Advertisement

Spinal muscular atrophy: from rags to riches

      Highlights

      • The paper provides a short history of spinal muscular atrophy.
      • The paper highlights the new challenges related to the new therapies
      • We report new issues in the classification of spinal muscular atrophy.
      • New phenotypes, assessments and care recommendations are also reported.
      • Results in presymptomatic patients highlight the need for neonatal screening.

      Abstract

      The aim of this paper is to provide a short history of spinal muscular atrophy, from the first descriptions of the disease to the impact of the most recent therapeutical advances on the disease course. The paper provides an overview of how the field has progressed over the years after the availability of care recommendations and, more recently of the new therapies. The paper also highlights the new challenges related to the interpretation of the efficacy of the new therapies and how these are likely to affect several aspects such as the classification of spinal muscular atrophy. We will also discuss the need for further work to better define possible new phenotypes and new methods of assessments and how these should be reflected in the care recommendations. The results in presymptomatic patients will finally highlight the need for neonatal screening.

      1. Introduction

      The recent advent of new therapeutical approaches in spinal muscular atrophy (SMA) is the crowning achievement of a long journey started over a century ago when the disease was first reported (Fig. 1). The first descriptions of spinal muscular atrophy dates to the last decade of the 19th century. In 1891 Guido Werdnig reported two brothers with weakness in whom degeneration of the anterior horn cells was found on autopsy [
      • Werdnig G.
      Zwei fruhinfantilehereditare Falle von progressive r Muskelatrophie unter dem bilde der dystrophie, aber auf neurotisscher grundlage.
      ]. A larger series was reported by Johan Hoffmann in the same decade [
      • Hoffmann J.
      Uber chronische spinale Muskelatrophie im Kindersalter auf familiarer basis.
      ]. In the following years other papers have provided further clinical details and the description of the typical phenotype characterized by jug handle posture of the arms, intercostal weakness and sparing of the diaphragm and no facial weakness.
      Figure 1
      Figure 1Timeline of events in SMA.
      SMA, spinal muscular atrophy; SMN, survival of motor neuron.
      a Werdnig G. Arch Psychiatr Nervenkr. 1891; 22:437480; b Hoffmann J. Deut Zeitsch Nervenheilkd 1893; 3:427470; c Kugelberg E & Welander L. AMA Arch Neurol Psychiatry 1956; 75:500509; d Dubowitz, V. Brain 1964;87:707-18; e Munsat TL, et al. Neuromuscul Disord 1992; 2:423428; f Brzustowicz LM, et al. Nature 1990 Apr 5;344:540-1.; Melki J, et al. Nature 1990;344:767-8.g Lefebvre S, et al. Cell 1995; 80:155165. h Frugier T, et al. Hum Mol Genet. 2000; 9:849858; Hsieh-Li HM, et al. Nat Genet 2000; 24:6670; I MacLeod MJ et al. Eur J Paediatr Neurol 1999;3:65-72. j Wang CH, et al. J Child Neurol. 2007; 22:102710497; k Mercuri E, et al. Neurology 2007; 68:5155; l Biogen Inc. SPINRAZATM (nusinersen) US prescribing information. m Dominguez E, et al. Hum Mol Genet 2011;20:681693; Foust KD, et al. Nat Biotechnol 2010; 28:271274; Passini MA, et al. J Clin Invest 2010; 120:12531264; n Chiriboga CA, et al. Neurology 2016;86:890-7.Finkel RS, et al. Lancet 2016;388:3017-26. Finkel RS, et al. N Engl J Med 2017;377:1723-32. Mercuri E et al. N Engl J Med 2018;378:625-35; o Naryshkin NA, et al. Science 2014. 345:688693;p Mercuri E, et al. Neuromuscul Disord 2018; 28:103115. Finkel et al. Neuromuscul Disord 2018; 28:1116125; q Mendell JR, et al. N Engl J Med 2017; 377: 171322. Day JW et al. Lancet Neurol 2021;20:284-293.; Mercuri E et al. Lancet Neurol, in press; r Baranello G, et al. N Engl J Med 2021;384:915-23. Darras B N Engl J Med 2021;385(5):427-435.
      After almost five decades, another form of hereditary motoneuron involvement with less severe phenotypes were described. Kugelberg and Welander reported a milder form, compatible with ambulation [
      • Kugelberg E.
      • Welander L.
      Heredofamilial juvenile muscular atrophy simulating muscular dystrophy.
      ], in whom proximal weakness and neurogenic signs on neurophysiology and muscle biopsy were consistent with motoneuron involvement and were labelled as a mild variant of Werdnig Hoffmann disease. A few other studies have reported both severe and milder phenotypes these findings suggesting a wider spectrum of clinical findings than the one originally reported [
      • Dubowitz V.
      Ramblings in the history of spinal muscular atrophy.
      ].
      Details of the first reported clinical findings can be found in a detailed and witty historical review [
      • Dubowitz V.
      Ramblings in the history of spinal muscular atrophy.
      ] written a few years ago by Victor Dubowitz, another important name in the SMA journey whose contribution to identify and better characterize the different forms of the disease is universally known. In 1964 Dubowitz reported a series of 12 cases with ‘almost non progressive’ form of neurogenic muscular atrophy with onset in infancy and longer survival than in the infantile form described by Werdnig and Hoffmann [
      • Dubowitz V.
      Infantile muscular atrophy. A prospective study with particular reference to a slowly progressive variety.
      ]. These findings provide the first systematic description of the ‘intermediate’ form as a new phenotype, with onset in infancy but associated with a slow progression.
      Other important steps were the discovery of the location of the gene for spinal muscular atrophy on chromosome 5 in 1990 [
      • Brzustowicz L.M.
      • Lehner T.
      • Castilla L.H.
      • Penchaszadeh G.K.
      • Wilhelmsen K.C.
      • Daniels R.
      • et al.
      Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3.
      ,
      • Melki J.
      • Abdelhak S.
      • Sheth P.
      • Bachelot M.F.
      • Burlet P.
      • Marcadet A.
      • et al.
      Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q.
      , and five years later, the identification of the Survival Motor Neuron (SMN1) gene [
      • Lefebvre S.
      • Burglen L.
      • Reboullet S.
      • Clermont O.
      • Burlet P.
      • Viollet L.
      • et al.
      Identification and characterization of a spinal muscular atrophy-determining gene.
      ], that allowed to confirm that the three known different phenotypes, ranging from severe to mild, were allelic forms related to mutations in the same gene rather than 3 genetically different diseases [
      • Dubowitz V.
      Hereditary proximal spinal muscularatrophy: single or multiple genes?.
      ,
      • Emery A.E.
      Clinical and genetic heterogeneity in spinal muscular atrophy–the multiple allele model.
      .
      This prompted a lot of discussion on how to classify the different SMA phenotypes that in some way is still ongoing even more than 30 years later [
      • Dubowitz V.
      Chaos in classification of the spinal muscular atrophies of childhood.
      ,
      • Dubowitz V.
      Chaos in the classification of SMA: a possible resolution.
      . The International Consortium on Spinal Muscular atrophy [
      • Munsat T.L.
      • Davies K.E.
      International SMA consortium meeting.
      ] proposed a classification that was a compromise between a numerical approach (type 1, 2 and 3), mainly based on age at onset and survival, and another approach based on severity (severe, intermediate and mild) and on the ability to achieve important motor milestones (sitting, standing/walking).
      This classification has proved to be very useful over the years but still did not take into account the large variability that can occur within each type. Over the years there have been several attempts to add further criteria to reduce the intra-type variability. The most used approach is the decimal subclassification proposed by Dubowitz that allows to identify patients with different severity within each type (1.1 to 1.9 for type 1, 2.1 to 2.9 for type 2 an 3–1 to 3.9 for type 3) [
      • Dubowitz V.
      Chaos in classification of the spinal muscular atrophies of childhood.
      ].
      Another used approach is mainly based on age at onset symptom. Type 1 patients have been subclassified into 1a, b and c [
      • Finkel R.
      • Bertini E.
      • Muntoni F.
      • Mercuri E.
      • Group E.S.W.S.
      209th ENMC international workshop: outcome measures and clinical trial readiness in spinal muscular atrophy 7-9 November 2014.
      ,
      • Mercuri E.
      • Bertini E.
      • Iannaccone S.T.
      Childhood spinal muscular atrophy: controversies and challenges.
      . Type 1a includes infants with neonatal onset, type 1b infants with onset after the first month who do not achieve head control and 1c including those who generally have onset of signs after 3 months and generally achieve head control. This classification is mainly based on age at onset of clinical signs and is often, but not always, associated with the overall severity that is better characterized in the decimal classification [
      • De Sanctis R.
      • Pane M.
      • Coratti G.
      • Palermo C.
      • Leone D.
      • Pera M.C.
      • et al.
      Clinical phenotypes and trajectories of disease progression in type 1 spinal muscular atrophy.
      ].
      Type 3 patients have often been subdivided into 3a, onset before the age of 3 years, and 3 b (onset after the age of 3 years) [
      • Zerres K.
      • Rudnik-Schoneborn S.
      • Forrest E.
      • Lusakowska A.
      • Borkowska J.
      Hausmanowa-Petrusewicz I. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients.
      ].
      The possibility to test for mutations in the SMN1 gene in patients with less common phenotypes has allowed to identify a new phenotype, with prenatal onset, absent or extremely reduced fetal movements, contractures and severe motor and respiratory involvement at birth, that has been labelled as Type 0 [
      • MacLeod M.J.
      • Taylor J.E.
      • Lunt P.W.
      • Mathew C.G.
      • Robb S.A.
      Prenatal onset spinal muscular atrophy.
      ,
      • Dubowitz V.
      Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype.
      . There is still debate whether, at the end of the spectrum, the forms with late adult onset and a mild phenotype should be labelled as type 4 or whether this should be considered as the mild end of the spectrum of type 3.
      The whole classification system is however currently under debate. With neonatal screening and the possibility to treat infants before the onset of clinical signs, it will be difficult to use the traditional criteria for classification as both onset and severity are being affected by the new treatments. Because of this there is a suggestion to identify presymptomatic patients according to the SMN2 copy number but there is no consensus because, although there is an overall correlation between copy number and severity, this does not always apply to individual cases [
      • Calucho M.
      • Bernal S.
      • Alias L.
      • March F.
      • Vencesla A.
      • Rodriguez-Alvarez F.J.
      • et al.
      Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases.
      ,
      • Feldkotter M.
      • Schwarzer V.
      • Wirth R.
      • Wienker T.F.
      • Wirth B.
      Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.
      . A functional classification (non sitters, sitters, walkers) is currently often used in natural history studies [
      • Finkel R.
      • Bertini E.
      • Muntoni F.
      • Mercuri E.
      • Group E.S.W.S.
      209th ENMC international workshop: outcome measures and clinical trial readiness in spinal muscular atrophy 7-9 November 2014.
      ,
      • Coratti G.
      • Pera M.C.
      • Lucibello S.
      • Montes J.
      • Pasternak A.
      • Mayhew A.
      • et al.
      Age and baseline values predict 12 and 24-month functional changes in type 2 SMA.
      ,
      • Coratti G.
      • Messina S.
      • Lucibello S.
      • Pera M.C.
      • Montes J.
      • Pasternak A.
      • et al.
      Clinical variability in spinal muscular atrophy type III.
      .

