{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T20:24:44Z","timestamp":1791059084612,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2010,12,23]],"date-time":"2010-12-23T00:00:00Z","timestamp":1293062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous mutations of the SMN1 gene. Based on clinical severity, three forms of SMA are recognized (type I\u2013III). All patients have at least one (usually 2\u20134) copies of a highly homologous gene (SMN2) which produces insufficient levels of functional SMN protein, due to alternative splicing of exon7. Recently, evidence has been provided that SMN2 expression can be enhanced by different strategies. The availability of potential candidates to treat SMA has raised a number of issues, including the availability of data on the natural history of the disease, the reliability and sensitivity of outcome measures, the duration of the studies, and the number and clinical homogeneity of participating patients. Equally critical is the availability of reliable biomarkers. So far, different tools have been proposed as biomarkers in SMA, classifiable into two groups: instrumental (the Compound Motor Action Potential, the Motor Unit Number Estimation, and the Dual-energy X-ray absorptiometry) and molecular (SMN gene products dosage, either transcripts or protein). However, none of the biomarkers available so far can be considered the gold standard. Preclinical studies on SMA animal models and double-blind, placebo-controlled studies are crucial to evaluate the appropriateness of biomarkers, on the basis of correlations with clinical outcome.<\/jats:p>","DOI":"10.3390\/ijms12010024","type":"journal-article","created":{"date-parts":[[2010,12,26]],"date-time":"2010-12-26T13:29:00Z","timestamp":1293370140000},"page":"24-38","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Biomarkers in Rare Disorders: The Experience with Spinal Muscular Atrophy"],"prefix":"10.3390","volume":"12","author":[{"given":"Francesco D.","family":"Tiziano","sequence":"first","affiliation":[{"name":"Institute of Medical Genetics, Catholic University of Sacro Cuore, Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Neri","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, Catholic University of Sacro Cuore, Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Brahe","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, Catholic University of Sacro Cuore, Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2010,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1016\/S0140-6736(08)60921-6","article-title":"Spinal muscular atrophy","volume":"371","author":"Lunn","year":"2008","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0960-8966(94)00075-K","article-title":"Chaos in the classification of SMA: a possible resolution","volume":"5","author":"Dubowitz","year":"1995","journal-title":"Neuromuscul. Disord"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and characterization of a spinal muscular atrophy-determining gene","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9","article-title":"An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA)","volume":"15","author":"Wirth","year":"2000","journal-title":"Hum. Mut"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/ng0797-265","article-title":"Correlation between severity and SMN protein level in spinal muscular atrophy","volume":"16","author":"Lefebvre","year":"1997","journal-title":"Nat. Genet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1093\/hmg\/6.8.1205","article-title":"The survival motor neuron protein in spinal muscular atrophy","volume":"6","author":"Coovert","year":"1997","journal-title":"Hum. Mol. Genet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/sj.ejhg.5200286","article-title":"SMN protein analysis in fibroblast, amniocyte, and CVS cultures from spinal muscular atrophy patients and its relevance for diagnosis","volume":"7","author":"Patrizi","year":"1999","journal-title":"Eur. J. Hum. Genet"},{"key":"ref_8","first-page":"289","article-title":"Spinal muscular atrophy and a model for survival of motor neuron protein function in axonal ribonucleoprotein complexes","volume":"48","author":"Rossoll","year":"2009","journal-title":"Results Probl. Cell Differ"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1086\/338627","article-title":"Quantitative analysis of SMN1 and SMN2 based on real-time LightCycler PCR: Fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy","volume":"70","author":"Schwarzer","year":"2002","journal-title":"Am. J. Hum. Genet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.nmd.2007.02.006","article-title":"The Hammersmith functional score correlates with the SMN2 copy number: a multicentric study","volume":"17","author":"Tiziano","year":"2007","journal-title":"Neuromuscul. Disord"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1007\/s00439-006-0156-7","article-title":"Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number","volume":"119","author":"Wirth","year":"2006","journal-title":"Hum. Genet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9808","DOI":"10.1073\/pnas.171105098","article-title":"Treatment of spinal muscular atrophy by sodium butyrate","volume":"98","author":"Chang","year":"2001","journal-title":"Proc. Natl. Acad. Sci USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1093\/hmg\/ddg256","article-title":"Valproic acid increases the SMN2 protein level: A well-known drug as a potential therapy for spinal muscular atrophy","volume":"12","author":"Brichta","year":"2003","journal-title":"Hum. Mol. Genet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/ana.10743","article-title":"Valproic acid increases SMN levels in spinal muscular