022 Feb 17 (Print Publication: 2022).
DOI:	10.3389/fneur.2022.793937
Abstrakt:	Objective: To characterize serum biomarkers in mitochondrial CHCHD10-linked spinal muscular atrophy Jokela (SMAJ) type for disease monitoring and for the understanding of pathogenic mechanisms. Methods: We collected serum samples from a cohort of 49 patients with SMAJ, 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. Creatine kinase and creatinine were measured by standard methods. Neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were measured with single molecule array (Simoa), fibroblast growth factor 21 (FGF-21), and growth differentiation factor 15 (GDF-15) with an enzyme-linked immunosorbent assay. For non-targeted plasma metabolite profiling, samples were analyzed with liquid chromatography high-resolution mass spectrometry. Disease severity was evaluated retrospectively by calculating a symptom-based score. Results: Axon degeneration marker, NfL, was unexpectedly not altered in the serum of patients with SMAJ, whereas astrocytic activation marker, GFAP, was slightly decreased. Creatine kinase was elevated in most patients, particularly men. We identified six metabolites that were significantly altered in serum of patients with SMAJ in comparison 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 was not changed. Conclusions: Biomarkers 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. Competing Interests: HZ has served on Scientific Advisory Boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. EY has served on Scientific Advisory Boards for Biogen Inc. and has received presentation fees from Roche Inc. and Sanofi Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Järvilehto, Harjuhaahto, Palu, Auranen, Kvist, Zetterberg, Koskivuori, Lehtonen, Saukkonen, Jokela, Ylikallio and Tyynismaa.)
Databáze:	MEDLINE
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