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

Auranen Mari; Lehtonen Marko; Koskivuori Johanna; Zetterberg Henrik; Harjuhaahto Sandra; Jokela Manu; Saukkonen Anna Maija; Palu Edourad; Kvist Jouni; Järvilehto Julius; Ylikallio Emil; Tyynismaa Henna

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

Auranen Mari
Lehtonen Marko
Koskivuori Johanna
Zetterberg Henrik
Harjuhaahto Sandra
Jokela Manu
Saukkonen Anna Maija
Palu Edourad
Kvist Jouni
Järvilehto Julius
Ylikallio Emil
Tyynismaa Henna
Katso/Avaa
fneur-13-793937.pdf (1022.Kb)
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FRONTIERS MEDIA SA
doi:10.3389/fneur.2022.793937
URI
https://doi.org/10.3389/fneur.2022.793937
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2022081153697
Tiivistelmä

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.

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