Advertisement

Overturning the Paradigm of Spinal Muscular Atrophy as Just a Motor Neuron Disease

  • Crystal Jing Jing Yeo
    Correspondence
    Communications should be addressed to: Dr. Yeo; Medical Director; Experimental Drug Development Center; Group Leader; Translational Neuromuscular Medicine Laboratory; Institute of Molecular and Cell Biology, Singapore; and Associated Staff; Boston Children’s Hospital; Boston, MA.
    Affiliations
    Department of Neurology, Neuromuscular Center and SMA Program, Boston Children’s Hospital, Boston, Massachusetts

    Harvard Medical School, Boston, Massachusetts

    Division of Neuromuscular Medicine, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts

    Division of Neuromuscular Medicine, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts

    Translational Neuromuscular Medicine Laboratory, Institute of Molecular and Cell Biology, Singapore

    Experimental Drug Development Center, Singapore
    Search for articles by this author
  • Basil T. Darras
    Correspondence
    Communications should be addressed to: Dr. Darras; Chief; Division of Clinical Neurology; Department of Neurology; Boston Children’s Hospital; Boston, MA.
    Affiliations
    Department of Neurology, Neuromuscular Center and SMA Program, Boston Children’s Hospital, Boston, Massachusetts

    Harvard Medical School, Boston, Massachusetts
    Search for articles by this author