      2. New standards of care

      Even before the advent of therapeutic approaches, survival and disease progression had already changed following the introduction of standardized care recommendations, originally published in 2007 [
      • Wang C.H.
      • Finkel R.S.
      • Bertini E.S.
      • Schroth M.
      • Simonds A.
      • Wong B.
      • et al.
      Consensus statement for standard of care in spinal muscular atrophy.
      ] and revised in 2018 [
      • Finkel R.S.
      • Mercuri E.
      • Meyer O.H.
      • Simonds A.K.
      • Schroth M.K.
      • Graham R.J.
      • et al.
      Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics.
      ,
      • Mercuri E.
      • Finkel R.S.
      • Muntoni F.
      • Wirth B.
      • Montes J.
      • Main M.
      • et al.
      Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care.
      . The revised recommendations include different topics: Diagnosis and genetics, Physical therapy and rehabilitation, Orthopedic care, growth and bone health care; Nutrition, Pulmonary care, Ethics and palliative care, Acute care, Other organ system involvement, Medication.
      The recommendations highlight the need to have regular and reliable assessments as part of the clinical routine and provides details of the type and frequency of intervention in the different areas. Particular attention was devoted to the new information on management of scoliosis, with recommendation for earlier surgical treatment of spine deformity with new techniques.
      A new section on Acute Care was added to introduce the need for setting home and local hospital care including individualized anticipatory care plans, criteria for presentation to emergency care, and instructions to be shared with community first responders.

