Vol 53, No 3 (2019)
Invited Review Article
Published online: 2019-06-10
Molecular biomarkers for neuromuscular disorders – challenges and future perspectives
Abstract
There is an ever-growing need for molecular biomarkers in assessing clinical course and diagnosing neuromuscular disorders, as well as in monitoring drug therapy. With the development of high throughput techniques, there has been an acceleration in the discovery of potential biomarkers. It is quite easy to find potential candidates, but difficult to validate them and translate into a clinical setting. Neuromuscular diseases (NMD) are a major challenge in terms of finding potential molecular biomarkers, mainly because of their heterogeneous aetiology and variability in phenotype, their as yet incompletely understood pathophysiology, and their slow clinical progression. Furthermore, it is challenging to assemble a large cohort of patients, as many NMDs are rare diseases. In this literature review, we provide an update on the latest discoveries in DNA, RNA, miRNA, epigenetic, protein, metabolic and cellular biomarkers for NMD. The advantages and potential difficulties of clinical application and the role of identification of biomarker panels are discussed. We have especially sought to highlight translational biomarkers which can be easily transferred to the clinic, where they may eventually present possible future therapies related to molecular biomarker discoveries.
Keywords: translational biomarkersneuromuscular diseasesNMDbiomarkers
References
- Lim KR, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017; 11: 533–545.
- Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS. 2010; 5(6): 463–466.
- Scotton C, Ferlini A. Biomarkers in Rare Genetic Diseases. Role of Biomarkers in Medicine. 2016.
- Jain K. The Handbook of Biomarkers. 2017.
- Mayeux R. Biomarkers: potential uses and limitations. NeuroRx. 2004; 1(2): 182–188.
- Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012; 31(25): 2973–2984.
- Califf RM. Biomarker definitions and their applications. Exp Biol Med (Maywood). 2018; 243(3): 213–221.
- Tasker R, Darras B. Neuromuscular disorders. Current Opinion in Pediatrics. 2013; 25(6): 674–675.
- Bonne G., Rivier F. Gene Table of Neuromuscular Disorders. http://www.musclegenetable.fr.
- Scotton C, Passarelli C, Neri M, et al. Biomarkers in rare neuromuscular diseases. Exp Cell Res. 2014; 325(1): 44–49.
- Aartsma-Rus A, Spitali P. Circulating Biomarkers for Duchenne Muscular Dystrophy. J Neuromuscul Dis. 2015; 2(s2): S49–S58.
- Flanigan KM, Ceco E, Lamar KM, et al. United Dystrophinopathy Project. LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy. Ann Neurol. 2013; 73(4): 481–488.
- Szigyarto CAK, Spitali P. Biomarkers of Duchenne muscular dystrophy: current findings. Degener Neurol Neuromuscul Dis. 2018; 8: 1–13.
- Vianello S, Pantic B, Fusto A, et al. SPP1 genotype and glucocorticoid treatment modify osteopontin expression in Duchenne muscular dystrophy cells. Hum Mol Genet. 2017; 26(17): 3342–3351.
- Lamar KM, McNally EM. Genetic Modifiers for Neuromuscular Diseases. J Neuromuscul Dis. 2014; 1(1): 3–13.
- Tao F, Beecham GW, Rebelo AP, et al. Inherited Neuropathy Consortium. Variation in SIPA1L2 is correlated with phenotype modification in Charcot- Marie- Tooth disease type 1A. Ann Neurol. 2019; 85(3): 316–330.
- Novelli G, Ciccacci C, Borgiani P, et al. Genetic tests and genomic biomarkers: regulation, qualification and validation. Clin Cases Miner Bone Metab. 2008; 5(2): 149–154.
- Høyer H, Braathen GJ, Eek AK, et al. Copy number variations in a population-based study of Charcot-Marie-Tooth disease. Biomed Res Int. 2015; 2015: 960404.
- Uyan Ö, Ömür Ö, Ağım ZS, et al. Genome-wide copy number variation in sporadic amyotrophic lateral sclerosis in the Turkish population: deletion of EPHA3 is a possible protective factor. PLoS One. 2013; 8(8): e72381.