      Abstract

      Spinal muscular atrophy is typically characterized as a motor neuron disease. Untreated patients with the most severe form, spinal muscular atrophy type 1, die early with infantile-onset progressive skeletal, bulbar, and respiratory muscle weakness. Such patients are now living longer due to new disease-modifying treatments such as gene replacement therapy (onasemnogene abeparvovec), recently approved by the US Food and Drug Administration, and nusinersen, a central nervous system-directed treatment which was approved by the US Food and Drug Administration three years ago. This has created an area of pressing clinical need: if spinal muscular atrophy is a multisystem disease, dysfunction of peripheral tissues and organs may become significant comorbidities as these patients survive into childhood and adulthood. In this review, we have compiled autopsy data, case reports, and cohort studies of peripheral tissue involvement in patients and animal models with spinal muscular atrophy. We have also evaluated preclinical studies addressing the question of whether peripheral expression of survival motor neuron is necessary and/or sufficient for motor neuron function and survival. Indeed, spinal muscular atrophy patient data suggest that spinal muscular atrophy is a multisystem disease with dysfunction in skeletal muscle, heart, kidney, liver, pancreas, spleen, bone, connective tissues, and immune systems. The peripheral requirement of SMN in each organ and how these contribute to motor neuron function and survival remains to be answered. A systemic (peripheral and central nervous system) approach to therapy during early development is most likely to effectively maximize positive clinical outcome.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Pediatric Neurology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lefebvre S.
        • Bürglen L.
        • Reboullet S.
        • et al.
        Identification and characterization of a spinal muscular atrophy-determining gene.
        Cell. 1995; 80: 155-165
        • Darras BT M.J.
        • Monani U.R.
        • De Vivo D.C.
        Spinal Muscular Atrophies. Neuromuscular Disorders of Infancy, Childhood, and Adolescence.
        Elsevier, San Diego, CA2015: 117-145
        • Butchbach M.E.
        Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases.
        Front Mol Biosci. 2016; 3: 7
        • Finkel R.S.
        • Mercuri E.
        • Darras B.T.
        • 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.
        • et al.
        Nusinersen versus sham control in later-onset spinal muscular atrophy.
        N Engl J Med. 2018; 378: 625-635
        • Darras B.T.
        • Chiriboga C.A.
        • Iannaccone S.T.
        • et al.
        Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
        Neurology. 2019; 92: e2492-e2506
        • Kletzl H.
        • Marquet A.
        • Günther A.
        • et al.
        The oral splicing modifier RG7800 increases full length survival of motor neuron 2 mRNA and survival of motor neuron protein: results from trials in healthy adults and patients with spinal muscular atrophy.
        Neuromuscul Disord. 2019; 29: 21-29
        • Mendell J.R.
        • Al-Zaidy S.
        • Shell R.
        • et al.
        Single-dose gene-replacement therapy for spinal muscular atrophy.
        N Engl J Med. 2017; 377: 1713-1722
        • Darras B.T.
        • De Vivo D.C.
        Precious SMA natural history data: a benchmark to measure future treatment successes.
        Neurology. 2018; 91: 337-339
        • Glascock J.J.
        • Osman E.Y.
        • Wetz M.J.
        • Krogman M.M.
        • Shababi M.
        • Lorson C.L.
        Decreasing disease severity in symptomatic, Smn(-/-);SMN2(+/+), spinal muscular atrophy mice following scAAV9-SMN delivery.
        Hum Gene Ther. 2012; 23: 330-335
        • Ramos D.M.
        • d’Ydewalle C.
        • Gabbeta V.
        • et al.
        Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment.
        J Clin Invest. 2019; 29: 4817-4831
        • Wadman R.I.
        • Wijngaarde C.A.
        • Stam M.
        • et al.
        Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c–4.
        Eur J Neurol. 2018; 25: 512-518
        • Yeo C.J.J.
        • Simeone S.D.
        • Townsend E.
        • et al.
        Outcome measures for nusinersen efficacy in adults with spinal muscular atrophy (S5.008).
        Neurology. 2019; 92 (S5.008)
        • Darras B.T.