      3. New therapies

      In the last few years the field of SMA has completely changed. Three therapies have so far been approved, all targeting an increase in the production of SMN protein. This can be achieved going to the root of the genetic defect, with gene replacement of the defective SMN1 gene [
      • Farrar M.A.
      • Park S.B.
      • Vucic S.
      • Carey K.A.
      • Turner B.J.
      • Gillingwater T.H.
      • et al.
      Emerging therapies and challenges in spinal muscular atrophy.
      ,
      • Sumner C.J.
      • Crawford T.O.
      Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain.
      or by targeting SMN2 pre-mRNA splicing and promoting SMN2 exon 7 inclusion with subsequent increase of the production of full-length SMN protein [
      • Passini M.A.
      • Bu J.
      • Richards A.M.
      • Kinnecom C.
      • Sardi S.P.
      • Stanek L.M.
      • et al.
      Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy.
      ,
      • Hua Y.
      • Sahashi K.
      • Hung G.
      • Rigo F.
      • Passini M.A.
      • Bennett C.F.
      • et al.
      Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model.
      ,
      • Baranello G.
      • Darras B.T.
      • Day J.W.
      • Deconinck N.
      • Klein A.
      • Masson R.
      • et al.
      Risdiplam in type 1 spinal muscular atrophy.
      ].
      Viral gene therapy has been possible because of the small size of SMN1 that is compatible with the use of adeno-associated viral vectors (AAV9) as a vector [
      • Mendell J.R.
      • Al-Zaidy S.
      • Shell R.
      • Arnold WD
      • Rodino-Klapac LR
      • Prior TW
      • et al.
      Single-dose gene-replacement therapy for spinal muscular atrophy.
      ]. A phase I clinical trial using a single intravenous delivery of Onasemnogene Abeparvovec in infants with SMA-I (START, NCT02122952) showed clear signs of efficacy, both in term of survival and improved motor function, with a good safety profile [
      • Mendell J.R.
      • Al-Zaidy S.
      • Shell R.
      • Arnold WD
      • Rodino-Klapac LR
      • Prior TW
      • et al.
      Single-dose gene-replacement therapy for spinal muscular atrophy.
      ,
      • Al-Zaidy S.
      • Pickard A.S.
      • Kotha K.
      • Alfano L.N.
      • Lowes L.
      • Paul G.
      • et al.
      Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.
      . The administration was well tolerated with some cases of elevated serum aminotransferase levels that could be controlled by prednisolone administration. These results led to FDA approval in 2019, for infants with SMA. These results were followed by two larger open-label multicentre phase III studies in the US [STR1VE US, NCT03306277] [
      • Day J.W.
      • Finkel R.S.
      • Chiriboga C.A.
      • Connolly A.M.
      • Crawford T.O.
      • Darras B.T.
      • et al.
      Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
      ] and in Europe [STRIVE EU, NCT03461289] that are now both completed, showing similar clinical results and safety profile of the first study.
      Two different compounds targeting SMN2 pre-mRNA splicing with subsequent increase of the production of full-length SMN protein [
      • Passini M.A.
      • Bu J.
      • Richards A.M.
      • Kinnecom C.
      • Sardi S.P.
      • Stanek L.M.
      • et al.
      Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy.
      ,
      • Hua Y.
      • Sahashi K.
      • Hung G.
      • Rigo F.
      • Passini M.A.
      • Bennett C.F.
      • et al.
      Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model.
      are now commercially available. The first to be approved was Nusinersen, an antisense oligonucleotide. Two successful randomised double blind controlled clinical trials performed in infants under 7 months of age with SMA-I (ENDEAR, [
      • Finkel R.S.
      • Mercuri E.
      • Darras B.T.
      • Connolly A.M.
      • Kuntz N.L.
      • Kirschner J.
      • et al.
      Nusinersen versus sham control in infantile-onset spinal muscular atrophy.
      ]) and in children with late onset SMA (CHERISH, [
      • Mercuri E.
      • Darras B.T.
      • Chiriboga C.A.
      • Day J.W.
      • Campbell C.
      • Connolly A.M.
      • et al.
      Nusinersen versus sham control in later-onset spinal muscular atrophy.
      ]) led to the approval of Nusinersen in 2016 by the FDA, followed by European Medicines Agency (EMA) and several other countries worldwide. There are now over 11,000 patients treated with Nusinersen worldwide. There is a rapidly increasing number reporting efficacy of the drug in a real world setting. While most of the early real-world data focused on type 1 infants enrolled in early access programs, [
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • Messina S.
      • Bruno C.
      • Catteruccia M.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ,
      • Aragon-Gawinska K.
      • Seferian A.M.
      • Daron A.
      • Gargaun E.
      • Vuillerot C.
      • Cances C.
      • et al.
      Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: a cohort study.
      ,
      • Pechmann A.
      • Baumann M.
      • Bernert G.
      • Flotats-Bastardas M.
      • Gruber-Sedlmayr U.
      • von der Hagen M.
      • et al.
      Treatment with nusinersen - Challenges regarding the indication for children with SMA type 1.
      ] there has been a rapidly increase in the number of patients reporting real world data in adults [
      • Jochmann E.
      • Steinbach R.
      • Jochmann T.
      • Chung H.Y.
      • Rodiger A.
      • Neumann R.
      • et al.
      Experiences from treating seven adult 5q spinal muscular atrophy patients with nusinersen.
      ,
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • Govoni A.
      • Caponnetto C.
      • Passamano L.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ,
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • Schreiber-Katz O.
      • Osmanovic A.
      • Petri S.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ,
      • Walter M.C.
      • Wenninger S.
      • Thiele S.
      • Stauber J.
      • Hiebeler M.
      • Greckl E.
      • et al.
      Safety and treatment effects of nusinersen in longstanding adult 5q-SMA Type 3 - A prospective observational study.
      ,
      • Kessler T.
      • Latzer P.
      • Schmid D.
      • Warnken U.
      • Saffari A.
      • Ziegler A.
      • et al.
      Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy.
      ,
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ,
      • Osmanovic A.
      • Ranxha G.
      • Kumpe M.
      • Muschen L.
      • Binz C.
      • Wiehler F.
      • et al.
      Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • Van Camp E.
      • Geukens E.
      • Van Kerschaver G.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ,
      • Kizina K.
      • Stolte B.
      • Totzeck A.
      • Bolz S.
      • Schlag M.
      • Ose C.
      • et al.
      Fatigue in adults with spinal muscular atrophy under treatment with nusinersen.
      ,
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ,
      • Konersman C.G.
      • Ewing E.
      • Yaszay B.
      • Naheedy J.
      • Murphy S.
      • Skalsky A.
      Nusinersen treatment of older children and adults with spinal muscular atrophy.
      ,
      • Mendonca R.H.
      • Polido G.J.
      • Matsui C.
      • Silva A.M.S.
      • Solla D.J.F.
      • Reed U.C.
      • et al.
      Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
      ,

      Duong T., Wolford C., McDermott M.P., Macpherson C.E., Pasternak A., Glanzman A.M., et al. Nusinersen treatment in adults with spinal muscular atrophy. Neurology: Clinical Practice 2021: 10.1212/CPJ.0000000000001033.

