Disease mechanisms in spinal muscular atrophy with respiratory distress type 1 (SMARD1): what about motoneurons?

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Verena Surrey Sibylle Jablonka


Spinal muscular atrophy with respiratory distress type 1 (SMARD1), described as a fatal motoneuron disorder in children is characterized by α-motoneuron loss. Most of the SMARD1 patients suffer from diaphragmatic palsy leading to permanent ventilation at very early stages of disease. As muscular atrophy is the predominant clinical sign in SMARD1 patients, the question arises whether motoneuron degeneration occurs cell-autonomously. IGHMBP2, the disease causing gene in SMARD1, encodes for a helicase with still unknown function in motoneurons. Studies from a SMARD1 mouse model (Nmd2J mouse) revealed that degeneration of motor axons precedes muscle fiber atrophy in the gastrocnemius muscle aside from a pure myopathy of the diaphragm without affected motor nerve innervation. Nmd2J mice suffer from a reduced IGF1 level which can be compensated by external application of a polyethylene glycol (PEG)-coupled variant of IGF1 (PEG-IGF1). The beneficial effects in striated muscles corresponded to a marked activation of the IGF1 receptor (IGF1R), resulting in enhanced phosphorylation of Akt (protein kinase B) and the ribosomal protein S6 kinase. Unfortunately, no protective effects of PEG-IGF1 were observed at the level of motoneuron survival. Fast motor axon loss innervating the gastrocnemius muscle of Nmd2J mice does not correspond to morphological and functional alterations at the neuromuscular endplate as it is described in mouse models for proximal spinal muscular atrophy (SMA). However, the high capacity for axonal sprouting in Nmd2J mice indicates the functionality of the remaining motoneurons. These observations argue for additional non-cell-autonomous disease mechanisms which do not primarily affect the neuromuscular endplate and in general the functionality of Ighmbp2 deficient motoneurons.

Keywords: SMARD1, IGHMBP2, helicase, motoneuron

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SURREY, Verena; JABLONKA, Sibylle. Disease mechanisms in spinal muscular atrophy with respiratory distress type 1 (SMARD1): what about motoneurons?. Medical Research Archives, [S.l.], v. 6, n. 2, feb. 2018. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/1689>. Date accessed: 25 mar. 2023. doi: https://doi.org/10.18103/mra.v6i2.1689.
Review Articles