        • Crawford T.O.
        • Finkel R.S.
        • et al.
        Neurofilament as a potential biomarker for spinal muscular atrophy.
        Ann Clin Transl Neurol. 2019; 6: 932-944
        • Park G.-H.
        • Maeno-Hikichi Y.
        • Awano T.
        • Landmesser L.T.
        • Monani U.R.
        Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric SMN2 gene.
        J Neurosci. 2010; 30: 12005-12019
        • Passini M.A.
        • Bu J.
        • Roskelley E.M.
        • et al.
        CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy.
        J Clin Invest. 2010; 120: 1253-1264
        • Hua Y.
        • Sahashi K.
        • Rigo F.
        • et al.
        Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model.
        Nature. 2011; 478: 123-126
        • Porensky P.N.
        • Mitrpant C.
        • McGovern V.L.
        • et al.
        A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse.
        Hum Mol Genet. 2012; 21: 1625-1638
        • Zhou H.
        • Janghra N.
        • Mitrpant C.
        • et al.
        A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice.
        Hum Gene Ther. 2013; 24: 331-342
        • Hua Y.
        • Liu Y.H.
        • Sahashi K.
        • Rigo F.
        • Bennett C.F.
        • Krainer A.R.
        Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models.
        Genes Dev. 2015; 29: 288-297
        • Gavrilina T.O.
        • McGovern V.L.
        • Workman E.
        • et al.
        Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect.
        Hum Mol Genet. 2008; 17: 1063-1075
        • Martinez T.L.
        • Soler-Botija C.
        • Also E.
        • et al.
        Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.
        J Neurosci. 2012; 32: 8703-8715
        • Fischer U.
        • Liu Q.
        • Dreyfuss G.
        The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis.
        Cell. 1997; 90: 1023-1029
        • Nichterwitz S.
        • Storvall H.
        • Nijssen J.
        • et al.
        LCM-seq reveals unique transcriptional adaption mechanisms of resistant neurons in spinal muscular atrophy.
        bioRxiv. 2018; : 356113
        • Schrank B.
        • Gotz R.
        • Gunnersen J.M.
        • et al.
        Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos.
        Proc Natl Acad Sci U S A. 1997; 94: 9920-9925
        • Hor J.H.
        • Soh E.S.-Y.
        • Tan L.Y.
        • et al.
        Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy.
        Cell Death Dis. 2018; 9: 1100
        • Hamilton G.
        • Gillingwater T.H.
        Spinal muscular atrophy: going beyond the motor neuron.
        Trends Mol Med. 2013; 19: 40-50
        • Shanmugarajan S.
        • Tsuruga E.
        • Swoboda K.J.
        • Maria B.L.
        • Ries W.L.
        • Reddy S.V.
        Bone loss in survival motor neuron (Smn(-/-) SMN2) genetic mouse model of spinal muscular atrophy.
        J Pathol. 2009; 219: 52-60
        • Heier C.R.
        • Satta R.
        • Lutz C.
        • DiDonato C.J.
        Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice.
        Hum Mol Genet. 2010; 19: 3906-3918
        • Hsieh-Li H.M.
        • Chang J.-G.
        • Jong Y.-J.
        • et al.
        A mouse model for spinal muscular atrophy.
        Nat Genet. 2000; 24: 66-70
        • Mutsaers C.A.
        • Wishart T.M.
        • Lamont D.J.
        • et al.
        Reversible molecular pathology of skeletal muscle in spinal muscular atrophy.
        Hum Mol Genet. 2011; 20: 4334-4344
        • Szunyogova E.
        • Zhou H.
        • Maxwell G.K.
        • et al.
        Survival Motor Neuron (SMN) protein is required for normal mouse liver development.
        Sci Rep. 2016; 6: 34635
        • Bowerman M.
        • Swoboda K.J.
        • Michalski J.-P.
        • et al.
        Glucose metabolism and pancreatic defects in spinal muscular atrophy.
        Ann Neurol. 2012; 72: 256-268
        • Deguise M.O.
        • Kothary R.
        New insights into SMA pathogenesis: immune dysfunction and neuroinflammation.
        Ann Clin Transl Neurol. 2017; 4: 522-530
        • Cifuentes-Diaz C.
        • Frugier T.
        • Tiziano F.D.
        • et al.
        Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy.
        J Cell Biol. 2001; 152: 1107-1114
        • Shafey D.
        • Côté P.D.
        • Kothary R.
        Hypomorphic SMN knockdown C2C12 myoblasts reveal intrinsic defects in myoblast fusion and myotube morphology.