      ,
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • Kwon J.
      • Baker L.
      • Collins E.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ] and older children [
      • Szabo L.
      • Gergely A.
      • Jakus R.
      • Fogarasi A.
      • Grosz Z.
      • Molnar M.J.
      • et al.
      Efficacy of nusinersen in type 1, 2 and 3 spinal muscular atrophy: real world data from Hungarian patients.
      ,
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • Ramirez-Garcia P.
      • Durigneux J.
      • Barnerias C.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Gomez-Garcia de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • Pruvost S.
      • Barnerias C.
      • Dabaj I.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ,
      • Coratti G.
      • Pane M.
      • Lucibello S.
      • Pera M.C.
      • Pasternak A.
      • Montes J.
      • et al.
      Age related treatment effect in type II spinal muscular atrophy pediatric patients treated with nusinersen.
      ,
      • Pera M.C.
      • Coratti G.
      • Bovis F.
      • Pane M.
      • Pasternak A.
      • Montes J.
      • et al.
      Nusinersen in pediatric and adult patients with type III spinal muscular atrophy.
      ] covering the whole spectrum of SMA, from young infants with the severe neonatal onset forms to adults with milder phenotypes. The real-world data have expanded our knowledge on safety and efficacy of the drug in a much larger population of SMA patients than those reported in the pivotal studies.
      The other approach targeting to modify SMN2 exon 7 splicing and regulating SMN2 exon 7 inclusion, implies the use of small molecules. One of them, risdiplam, has completed randomized, placebo-controlled studies in both early onset type I patients (FIREFISH, NCT02913482)[31], and in children and young adults with later-onset SMA (SUNFISH, NCT02908685), therefore including also patients older than 12 years that had not been included in previous studies. The results of the trials showed a significant improvement in survival I type 1 infants and improved motor function with an excellent safety profile. One of the advantages of using a small molecule is that they are able to cross the blood brain barrier and may therefore have also a CNS and a peripheral effect [
      • Poirier A.
      • Weetall M.
      • Heinig K.
      • Bucheli F.
      • Schoenlein K.
      • Alsenz J.
      • et al.
      Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs.
      ,
      • Ratni H.
      • Ebeling M.
      • Baird J.
      • Bendels S.
      • Bylund J.
      • Chen K.S.
      • et al.
      Discovery of risdiplam, a selective survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA).
      The drug is now becoming available in most countries after approval or for compassionate use and
      The results of the three clinical trials studies performed in infants in the first 6–7 months of age have clearly demonstrated that in symptomatic type 1 infants the dramatic increase in survival is associated with a functional improvement that is better seen in infants treated in the first months, who often achieve the ability to sit, never achieved before treatments became available. The long term results of the trials confirm that the efficacy is sustained over time [
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • McColly M.
      • Lowes L.P.
      • Alfano L.N.
      • et al.
      Five-Year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      ,
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • Swoboda K.J.
      • Montes J.
      • Mignon L.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      . Real world data have allowed to collect real world data in patients that had not been included in the pivotal studies[
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • Messina S.
      • Bruno C.
      • Catteruccia M.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ,
      • Day J.W.
      • Finkel R.S.
      • Chiriboga C.A.
      • Connolly A.M.
      • Crawford T.O.
      • Darras B.T.
      • et al.
      Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
      ,
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • Vanden Brande L.
      • Seferian A.
      • Gidaro T.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Pechmann A.
      • Langer T.
      • Schorling D.
      • Stein S.
      • Vogt S.
      • Schara U.
      • et al.
      Evaluation of children with SMA type 1 under treatment with nusinersen within the expanded access program in Germany.
      ,
      • Pechmann A.
      • Langer T.
      • Wider S.
      • Kirschner J.
      Single-center experience with intrathecal administration of nusinersen in children with spinal muscular atrophy type 1.
      . The first published results of the real world usage of Nusinersen, mainly focused on SMA-I patients but with a much wider spectrum of age than those enrolled in the ENDEAR study, confirmed that the best results were found in the younger patients treated before 6 months but significant motor function improvements could also be found in infants treated between 7 and 24 months [
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • Messina S.
      • Catteruccia M.
      • Bruno C.
      • et al.
      Type I SMA "new natural history": long-term data in nusinersen-treated patients.
      ]. A smaller degree of improvement could also be found in the older children. Similar findings were also found when exploring respiratory function [
      • Sansone V.A.
      • Pirola A.
      • Albamonte E.
      • Pane M.
      • Lizio A.
      • D'Amico A.
      • et al.
      Respiratory needs in patients with type 1 spinal muscular atrophy treated with nusinersen.
      ,
      • LoMauro A.
      • Mastella C.
      • Alberti K.
      • Masson R.
      • Aliverti A.
      • Baranello G.
      Effect of nusinersen on respiratory muscle function in different subtypes of type 1 spinal muscular atrophy.
      . Promising data have also recently become available in infants older than 6 months treated with Onasemnogene abeparvovec.
      Other studies have subsequently reported data using nusinersen in adults [
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • Schreiber-Katz O.
      • Osmanovic A.
      • Petri S.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ,
      • Walter M.C.
      • Wenninger S.
      • Thiele S.
      • Stauber J.
      • Hiebeler M.
      • Greckl E.
      • et al.
      Safety and treatment effects of nusinersen in longstanding adult 5q-SMA Type 3 - A prospective observational study.
      , and there is a rapidly increasing number of studies reporting the use of nusinersen in type 2 and 3 patients of all ages showing concordant positive changes on all the functional measures explored, at difference with the natural history studies consistently showing negative changes. These accumulating data indicate that nusinersen appears to have a favorable response in motor function across the spectrum of age and severity of disease and that the expectations from treatment in an individual patient need to be adjusted accordingly. Real world data are currently being collected also for Onasemnogene abeparvovec [
      • Friese J.
      • Geitmann S.
      • Holzwarth D.
      • Muller N.
      • Sassen R.
      • Baur U.
      • et al.
      Safety monitoring of gene therapy for spinal muscular atrophy with onasemnogene abeparvovec -A single centre experience.
      ] and risdiplam, that have recently become available.
      Other studies are exploring other mechanisms, such as those using fast skeletal muscle troponin activators or targeting myostatin, a potent negative regulator of skeletal muscle growth [
      • Zhou H.
      • Meng J.
      • Malerba A.
      • Catapano F.
      • Sintusek P.
      • Jarmin S.
      • et al.
      Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy.
      ]. A study exploring the effect of SRK-015, a fully human anti-pro-Myostatin monoclonal antibody in patients with and without treatment with Nusinersen has shown promising preliminary results (NCT03921528).