atrophy patient cells","volume":"54","author":"Sumner","year":"2003","journal-title":"Ann. Neurol"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/sj.ejhg.5201102","article-title":"Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy","volume":"12","author":"Andreassi","year":"2004","journal-title":"Eur. J. Hum. Genet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/sj.ejhg.5201320","article-title":"Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients","volume":"13","author":"Brahe","year":"2005","journal-title":"Eur. J. Hum. Genet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1002\/ana.20836","article-title":"In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate","volume":"59","author":"Brichta","year":"2006","journal-title":"Ann. Neurol"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1002\/ana.20548","article-title":"Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells","volume":"58","author":"Grzeschik","year":"2005","journal-title":"Ann. Neurol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1093\/hmg\/ddi205","article-title":"Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: early leads towards a therapeutic for spinal muscular atrophy","volume":"14","author":"Jarecki","year":"2005","journal-title":"Hum. Mol. Genet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1136\/jmg.2007.051177","article-title":"Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells","volume":"45","author":"Angelozzi","year":"2008","journal-title":"J. Med. Genet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.nmd.2008.05.004","article-title":"Daily salbutamol in young patients with SMA type II","volume":"18","author":"Pane","year":"2008","journal-title":"Neuromuscul. Disord"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1212\/01.wnl.0000249142.82285.d6","article-title":"Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy","volume":"68","author":"Mercuri","year":"2007","journal-title":"Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1212\/01.wnl.0000231139.26253.d0","article-title":"Valproate may improve strength and function in patients with type III\/IV spinal muscle atrophy","volume":"67","author":"Weihl","year":"2006","journal-title":"Neurology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jns.2007.11.012","article-title":"The effect of hydroxyurea in spinal muscular atrophy cells and patients","volume":"268","author":"Liang","year":"2008","journal-title":"J. Neurol. Sci"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1136\/jmg.2010.080366","article-title":"Salbutamol increases SMN transcript levels in leukocytes of spinal muscular atrophy patients: relevance for clinical trial design","volume":"47","author":"Tiziano","year":"2010","journal-title":"J. Med. Genet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1101\/gad.1941310","article-title":"Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model","volume":"24","author":"Hua","year":"2010","journal-title":"Genes Dev"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7633","DOI":"10.1523\/JNEUROSCI.0950-09.2009","article-title":"Oligonucleotide-mediated survival of motor neuron protein expression in CNS improves phenotype in a mouse model of spinal muscular atrophy","volume":"29","author":"Williams","year":"2009","journal-title":"J. Neurosci"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"341","DOI":"10.4161\/rna.6.3.8723","article-title":"A short antisense oligonucleotide masking a unique intronic motif prevents skipping of a critical exon in spinal muscular atrophy","volume":"6","author":"Singh","year":"2009","journal-title":"RNA Biol"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1001\/archneur.60.11.1601","article-title":"A phase 1 trial of riluzole in spinal muscular atrophy","volume":"60","author":"Russman","year":"2003","journal-title":"Arch. Neurol"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1002\/mus.10455","article-title":"Riluzole attenuates spinal muscular atrophy disease progression in a mouse model","volume":"28","author":"Haddad","year":"2003","journal-title":"Muscle Nerve"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1177\/08830738030180080501","article-title":"Role of gabapentin in spinal muscular atrophy: results of a multicenter, randomized Italian study","volume":"18","author":"Merlini","year":"2003","journal-title":"J. Child Neurol"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e5268","DOI":"10.1371\/journal.pone.0005268","article-title":"Phase II open label study of valproic acid in spinal muscular atrophy","volume":"4","author":"Swboda","year":"2009","journal-title":"PLoS One"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e12140","DOI":"10.1371\/journal.pone.0012140","article-title":"SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy","volume":"5","author":"Swoboda","year":"2010","journal-title":"PLoS One"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.nmd.2006.12.001","article-title":"Issues in SMA clinical trial design. The International Coordinating Committee (ICC) for SMA Subcommittee on SMA Clinical Trial Design","volume":"17","author":"Kaufmann","year":"2007","journal-title":"Neuromuscul. Disord"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/mus.10351","article-title":"Statistical motor unit number estimation: from theory to practice","volume":"28","author":"Slawnych","year":"2003","journal-title":"Muscle Nerve"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1002\/mus.880131108","article-title":"A review of techniques employed to estimate the number of motor units in a muscle","volume":"13","author":"Slawnych","year":"1990","journal-title":"Muscle Nerve"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1002\/mus.1128","article-title":"Depletion