- Sagath L, Lehtokari VL, Välipakka S, et al. An Extended Targeted Copy Number Variation Detection Array Including 187 Genes for the Diagnostics of Neuromuscular Disorders. J Neuromuscul Dis. 2018; 5(3): 307–314.
- Final Report Summary - BIO-NMD (Identifying and validating pre-clinical biomarkers for diagnostics and therapeutics of Neuromuscular Disorders). https://cordis.europa.eu/project/rcn/93293/reporting/en.
- Lanzuolo C. Epigenetic alterations in muscular disorders. Comp Funct Genomics. 2012; 2012: 256892.
- Haynes P, Bomsztyk K, Miller DG. Sporadic DUX4 expression in FSHD myocytes is associated with incomplete repression by the PRC2 complex and gain of H3K9 acetylation on the contracted D4Z4 allele. Epigenetics Chromatin. 2018; 11(1): 47.
- Collins CM, Ellis JA, Holaska JM. MAPK signaling pathways and HDAC3 activity are disrupted during differentiation of emerin-null myogenic progenitor cells. Dis Model Mech. 2017; 10(4): 385–397.
- Nakamori M, Sobczak K, Puwanant A, et al. Splicing biomarkers of disease severity in myotonic dystrophy. Ann Neurol. 2013; 74(6): 862–872.
- Crawford TO, Paushkin SV, Kobayashi DT, et al. Pilot Study of Biomarkers for Spinal Muscular Atrophy Trial Group. Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. PLoS One. 2012; 7(4): e33572.
- Fledrich R, Mannil M, Leha A, et al. Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A. J Neurol Neurosurg Psychiatry. 2017; 88(11): 941–952.
- van Rheenen W, Diekstra FP, Harschnitz O, et al. Whole blood transcriptome analysis in amyotrophic lateral sclerosis: A biomarker study. PLoS One. 2018; 13(6): e0198874.
- Almeida CF, Martins PCm, Vainzof M. Comparative transcriptome analysis of muscular dystrophy models Large(myd), Dmd(mdx)/Large(myd) and Dmd(mdx): what makes them different? Eur J Hum Genet. 2016; 24(9): 1301–1309.
- Eisenberg I, Alexander MS, Kunkel LM. miRNAS in normal and diseased skeletal muscle. J Cell Mol Med. 2009; 13(1): 2–11.
- Zaharieva IT, Calissano M, Scoto M, et al. Dystromirs as serum biomarkers for monitoring the disease severity in Duchenne muscular Dystrophy. PLoS One. 2013; 8(11): e80263.
- Matsuzaka Y, Kishi S, Aoki Y, et al. Three novel serum biomarkers, miR-1, miR-133a, and miR-206 for Limb-girdle muscular dystrophy, Facioscapulohumeral muscular dystrophy, and Becker muscular dystrophy. Environ Health Prev Med. 2014; 19(6): 452–458.
- Roberts TC, Blomberg KE, McClorey G, et al. Expression analysis in multiple muscle groups and serum reveals complexity in the microRNA transcriptome of the mdx mouse with implications for therapy. Mol Ther Nucleic Acids. 2012; 1: e39.
- Waller R, Goodall EF, Milo M, et al. Serum miRNAs miR-206, 143-3p and 374b-5p as potential biomarkers for amyotrophic lateral sclerosis (ALS). Neurobiol Aging. 2017; 55: 123–131.
- Magri F, Vanoli F, Corti S. miRNA in spinal muscular atrophy pathogenesis and therapy. J Cell Mol Med. 2018; 22(2): 755–767.
- Tarallo A, Carissimo A, Gatto F, et al. microRNAs as biomarkers in Pompe disease. Genet Med. 2019; 21(3): 591–600.
- Coenen-Stass AML, Sork H, Gatto S, et al. Comprehensive RNA-Sequencing Analysis in Serum and Muscle Reveals Novel Small RNA Signatures with Biomarker Potential for DMD. Mol Ther Nucleic Acids. 2018; 13: 1–15.
- Hathout Y. Proteomic methods for biomarker discovery and validation. Are we there yet? Expert Rev Proteomics. 2015; 12(4): 329–331.
- Weydt P, Oeckl P, Huss A, et al. Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis. Ann Neurol. 2016; 79(1): 152–158.