[1] Grohmann K, Wienker TF, Saar K, et al. Diaphragmatic spinal muscular atrophy with respiratory distress is heterogeneous, and one form Is linked to chromosome 11q13-q21. AmJHumGenet. 1999; 65(5):1459-62.
[2] Bertini E, Gadisseux JL, Palmieri G, et al. Distal infantile spinal muscular atrophy associated with paralysis of the diaphragm: a variant of infantile spinal muscular atrophy. AmJMedGenet. 1989; 33(3):328-35.
[3] Grohmann K, Schuelke M, Diers A, et al. Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. NatGenet. 2001; 29(1):75-7.
[4] Diers A, Kaczinski M, Grohmann K, et al. The ultrastructure of peripheral nerve, motor end-plate and skeletal muscle in patients suffering from spinal muscular atrophy with respiratory distress type 1 (SMARD1). Acta Neuropathol. 2005; 110(3):289-97.
[5] Kaindl AM, Guenther UP, Rudnik-Schoneborn S, et al. [Distal spinal-muscular atrophy 1 (DSMA1 or SMARD1)]. ArchPediatr. 2008; 15(10):1568-72.
[6] Grohmann K, Varon R, Stolz P, et al. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). AnnNeurol. 2003; 54(6):719-24.
[7] Rudnik-Schoneborn S, Stolz P, Varon R, et al. Long-term observations of patients with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Neuropediatrics. 2004; 35(3):174-82.
[8] Vanoli F, Rinchetti P, Porro F, et al. Clinical and molecular features and therapeutic perspectives of spinal muscular atrophy with respiratory distress type 1. Journal of cellular and molecular medicine. 2015; 19(9):2058-66.
[9] Eckart M, Guenther UP, Idkowiak J, et al. The natural course of infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Pediatrics. 2012; 129(1):e148-e56.
[10] Joseph S, Robb SA, Mohammed S, et al. Interfamilial phenotypic heterogeneity in SMARD1. Neuromuscular disorders : NMD. 2009; 19(3):193-5.
[11] Blaschek A, Glaser D, Kuhn M, et al. Early infantile sensory-motor neuropathy with late onset respiratory distress. Neuromuscular disorders : NMD. 2014; 24(3):269-71.
[12] Guenther UP, Handoko L, Varon R, et al. Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease. JMolMed(Berl). 2009; 87(1):31-41.
[13] Guenther UP, Handoko L, Laggerbauer B, et al. IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1 (DSMA1). HumMolGenet. 2009; 18(7):1288-300.
[14] Pitt M, Houlden H, Jacobs J, et al. Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1. Brain. 2003; 126(Pt 12):2682-92.
[15] Cottenie E, Kochanski A, Jordanova A, et al. Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. Am J Hum Genet. 2014; 95(5):590-601.
[16] Fairman-Williams ME, Guenther UP, Jankowsky E. SF1 and SF2 helicases: family matters. Current opinion in structural biology. 2010; 20(3):313-24.
[17] Jankowsky E. RNA helicases at work: binding and rearranging. Trends BiochemSci. 2011; 36(1):19-29.
[18] Gorbalenya AE, Koonin EV, Donchenko AP, et al. Two related superfamilies of putative helicases involved in replication, recombination, repair and expression of DNA and RNA genomes. Nucleic Acids Res. 1989; 17(12):4713-30.
[19] Kervestin S, Jacobson A. NMD: a multifaceted response to premature translational termination. NatRevMolCell Biol. 2012; 13(11):700-12.
[20] Skourti-Stathaki K, Proudfoot NJ, Gromak N. Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. MolCell. 2011; 42(6):794-805.
[21] Chen YZ, Bennett CL, Huynh HM, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). AmJHumGenet. 2004; 74(6):1128-35.
[22] Barmada SJ, Ju S, Arjun A, et al. Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1. Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(25):7821-6.
[23] Mizuta TR, Fukita Y, Miyoshi T, et al. Isolation of cDNA encoding a binding protein specific to 5'-phosphorylated single-stranded DNA with G-rich sequences. Nucleic Acids Res. 1993; 21(8):1761-6.
[24] Lim SC, Bowler MW, Lai TF, et al. The Ighmbp2 helicase structure reveals the molecular basis for disease-causing mutations in DMSA1. Nucleic Acids Res. 2012; 40(21):11009-22.
[25] Grishin NV. The R3H motif: a domain that binds single-stranded nucleic acids. Trends Biochem Sci. 1998; 23(9):329-30.
[26] de Planell-Saguer M, Schroeder DG, Rodicio MC, et al. Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery. HumMolGenet. 2009; 18(12):2115-26.
[27] Grohmann K, Rossoll W, Kobsar I, et al. Characterization of Ighmbp2 in motor neurons and implications for the pathomechanism in a mouse model of human spinal muscular atrophy with respiratory distress type 1 (SMARD1). HumMolGenet. 2004; 13(18):2031-42.
[28] Cox GA, Mahaffey CL, Frankel WN. Identification of the mouse neuromuscular degeneration gene and mapping of a second site suppressor allele. Neuron. 1998; 21(6):1327-37.
[29] Cook SA, Johnson KR, Bronson RT, et al. Neuromuscular degeneration (nmd): a mutation on mouse chromosome 19 that causes motor neuron degeneration. MammGenome. 1995; 6:187-91.
[30] Krieger F, Elflein N, Ruiz R, et al. Fast motor axon loss in SMARD1 does not correspond to morphological and functional alterations of the NMJ. NeurobiolDis. 2013; 54:169-82.
[31] Maddatu TP, Garvey SM, Schroeder DG, et al. Transgenic rescue of neurogenic atrophy in the nmd mouse reveals a role for Ighmbp2 in dilated cardiomyopathy. HumMolGenet. 2004; 13(11):1105-15.
[32] Shababi M, Feng Z, Villalon E, et al. Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent. Molecular therapy : the journal of the American Society of Gene Therapy. 2016; 24(5):855-66.
[33] Krieger F, Elflein N, Saenger S, et al. Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1. Brain. 2014; 137:1374-93.
[34] Simone C, Nizzardo M, Rizzo F, et al. iPSC-Derived neural stem cells act via kinase inhibition to exert neuroprotective effects in spinal muscular atrophy with respiratory distress type 1. Stem cell reports. 2014; 3(2):297-311.
[35] Cifuentes-Diaz C, Nicole S, Velasco ME, et al. Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model. HumMolGenet. 2002; 11(12):1439-47.
[36] Park GH, Maeno-Hikichi Y, Awano T, et al. 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. JNeurosci. 2010; 30(36):12005-19.
[37] Kong L, Wang X, Choe DW, et al. Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice. JNeurosci. 2009; 29(3):842-51.
[38] Torres-Benito L, Neher MF, Cano R, et al. SMN requirement for synaptic vesicle, active zone and microtubule postnatal organization in motor nerve terminals. PLoSOne. 2011; 6(10):e26164.
[39] Ruiz R, Casanas JJ, Torres-Benito L, et al. Altered intracellular Ca2+ homeostasis in nerve terminals of severe spinal muscular atrophy mice. JNeurosci. 2010; 30(3):849-57.
[40] Murray LM, Beauvais A, Bhanot K, et al. Defects in neuromuscular junction remodelling in the Smn(2B/-) mouse model of spinal muscular atrophy. Neurobiology of disease. 2013; 49:57-67.
[41] Corti S, Locatelli F, Papadimitriou D, et al. Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1. HumMolGenet. 2006; 15(2):167-87.
[42] Simone C, Ramirez A, Bucchia M, et al. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications? Cellular and molecular life sciences : CMLS. 2016; 73(5):1003-20.