        Exp Cell Res. 2005; 311: 49-61
        • Boyer J.G.
        • Murray L.M.
        • Scott K.
        • De Repentigny Y.
        • Renaud J.-M.
        • Kothary R.
        Early onset muscle weakness and disruption of muscle proteins in mouse models of spinal muscular atrophy.
        Skelet Muscle. 2013; 3: 24
        • Deguise M.O.
        • Boyer J.G.
        • McFall E.R.
        • Yazdani A.
        • De Repentigny Y.
        • Kothary R.
        Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy.
        Sci Rep. 2016; 6: 28846
        • Arnold A.S.
        • Gueye M.
        • Guettier-Sigrist S.
        • et al.
        Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients.
        Lab Invest. 2004; 84: 1271-1278
        • Martinez-Hernandez R.
        • Soler-Botija C.
        • Also E.
        • et al.
        The developmental pattern of myotubes in spinal muscular atrophy indicates prenatal delay of muscle maturation.
        J Neuropathol Exp Neurol. 2009; 68: 474-481
        • Ripolone M.
        • Ronchi D.
        • Violano R.
        • et al.
        Impaired muscle mitochondrial biogenesis and myogenesis in spinal muscular atrophy.
        JAMA Neurol. 2015; 72: 666-675
        • Xu C.C.
        • Denton K.R.
        • Wang Z.-B.
        • Zhang X.
        • Li X.-J.
        Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy.
        Dis Model Mech. 2016; 9: 39-49
        • Hacer D.
        • Yilmaz R.
        • Gulsen-Parman Y.
        • et al.
        Muscle MRI in spinal muscular atrophy 3: selective and progressive involvement: muscle MRI in SMA 3.
        Muscle Nerve. 2016; 55
        • Sheng L.
        • Wan B.
        • Feng P.
        • et al.
        Downregulation of Survivin contributes to cell-cycle arrest during postnatal cardiac development in a severe spinal muscular atrophy mouse model.
        Hum Mol Genet. 2018; 27: 486-498
        • Bevan A.K.
        • Hutchinson K.R.
        • Foust K.D.
        • et al.
        Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery.
        Hum Mol Genet. 2010; 19: 3895-3905
        • Rudnik-Schoneborn S.
        • Heller R.
        • Berg C.
        • et al.
        Congenital heart disease is a feature of severe infantile spinal muscular atrophy.
        J Med Genet. 2008; 45: 635-638
        • Bianco F.
        • Pane M.
        • D’Amico A.
        • et al.
        Cardiac function in types II and III spinal muscular atrophy: should we change standards of care?.
        Neuropediatrics. 2015; 46: 33-36
        • Lipnick S.L.
        • Agniel D.M.
        • Aggarwal R.
        • et al.
        Systemic nature of spinal muscular atrophy revealed by studying insurance claims.
        PLoS One. 2019; 14: e0213680
        • Alves C.R.R.
        • Garner R.
        • Nery F.
        • et al.
        Contribution of cardiac defects to spinal muscular atrophy pathology: a human tissue study.
        J Neuromuscul Disord. 2019; 29: S1-S232
        • Hachiya Y.
        • Arai H.
        • Hayashi M.
        • et al.
        Autonomic dysfunction in cases of spinal muscular atrophy type 1 with long survival.
        Brain Dev. 2005; 27: 574-578
        • Bach J.R.
        Medical considerations of long-term survival of Werdnig-Hoffmann disease.
        Am J Phys Med Rehabil. 2007; 86: 349-355
        • Messina S.
        • Sframeli M.
        • Vita G.
        • et al.
        Autonomic nervous system involvement in spinal muscular atrophy type 1, 2 and 3.
        Neuromuscul Disord. 2017; 27: S133-S134
        • Zhou H.
        • Ying H.
        • Scoto M.
        • Brogan P.
        • Parson S.
        • Muntoni F.
        Microvascular abnormality in spinal muscular atrophy and its response to antisense oligonucleotide therapy.
        Neuromuscul Disord. 2015; 25: S193
        • Somers E.
        • Lees R.D.
        • Hoban K.
        • et al.
        Vascular defects and spinal cord hypoxia in spinal muscular atrophy.
        Ann Neurol. 2016; 79: 217-230
        • Araujo A.
        • Araujo M.
        • Swoboda K.J.
        Vascular perfusion abnormalities in infants with spinal muscular atrophy.
        J Pediatr. 2009; 155: 292-294
        • Gombash S.E.
        • Cowley C.J.
        • Fitzgerald J.A.
        • et al.
        SMN deficiency disrupts gastrointestinal and enteric nervous system function in mice.
        Hum Mol Genet. 2015; 24: 3847-3860
        • Sintusek P.