      4. New challenges

      The new therapies are a great achievement for the SMA patients but in a way also represent the beginning of a new era that will face several challenges to better understand the level of response and safety of the different drugs, alone or in combination, and of long term results and new phenotypes.
      Combinatorial studies with the existing available drugs are now being designed. Ongoing studies are collecting data from patients who may wish to switch from an existing treatment to another, such as the Jewelfish study proposing Risdiplam to patients previously exposed to Nusinersen or AVXS-101. (NCT03032172) or the RESTORE study targeting patients exposed to onasemnogene abeparvovec who will ‘add’ Nusinersen. The SRK-015 anti-myostatin study, previously described, also includes patients who will add the new compound to an existing treatment with nusinersen.
      Increasing attention has been devoted to treating presymptomatic patients. The results of a completed phase II, open-label, single-arm study, NURTURE (NCT02386553) using Nusinersen in presymptomatic infants [
      • De Vivo D.C.
      • Bertini E.
      • Swoboda K.J.
      • Hwu W.L.
      • Crawford T.O.
      • Finkel R.S.
      • et al.
      Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study.
      ] showed that not only all 25 children were alive and all achieved the ability to sit without support, but also that with few exceptions, most also achieved the ability to walk independently. Interestingly, infants with 3 SMN2 copy number participants were achieving these milestones tracking along the normal development curves.
      Preliminary data recently shown at various conferences, using risdiplam (RAINBOWFISH, NCT03779334) or onasemnogene abeparvovec (SPR1NT, NCT03505099) in ongoing open-label pre-symptomatic studies suggest similar efficacy and provide further evidence that initiation of treatment in presymptomatic patients can provide a much larger clinical effect than in symptomatic patients, highlighting the need for neonatal screening.
      Neonatal screening probably represents one of the most important challenges over the next few years. The emerging exciting data from clinical trials in presymptomatic patients has reinforced the need to [
      • Catapano F.
      • Zaharieva I.
      • Scoto M.
      • Marrosu E.
      • Morgan J.
      • Muntoni F.
      • et al.
      Altered levels of microRNA-9, -206, and -132 in spinal muscular atrophy and their response to antisense oligonucleotide therapy.
      ] add SMA to the newborn screening panels. After the FDA approval of nusinersen in 2018 approximately 30 states have adopted adding SMA to the US State's panel. Screening programs, often in the form of pilot studies have also started in some European countries. While there is consensus that the screening is much needed at the time new therapies are available and there is evidence of the efficacy in presymptomatic patients, there is less consensus on which patient, once identified, should be treated. A panel of US experts in 2017 recommended treatment of all patients with 2 or 3 copies of SMN2 [
      • Glascock J.
      • Sampson J.
      • Haidet-Phillips A.
      • Connolly A.
      • Darras B.
      • Day J.
      • et al.
      Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening.
      ], but these recommendations were revised to include also patients with 4 copies [
      • Glascock J.
      • Sampson J.
      • Connolly A.M.
      • Darras B.T.
      • Day J.W.
      • Finkel R.
      • et al.
      Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2.
      ]. These recommendations have not been adopted in all the other countries and the inclusion criteria for treating presymptomatic patients according to SMN2 copy number is still variable ranging from 2 to 4 copies.
      Other new challenges include a better understanding of new phenotypes and the need to adapt standards of care. The new therapies have completely changed the progression of the disease course in all SMA types and there is increasing evidence of new phenotypes within each form that were not previously observed. Treated type 1 patients are not only surviving longer but also consistently show an improvement of their functional abilities and often acquire developmental milestones, including unsupported sitting, that had never previously been achieved in type I SMA [
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • Messina S.
      • Bruno C.
      • Catteruccia M.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ,
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • Vanden Brande L.
      • Seferian A.
      • Gidaro T.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Pechmann A.
      • Langer T.
      • Schorling D.
      • Stein S.
      • Vogt S.
      • Schara U.
      • et al.
      Evaluation of children with SMA type 1 under treatment with nusinersen within the expanded access program in Germany.
      . The unexpected abilities achieved in treated patients are however often associated with signs that need further attention, such as the presence of kyphosis and scoliosis that require careful surveillance and the use of postural devices and orthoses. Similarly, in children with SMA-II who acquire the ability to walk, the gait is often different from that observed in ambulant type III, probably related to the fact that treated type II patients may already have more muscle impairment than in type 3 patients, as also suggested by muscle MRI studies, and may use additional muscles for compensation. There is therefore the need to record all the clinical features observed in the treated patients in order to establish the variability of the new phenotypes and contribute to the evidence of the new course of progression in patients treated with different drugs. Care recommendations, even if revised relatively recently, will also need to be further revised in order to accommodate the new clinical features associated to the emerging phenotypes.
      Finally, work is in progress to validate metabolomic and proteomic biomarkers that have been identified as possible prognostic biomarkers in SMA patients [
      • Crawford T.O.
      • Paushkin S.V.
      • Kobayashi D.T.
      • Forrest S.J.
      • Joyce C.L.
      • Finkel R.S.
      • et al.
      Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study.
      ,
      • Finkel R.S.
      • Crawford T.O.
      • Swoboda K.J.
      • Kaufmann P.
      • Juhasz P.
      • Li X.
      • et al.
      Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) clinical study.
      . Particular attention has been paid to light chain and phosphorylated heavy chain neurofilaments levels in blood and CSF in both pre-symptomatic and symptomatic patients. Other biomarkers include circulating serum miRNA [
      • Catapano F.
      • Zaharieva I.
      • Scoto M.
      • Marrosu E.
      • Morgan J.
      • Muntoni F.
      • et al.
      Altered levels of microRNA-9, -206, and -132 in spinal muscular atrophy and their response to antisense oligonucleotide therapy.
      ] and lymphocyte levels of SMN protein [
      • Also-Rallo E.
      • Alias L.
      • Martinez-Hernandez R.
      • Caselles L.
      • Barcelo M.J.
      • Baiget M.
      • et al.
      Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability.
      ].