and sizes of motor units in spinal muscular atrophy","volume":"24","author":"Galea","year":"2001","journal-title":"Muscle Nerve"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.expneurol.2003.07.008","article-title":"Counting motor units in chronic motor neuropathies","volume":"184","author":"Bromberg","year":"2003","journal-title":"Exp. Neurol"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1002\/ana.20473","article-title":"Natural history of denervation in SMA: relation to age, SMN2 copy number, and function","volume":"57","author":"Swoboda","year":"2005","journal-title":"Ann. Neurol"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1212\/01.wnl.0000290830.40544.b9","article-title":"The changing natural history of spinal muscular atrophy type I","volume":"69","author":"Oskoui","year":"2007","journal-title":"Neurology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0022-510X(96)00284-5","article-title":"A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients","volume":"146","author":"Zerres","year":"1997","journal-title":"J. Neurol. Sci"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/BF02282993","article-title":"Prospective study of gross motor development in children with SMA type II","volume":"16","author":"Bono","year":"1995","journal-title":"Ital. J. Neurol. Sci"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1212\/01.wnl.0000324623.89105.c4","article-title":"Natural history of SMA IIIb: Muscle strength decreases in a predictable sequence and magnitude","volume":"71","author":"Deymeer","year":"2008","journal-title":"Neurology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1093\/hmg\/9.16.2451","article-title":"Animal models of spinal muscular atrophy","volume":"9","author":"Monani","year":"2000","journal-title":"Hum. Mol. Genet"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.bone.2004.06.009","article-title":"The relationship between lean body mass and bone mineral content in paediatric health and disease","volume":"35","author":"Crabtree","year":"2004","journal-title":"Bone"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/CND.0b013e318183e0fa","article-title":"Low bone mineral density in spinal muscular atrophy","volume":"10","author":"Khatri","year":"2008","journal-title":"Neuromuscul. Disord"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1055\/s-2004-830366","article-title":"Bone mineral density in a paediatric spinal muscular atrophy population","volume":"35","author":"Kinali","year":"2004","journal-title":"Neuropediatrics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/path.2566","article-title":"Bone loss in survival motor neuron (Smn(\u2212\/\u2212) SMN2) genetic mouse model of spinal muscular atrophy","volume":"219","author":"Shanmugarajan","year":"2009","journal-title":"J. Pathol"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1471-2377-6-6","article-title":"A novel cell immunoassay to measure survival of motor neurons protein in blood cells","volume":"6","author":"Kolb","year":"2006","journal-title":"BMC Neurol"},{"key":"ref_50","first-page":"1757","article-title":"A two-site ELISA can quantify uperegulation of SMN protein by drugs for spinal muscular atrophy","volume":"22","author":"Humphrey","year":"2008","journal-title":"Neurology"},{"key":"ref_51","unstructured":"Piepers, S, Cobben, JM, Sodaar, P, Jansen, MD, Wadman, RI, Meester-Delver, A, Poll-The, BT, Lemmink, HH, Wokke, JH, van der Pol, WL, and van den Berg, LH (2009). J Neurol Neurosurg Psychiatry."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1212\/01.wnl.0000201929.56928.13","article-title":"SMN mRNA and protein levels in peripheral blood","volume":"66","author":"Sumner","year":"2006","journal-title":"Neurology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1212\/01.wnl.0000252934.70676.ab","article-title":"Preclinical validation of a multiplex real-time assay to quantify SMN mRNA in patients with SMA","volume":"68","author":"Simard","year":"2007","journal-title":"Neurology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1038\/sj.ejhg.5201885","article-title":"A sensitive assay for measuring SMN mRNA levels in peripheral blood and in muscle samples of patients affected with spinal muscular atrophy","volume":"15","author":"Vezain","year":"2007","journal-title":"Eur. J. Hum. Genet"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/ejhg.2009.116","article-title":"SMN transcript levels in leukocytes of SMA patients determined by absolute real time PCR","volume":"18","author":"Tiziano","year":"2010","journal-title":"Eur. J. Hum. Genet"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0003-2697(02)00311-1","article-title":"Quantitative real-time reverse transcription polymerase chain reaction: normalization to rRNA or single housekeeping genes is inappropriate for human tissue biopsies","volume":"309","author":"Tricarico","year":"2002","journal-title":"Anal. Biochem"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.jpeds.2008.08.050","article-title":"Correlation of survival motor neuron expression in leukocytes and spinal cord in spinal muscular atrophy","volume":"154","author":"Tsai","year":"2009","journal-title":"J. Pediatr"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/12\/1\/24\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:04:12Z","timestamp":1760220252000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/12\/1\/24"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,12,23]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2011,1]]}},"alternative-id":["ijms12010024"],"URL":"https:\/\/doi.org\/10.3390\/ijms12010024","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,12,23]]}}}