        • Catapano F.
        • Angkathunkayul N.
        • et al.
        Histopathological defects in intestine in severe spinal muscular atrophy mice are improved by systemic antisense oligonucleotide treatment.
        PLoS One. 2016; 11: e0155032
        • Davis R.H.
        • Godshall B.J.
        • Seffrood E.
        • et al.
        Nutritional practices at a glance: spinal muscular atrophy type I nutrition survey findings.
        J Child Neurol. 2014; 29: 1467-1472
        • Deguise M.-O.
        • De Repentigny Y.
        • Beauvais A.
        • Bowerman M.
        • Kothary R.
        Abnormal fatty acid metabolism is a core component of spinal muscular atrophy.
        Ann Clin Transl Neurol. 2019; 6: 1519-1532
        • Crawford T.O.
        • Sladky J.T.
        • Hurko O.
        • Besner-Johnston A.
        • Kelley R.I.
        Abnormal fatty acid metabolism in childhood spinal muscular atrophy.
        Ann Neurol. 1999; 45: 337-343
        • Yesbek Kaymaz A.
        • Bal A.
        • Bora-Tatar G.
        • et al.
        Serum IGF1 and IGFBP3 levels in SMA patients.
        Neuromuscul Disord. 2016; 26: S105
        • Vai S.
        • Bianchi M.L.
        • Moroni I.
        • et al.
        Bone and spinal muscular atrophy.
        Bone. 2015; 79: 116-120
        • Wasserman H.M.
        • Hornung L.N.
        • Stenger P.J.
        • et al.
        Low bone mineral density and fractures are highly prevalent in pediatric patients with spinal muscular atrophy regardless of disease severity.
        Neuromuscul Disord. 2017; 27: 331-337
        • Vestergaard P.
        • Glerup H.
        • Steffensen B.F.
        • et al.
        Fracture risk in patients with muscular dystrophy and spinal muscular atrophy.
        J Rehabil Med. 2001; 33: 150-155
        • Haaker G.
        • Fujak A.
        Proximal spinal muscular atrophy: current orthopedic perspective.
        Appl Clin Genet. 2013; 6: 113-120
        • Dhawan S.R.
        • Saini L.
        • Ramachandran R.P.
        • Sankhyan N.
        Joint hyperlaxity, proximal contractures, and facial weakness in child with spinal muscular atrophy.
        J Clin Neuromuscul Dis. 2019; 20: 138-140
        • Nery F.C.
        • Siranosian J.J.
        • Rosales I.
        • et al.
        Impaired kidney structure and function in spinal muscular atrophy.
        Neurol Genet. 2019; 5: e353
        • Khairallah M.T.
        • Astroski J.
        • Custer S.K.
        • Androphy E.J.
        • Franklin C.L.
        • Lorson C.L.
        SMN deficiency negatively impacts red pulp macrophages and spleen development in mouse models of spinal muscular atrophy.
        Hum Mol Genet. 2017; 26: 932-941
        • Wan B.
        • Feng P.
        • Guan Z.
        • Sheng L.
        • Liu Z.
        • Hua Y.
        A severe mouse model of spinal muscular atrophy develops early systemic inflammation.
        Hum Mol Genet. 2018; 27: 4061-4076
        • Harding B.N.
        • Kariya S.
        • Monani U.R.
        • et al.
        Spectrum of neuropathophysiology in spinal muscular atrophy type I.
        J Neuropathol Exp Neurol. 2015; 74: 15-24
        • Kolb S.J.
        • Coffey C.S.
        • Yankey J.W.
        • et al.
        Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study.
        Ann Clin Transl Neurol. 2016; 3: 132-145
        • Davis R.H.
        • Godshall B.J.
        • Seffrood E.
        • et al.
        Responses to fasting and glucose loading in a cohort of well children with spinal muscular atrophy type II.
        J Pediatr. 2015; 167: 1362-1368.e1
        • Sproule D.M.
        • Montes J.
        • Montgomery M.
        • et al.
        Increased fat mass and high incidence of overweight despite low body mass index in patients with spinal muscular atrophy.
        Neuromuscul Disord. 2009; 19: 391-396
        • Kölbel H.
        • Hauffa B.P.
        • Wudy S.A.
        • Bouikidis A.
        • Della Marina A.
        • Schara U.
        Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III.
        PLoS One. 2017; 12: e0173144
        • Finkel R.S.
        • Crawford T.O.
        • Swoboda K.J.
        • et al.
        Candidate proteins, metabolites and transcripts in the biomarkers for spinal muscular atrophy (BforSMA) clinical study.
        PLoS One. 2012; 7: e35462
        • Philips T.
        • Robberecht W.
        Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease.
        Lancet Neurol. 2011; 10: 253-263