      Declaration of Competing Interest

      Eugenio Mercuri reports personal fees from NOVARTIS/AVEXIS, ROCHE, BIOGEN S.R.L., SCHOLAR ROCK for advisory boards and as PI, outside the submitted work. He is affiliated to an institution that receives funds for a SMA disease registry (ISMAR);

      References

        • Werdnig G.
        Zwei fruhinfantilehereditare Falle von progressive r Muskelatrophie unter dem bilde der dystrophie, aber auf neurotisscher grundlage.
        Arch Psychiatr Nervenkr (1970). 1891; 22: 437-481
        • Hoffmann J.
        Uber chronische spinale Muskelatrophie im Kindersalter auf familiarer basis.
        Deut Zeitsch Nervenheilkd. 1893; 3: 427-470
        • Kugelberg E.
        • Welander L.
        Heredofamilial juvenile muscular atrophy simulating muscular dystrophy.
        AMA Arch Neurol Psychiatry. 1956; 75: 500-509
        • Dubowitz V.
        Ramblings in the history of spinal muscular atrophy.
        Neuromuscul Disord. 2009; 19: 69-73
        • Dubowitz V.
        Infantile muscular atrophy. A prospective study with particular reference to a slowly progressive variety.
        Brain. 1964; 87: 707-718
        • Brzustowicz L.M.
        • Lehner T.
        • Castilla L.H.
        • Penchaszadeh G.K.
        • Wilhelmsen K.C.
        • Daniels R.
        • et al.
        Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3.
        Nature. 1990; 344: 540-541
        • Melki J.
        • Abdelhak S.
        • Sheth P.
        • Bachelot M.F.
        • Burlet P.
        • Marcadet A.
        • et al.
        Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q.
        Nature. 1990; 344: 767-768
        • Lefebvre S.
        • Burglen L.
        • Reboullet S.
        • Clermont O.
        • Burlet P.
        • Viollet L.
        • et al.
        Identification and characterization of a spinal muscular atrophy-determining gene.
        Cell. 1995; 80: 155-165
        • Dubowitz V.
        Hereditary proximal spinal muscularatrophy: single or multiple genes?.
        (In: Barbeau A, eds, B J R editor)2nd international congress on neurogenetics and neuro-opthalmology. Amasterdam Excerpta Medica, Montreal1969: 17-23 (September 1967)
        • Emery A.E.
        Clinical and genetic heterogeneity in spinal muscular atrophy–the multiple allele model.
        Neuromuscul Disord. 1991; 1: 307-308
        • Dubowitz V.
        Chaos in classification of the spinal muscular atrophies of childhood.
        Neuromuscul Disord. 1991; 1: 77-80
        • Dubowitz V.
        Chaos in the classification of SMA: a possible resolution.
        Neuromuscul Disord. 1995; 5: 3-5
        • Munsat T.L.
        • Davies K.E.
        International SMA consortium meeting.
        26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992; 2: 423-428
        • Finkel R.
        • Bertini E.
        • Muntoni F.
        • Mercuri E.
        • Group E.S.W.S.
        209th ENMC international workshop: outcome measures and clinical trial readiness in spinal muscular atrophy 7-9 November 2014.
        Neuromuscul Disord. 2015; 25 (Heemskerk, The Netherlands): 593-602
        • Mercuri E.
        • Bertini E.
        • Iannaccone S.T.
        Childhood spinal muscular atrophy: controversies and challenges.
        Lancet Neurol. 2012; 11: 443-452
        • De Sanctis R.
        • Pane M.
        • Coratti G.
        • Palermo C.
        • Leone D.
        • Pera M.C.
        • et al.
        Clinical phenotypes and trajectories of disease progression in type 1 spinal muscular atrophy.
        Neuromuscul Disord. 2018; 28: 24-28
        • Zerres K.
        • Rudnik-Schoneborn S.
        • Forrest E.
        • Lusakowska A.
        • Borkowska J.
        Hausmanowa-Petrusewicz I. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients.
        J Neurol Sci. 1997; 146: 67-72
        • MacLeod M.J.
        • Taylor J.E.
        • Lunt P.W.
        • Mathew C.G.
        • Robb S.A.
        Prenatal onset spinal muscular atrophy.
        Eur J Paediatr Neurol. 1999; 3: 65-72
        • Dubowitz V.
        Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype.
        Eur J Paediatr Neurol. 1999; 3: 49-51
        • Calucho M.
        • Bernal S.
        • Alias L.
        • March F.
        • Vencesla A.
        • Rodriguez-Alvarez F.J.
        • et al.
        Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases.
        Neuromuscul Disord. 2018; 28: 208-215
        • Feldkotter M.
        • Schwarzer V.
        • Wirth R.
        • Wienker T.F.
        • Wirth B.
        Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.
        Am J Hum Genet. 2002; 70: 358-368
        • Coratti G.
        • Pera M.C.
        • Lucibello S.
        • Montes J.
        • Pasternak A.
        • Mayhew A.
        • et al.
        Age and baseline values predict 12 and 24-month functional changes in type 2 SMA.
        Neuromuscul Disord. 2020; 30: 756-764
        • Coratti G.
        • Messina S.
        • Lucibello S.
        • Pera M.C.
        • Montes J.
        • Pasternak A.
        • et al.
        Clinical variability in spinal muscular atrophy type III.
        Ann Neurol. 2020; 88: 1109-1117
        • Wang C.H.
        • Finkel R.S.
        • Bertini E.S.
        • Schroth M.
        • Simonds A.
        • Wong B.
        • et al.
        Consensus statement for standard of care in spinal muscular atrophy.
        J Child Neurol. 2007; 22: 1027-1049
        • Finkel R.S.
        • Mercuri E.
        • Meyer O.H.
        • Simonds A.K.
        • Schroth M.K.
        • Graham R.J.
        • et al.
        Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics.
        Neuromuscul Disord. 2018; 28: 197-207
        • Mercuri E.
        • Finkel R.S.
        • Muntoni F.
        • Wirth B.
        • Montes J.
        • Main M.
        • et al.
        Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care.
        Neuromuscul Disord. 2018; 28: 103-115
        • Farrar M.A.
        • Park S.B.
        • Vucic S.
        • Carey K.A.
        • Turner B.J.
        • Gillingwater T.H.
        • et al.
        Emerging therapies and challenges in spinal muscular atrophy.
        Ann Neurol. 2017; 81: 355-368
        • Sumner C.J.
        • Crawford T.O.
        Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain.
        J Clin Invest. 2018; 128: 3219-3227
        • Passini M.A.
        • Bu J.
        • Richards A.M.
        • Kinnecom C.
        • Sardi S.P.
        • Stanek L.M.
        • et al.
        Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy.
        Sci Transl Med. 2011; 3 (72ra18)
        • Hua Y.
        • Sahashi K.
        • Hung G.
        • Rigo F.
        • Passini M.A.
        • Bennett C.F.
        • et al.
        Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model.
        Genes Dev. 2010; 24: 1634-1644
        • Baranello G.
        • Darras B.T.
        • Day J.W.
        • Deconinck N.
        • Klein A.
        • Masson R.
        • et al.
        Risdiplam in type 1 spinal muscular atrophy.
        N Engl J Med. 2021; 384: 915-923
        • Mendell J.R.
        • Al-Zaidy S.
        • Shell R.
        • Arnold WD
        • Rodino-Klapac LR
        • Prior TW
        • et al.
        Single-dose gene-replacement therapy for spinal muscular atrophy.
        N Engl J Med. 2017; 377: 1713-1722
        • Al-Zaidy S.
        • Pickard A.S.
        • Kotha K.
        • Alfano L.N.
        • Lowes L.
        • Paul G.
        • et al.
        Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.
        Pediatr Pulmonol. 2019; 54: 179-185
        • Day J.W.
        • Finkel R.S.
        • Chiriboga C.A.
        • Connolly A.M.
        • Crawford T.O.
        • Darras B.T.
        • et al.
        Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
        Lancet Neurol. 2021; 20: 284-293
        • Finkel R.S.
        • Mercuri E.
        • Darras B.T.
        • Connolly A.M.
        • Kuntz N.L.
        • Kirschner J.
        • et al.
        Nusinersen versus sham control in infantile-onset spinal muscular atrophy.
        N Engl J Med. 2017; 377: 1723-1732
        • Mercuri E.
        • Darras B.T.
        • Chiriboga C.A.
        • Day J.W.
        • Campbell C.
        • Connolly A.M.
        • et al.
        Nusinersen versus sham control in later-onset spinal muscular atrophy.
        N Engl J Med. 2018; 378: 625-635
        • Pane M.
        • Coratti G.
        • Sansone V.A.
        • Messina S.
        • Bruno C.
        • Catteruccia M.
        • et al.
        Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
        Ann Neurol. 2019; 86: 443-451
        • Aragon-Gawinska K.
        • Seferian A.M.
        • Daron A.
        • Gargaun E.
        • Vuillerot C.
        • Cances C.
        • et al.
        Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: a cohort study.
        Neurology. 2018; 91: e1312-e1318
        • Pechmann A.
        • Baumann M.
        • Bernert G.
        • Flotats-Bastardas M.
        • Gruber-Sedlmayr U.
        • von der Hagen M.
        • et al.
        Treatment with nusinersen - Challenges regarding the indication for children with SMA type 1.
        J Neuromuscul Dis. 2020; 7: 41-46
        • Jochmann E.
        • Steinbach R.
        • Jochmann T.
        • Chung H.Y.
        • Rodiger A.
        • Neumann R.
        • et al.
        Experiences from treating seven adult 5q spinal muscular atrophy patients with nusinersen.
        Ther Adv Neurol Disord. 2020; 131756286420907803
        • Maggi L.
        • Bello L.
        • Bonanno S.
        • Govoni A.
        • Caponnetto C.
        • Passamano L.
        • et al.
        Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
        J Neurol Neurosurg Psychiatry. 2020; 91: 1166-1174
        • Hagenacker T.
        • Wurster C.D.
        • Gunther R.
        • Schreiber-Katz O.
        • Osmanovic A.
        • Petri S.
        • et al.
        Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
        Lancet Neurol. 2020; 19: 317-325
        • Walter M.C.
        • Wenninger S.
        • Thiele S.
        • Stauber J.
        • Hiebeler M.
        • Greckl E.
        • et al.
        Safety and treatment effects of nusinersen in longstanding adult 5q-SMA Type 3 - A prospective observational study.
        J Neuromuscul Dis. 2019; 6: 453-465
        • Kessler T.
        • Latzer P.
        • Schmid D.
        • Warnken U.
        • Saffari A.
        • Ziegler A.
        • et al.
        Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy.
        J Neurochem. 2020; 153: 650-661
        • Yeo C.J.J.
        • Simeone S.D.
        • Townsend E.L.
        • Zhang R.Z.
        • Swoboda K.J.
        Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
        J Neuromuscul Dis. 2020; 7: 257-268
        • Osmanovic A.
        • Ranxha G.
        • Kumpe M.
        • Muschen L.
        • Binz C.
        • Wiehler F.
        • et al.
        Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy.
        J Neurol. 2020; 267: 2398-2407
        • De Wel B.
        • Goosens V.
        • Sobota A.
        • Van Camp E.
        • Geukens E.
        • Van Kerschaver G.
        • et al.
        Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
        J Neurol. 2021; 268: 923-935
        • Kizina K.
        • Stolte B.
        • Totzeck A.
        • Bolz S.
        • Schlag M.
        • Ose C.
        • et al.
        Fatigue in adults with spinal muscular atrophy under treatment with nusinersen.
        Sci Rep. 2020; 10: 11069
        • Moshe-Lilie O.
        • Visser A.
        • Chahin N.
        • Ragole T.
        • Dimitrova D.
        • Karam C.
        Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
        Neurology. 2020; 95: e413-e416
        • Konersman C.G.
        • Ewing E.
        • Yaszay B.
        • Naheedy J.
        • Murphy S.
        • Skalsky A.
        Nusinersen treatment of older children and adults with spinal muscular atrophy.
        Neuromuscul Disord. 2021; 31: 183-193
        • Mendonca R.H.
        • Polido G.J.
        • Matsui C.
        • Silva A.M.S.
        • Solla D.J.F.
        • Reed U.C.
        • et al.
        Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
        J Neuromuscul Dis. 2021; 8: 101-108
      1. Duong T., Wolford C., McDermott M.P., Macpherson C.E., Pasternak A., Glanzman A.M., et al. Nusinersen treatment in adults with spinal muscular atrophy. Neurology: Clinical Practice 2021: 10.1212/CPJ.0000000000001033.