- Sandelius Å, Zetterberg H, Blennow K, et al. Plasma neurofilament light chain concentration in the inherited peripheral neuropathies. Neurology. 2018; 90(6): e518–e524.
- Nicholson LV, Walls TJ, Nicholson LV. Serum myoglobin in muscular dystrophy and carrier detection. J Neurol Sci. 1981; 51(3): 411–426.
- Ohta M, Itagaki Y, Itoh N, et al. Carbonic anhydrase III in serum in muscular dystrophy and other neurological disorders: relationship with creatine kinase. Clin Chem. 1991; 37(1): 36–39.
- Ayoglu B, Chaouch A, Lochmüller H, et al. Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies. EMBO Mol Med. 2014; 6(7): 918–936.
- Nadarajah VD, van Putten M, Chaouch A, et al. Serum matrix metalloproteinase-9 (MMP-9) as a biomarker for monitoring disease progression in Duchenne muscular dystrophy (DMD). Neuromuscul Disord. 2011; 21(8): 569–578.
- Lourbakos A, Yau N, de Bruijn P, et al. Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne. Sci Rep. 2017; 7(1): 17888.
- Rouillon J, Poupiot J, Zocevic A, et al. Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies. Hum Mol Genet. 2015; 24(17): 4916–4932.
- Sumner CJ, Kolb SJ, Harmison GG, et al. SMN mRNA and protein levels in peripheral blood: biomarkers for SMA clinical trials. Neurology. 2006; 66(7): 1067–1073.
- Crawford TO, Paushkin SV, Kobayashi DT, et al. Pilot Study of Biomarkers for Spinal Muscular Atrophy Trial Group. Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. PLoS One. 2012; 7(4): e33572.
- Nash LA, McFall ER, Perozzo AM, et al. Survival Motor Neuron Protein is Released from Cells in Exosomes: A Potential Biomarker for Spinal Muscular Atrophy. Sci Rep. 2017; 7(1): 13859.
- Burch PM, Pogoryelova O, Goldstein R, et al. Muscle-Derived Proteins as Serum Biomarkers for Monitoring Disease Progression in Three Forms of Muscular Dystrophy. J Neuromuscul Dis. 2015; 2(3): 241–255.
- Soldevilla B, Cuevas-Martín C, Ibáñez C, et al. Plasma metabolome and skin proteins in Charcot-Marie-Tooth 1A patients. PLoS One. 2017; 12(6): e0178376.
- Jennings MJ, Roos A, Horvath R. Serum biomarker discovery for Charcot-Marie-Tooth disease. Neuromuscular Disorders. 2018; 28: S21.
- Katyal N, Govindarajan R. Shortcomings in the Current Amyotrophic Lateral Sclerosis Trials and Potential Solutions for Improvement. Front Neurol. 2017; 8: 521.
- Benatar M, Boylan K, Jeromin A, et al. ALS biomarkers for therapy development: State of the field and future directions. Muscle Nerve. 2016; 53(2): 169–182.
- Kim SuJ, Kim SuH, Kim JiH, et al. Understanding Metabolomics in Biomedical Research. Endocrinol Metab (Seoul). 2016; 31(1): 7–16.
- Nakagawa T, Takeuchi A, Kakiuchi R, et al. A prostaglandin D2 metabolite is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years old. Clin Chim Acta. 2013; 423: 10–14.
- Srivastava NK, Pradhan S, Mittal B, et al. High resolution NMR based analysis of serum lipids in Duchenne muscular dystrophy patients and its possible diagnostic significance. NMR Biomed. 2010; 23(1): 13–22.
- Hörster I, Weigt-Usinger K, Carmann C, et al. The L-arginine/NO pathway and homoarginine are altered in Duchenne muscular dystrophy and improved by glucocorticoids. Amino Acids. 2015; 47(9): 1853–1863.
- Buzkova J, Nikkanen J, Ahola S, et al. Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers. EMBO Mol Med. 2018; 10(12).
- Otsuki N, Arakawa R, Kaneko K, et al. A new biomarker candidate for spinal muscular atrophy: Identification of a peripheral blood cell population capable of monitoring the level of survival motor neuron protein. PLoS One. 2018; 13(8): e0201764.