        • Veerapandiyan A.
        • Eichinger K.
        • Guntrum D.
        • Kwon J.
        • Baker L.
        • Collins E.
        • et al.
        Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
        Muscle Nerve. 2020; 61: 222-226
        • Szabo L.
        • Gergely A.
        • Jakus R.
        • Fogarasi A.
        • Grosz Z.
        • Molnar M.J.
        • et al.
        Efficacy of nusinersen in type 1, 2 and 3 spinal muscular atrophy: real world data from Hungarian patients.
        Eur J Paediatr Neurol. 2020; 27: 37-42
        • Audic F.
        • de la Banda M.G.G.
        • Bernoux D.
        • Ramirez-Garcia P.
        • Durigneux J.
        • Barnerias C.
        • et al.
        Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
        Orphanet J Rare Dis. 2020; 15: 148
        • Gomez-Garcia de la Banda M.
        • Amaddeo A.
        • Khirani S.
        • Pruvost S.
        • Barnerias C.
        • Dabaj I.
        • et al.
        Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
        Pediatr Pulmonol. 2021; 56: 299-306
        • Coratti G.
        • Pane M.
        • Lucibello S.
        • Pera M.C.
        • Pasternak A.
        • Montes J.
        • et al.
        Age related treatment effect in type II spinal muscular atrophy pediatric patients treated with nusinersen.
        Neuromuscul Disord. 2021; 31: 596-602
        • Pera M.C.
        • Coratti G.
        • Bovis F.
        • Pane M.
        • Pasternak A.
        • Montes J.
        • et al.
        Nusinersen in pediatric and adult patients with type III spinal muscular atrophy.
        Ann Clin Transl Neurol. 2021; 8: 1622-1634
        • Poirier A.
        • Weetall M.
        • Heinig K.
        • Bucheli F.
        • Schoenlein K.
        • Alsenz J.
        • et al.
        Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs.
        Pharmacol Res Perspect. 2018; 6: e00447
        • Ratni H.
        • Ebeling M.
        • Baird J.
        • Bendels S.
        • Bylund J.
        • Chen K.S.
        • et al.
        Discovery of risdiplam, a selective survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA).
        J Med Chem. 2018; 61: 6501-6517
        • Mendell J.R.
        • Al-Zaidy S.A.
        • Lehman K.J.
        • McColly M.
        • Lowes L.P.
        • Alfano L.N.
        • et al.
        Five-Year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
        JAMA Neurol. 2021; 78: 834-841
        • Darras B.T.
        • Chiriboga C.A.
        • Iannaccone S.T.
        • Swoboda K.J.
        • Montes J.
        • Mignon L.
        • et al.
        Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
        Neurology. 2019; 92: e2492-e2506
        • Aragon-Gawinska K.
        • Daron A.
        • Ulinici A.
        • Vanden Brande L.
        • Seferian A.
        • Gidaro T.
        • et al.
        Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
        Dev Med Child Neurol. 2020; 62: 310-314
        • Pechmann A.
        • Langer T.
        • Schorling D.
        • Stein S.
        • Vogt S.
        • Schara U.
        • et al.
        Evaluation of children with SMA type 1 under treatment with nusinersen within the expanded access program in Germany.
        J Neuromuscul Dis. 2018; 5: 135-143
        • Pechmann A.
        • Langer T.
        • Wider S.
        • Kirschner J.
        Single-center experience with intrathecal administration of nusinersen in children with spinal muscular atrophy type 1.
        Eur J Paediatr Neurol. 2018; 22: 122-127
        • Pane M.
        • Coratti G.
        • Sansone V.A.
        • Messina S.
        • Catteruccia M.
        • Bruno C.
        • et al.
        Type I SMA "new natural history": long-term data in nusinersen-treated patients.
        Ann Clin Transl Neurol. 2021; 8: 548-557
        • Sansone V.A.
        • Pirola A.
        • Albamonte E.
        • Pane M.
        • Lizio A.
        • D'Amico A.
        • et al.
        Respiratory needs in patients with type 1 spinal muscular atrophy treated with nusinersen.
        J Pediatr. 2020; 219 (223–228 e4)
        • LoMauro A.
        • Mastella C.
        • Alberti K.
        • Masson R.
        • Aliverti A.
        • Baranello G.
        Effect of nusinersen on respiratory muscle function in different subtypes of type 1 spinal muscular atrophy.
        Am J Respir Crit Care Med. 2019; 200: 1547-1550
        • Friese J.
        • Geitmann S.
        • Holzwarth D.
        • Muller N.
        • Sassen R.
        • Baur U.
        • et al.
        Safety monitoring of gene therapy for spinal muscular atrophy with onasemnogene abeparvovec -A single centre experience.
        J Neuromuscul Dis. 2021; 8: 209-216
        • Zhou H.
        • Meng J.
        • Malerba A.
        • Catapano F.
        • Sintusek P.
        • Jarmin S.
        • et al.
        Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy.
        J Cachexia Sarcopenia Muscle. 2020; 11: 768-782
        • De Vivo D.C.
        • Bertini E.
        • Swoboda K.J.
        • Hwu W.L.
        • Crawford T.O.
        • Finkel R.S.
        • et al.
        Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study.
        Neuromuscul Disord. 2019; 29: 842-856
        • Catapano F.
        • Zaharieva I.
        • Scoto M.
        • Marrosu E.
        • Morgan J.
        • Muntoni F.
        • et al.
        Altered levels of microRNA-9, -206, and -132 in spinal muscular atrophy and their response to antisense oligonucleotide therapy.
        Mol Ther Nucleic Acids. 2016; 5: e331
        • Glascock J.
        • Sampson J.
        • Haidet-Phillips A.
        • Connolly A.
        • Darras B.
        • Day J.
        • et al.
        Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening.
        J Neuromuscul Dis. 2018; 5: 145-158
        • Glascock J.
        • Sampson J.
        • Connolly A.M.
        • Darras B.T.
        • Day J.W.
        • Finkel R.
        • et al.
        Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2.
        J Neuromuscul Dis. 2020; 7: 97-100
        • Crawford T.O.
        • Paushkin S.V.
        • Kobayashi D.T.
        • Forrest S.J.
        • Joyce C.L.
        • Finkel R.S.
        • et al.
        Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study.
        PLoS ONE. 2012; 7: e33572
        • Finkel R.S.
        • Crawford T.O.
        • Swoboda K.J.
        • Kaufmann P.
        • Juhasz P.
        • Li X.
        • et al.
        Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) clinical study.
        PLoS ONE. 2012; 7: e35462
        • Also-Rallo E.
        • Alias L.
        • Martinez-Hernandez R.
        • Caselles L.
        • Barcelo M.J.
        • Baiget M.
        • et al.
        Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability.
        Eur J Hum Genet. 2011; 19: 1059-1065