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Association of motor milestones, SMN2 copy and outcome in spinal muscular atrophy types 0–4
  1. Renske I Wadman1,
  2. Marloes Stam1,
  3. Marleen Gijzen2,
  4. Henny H Lemmink3,
  5. Irina N Snoeck4,
  6. Camiel A Wijngaarde1,
  7. Kees P J Braun5,
  8. Marja A G C Schoenmakers6,
  9. Leonard H van den Berg1,
  10. Dennis Dooijes2,
  11. W-Ludo van der Pol1
  1. 1Department of Neurology and Neurosurgery, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands
  2. 2Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  3. 3Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
  4. 4Department of Paediatric Neurology, Haga Teaching Hospital, The Hague, The Netherlands
  5. 5Department of Neurology and Child Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands
  6. 6Department of Child Development and Exercise Centre, University Medical Centre Utrecht, Utrecht, The Netherlands
  1. Correspondence to Dr W-Ludo van der Pol, Department of Neurology and Neurosurgery F02.230, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht 3508 GA, The Netherlands; W.L.vanderPol{at}

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Proximal hereditary spinal muscular atrophy (SMA) is caused by homozygous deletion of the survival motor neuron (SMN) 1 gene and has a wide range of severity.1 Onset may occur prenatally up to the fourth decade of life, and motor deficits range from neonatal hypotonia to mild weakness in adulthood. The current classification of SMA distinguishes five SMA types (ie, type 0–4) based on the combination of age at onset and two acquired gross motor milestones.1 ,2 Distinction of additional subtypes based on differences in the age at onset, first for SMA type 3 (ie, 3a and 3b) and more recently for type 1 (ie, 1a–1c), has been proposed. This may help to further clarify differences in prognosis within SMA types and to balance baseline characteristics in clinical trials. We aimed to gain further insight into the added predictive value of motor milestones for the occurrence of SMA outcome or common complications, that is, death, respiratory insufficiency, scoliosis surgery and loss of ambulation. We included SMN2 copy number in our analysis, since this is the most important genetic biomarker of severity.3

Patients and methods

We enrolled patients with SMA types 1–4 between September 2010 and August 2014.

Methods are described in the online supplementary file.


The clinical diagnosis of SMA was genetically confirmed in 200 patients. SMN2 copy number varied from 1 to 5 and overlapped between SMA types. SMN2 copy number correlated inversely with SMA type (p<0.001; table 1). Clinical characteristics are summarised in table 1.

Table 1

Patient characteristics

supplementary file

Motor milestones defined SMA type 1–3 in case of discrepancies with age of onset. SMA classification was eventually changed in 18 patients (9%) because of acquisition of new motor milestones.

We included 42 patients with SMA type 1 (table 1). Three patients had the most severe phenotype, type 0/1a, and 1 SMN2 copy. SMN2 copy number differed between SMA types 1a/b/c (p<0.05). A relatively good prognosis was associated with acquired head control or ability to roll (type 1c) and 3 SMN2 copies.

Ages at losing specific motor skills in SMA type 2 and 3 are shown in online supplementary file, figure S1. Learning to roll and to sit was delayed (defined as >95th centile of WHO Motor Development Study 2006) in 31 (36%) patients with SMA type 2. Sixteen (48%) of 33 patients with SMA type 3a were delayed in learning to stand and walk, whereas only one patient with SMA type 3b showed a delay in acquiring the ability to walk independently.

We observed differences between the groups of patients with SMA type 2 who had learnt to sit independently (ie, who sat without support after being placed in sitting position; ‘type 2a’) (57%) and those who additionally had learnt to stand (with or without support; ‘type 2b’) (43%) (see online supplementary file, figure S1). Patients with type 2b less often needed respiratory support at night than those with type 2a (p=0.01), were older at the time of scoliosis surgery (p=0.03) and were able to maintain sitting position until adolescence. Mean age at onset and SMN2 copy number differed between patients with SMA type 2b and 3a (p=0.02; p=0.02). Mean age at loss of ambulation differed between patients with SMA types 3a and 3b (p<0.01) (see online supplementary file, figure S1). Frequencies of 3 or 4 SMN2 copies differed between SMA types 3a and 3b (p<0.01).

Virtually all patients with SMA type 2 (90%) were over 10 years of age at time of scoliosis surgery. Only 9 of 33 (27%) patients with SMA type 3a and 1 patient (3%) with SMA type 3b underwent scoliosis surgery. Age at time of scoliosis surgery correlated with both SMA type and SMN2 copy number (both p<0.01).


We investigated the associations of age at onset, motor milestones and SMN2 copy number in a relatively large SMA cohort that encompasses the complete spectrum of severity.2 ,4 Prognosis was associated with acquired motor milestones that are not routinely used in the current classification system (ie, head lifting in prone position, rolling, standing or walking with help). SMN2 copy number has prognostic value in specific cases.

The distinction of patients with relatively poor and good prognosis within the well-known SMA types may be important to refine the individual's prognosis and to balance baseline characteristics in trials. Additions to the SMA classification system are based on age at onset while the value of other motor milestones has been less explored. Discrepancies between age at onset and acquired motor milestones are not uncommon (in this study: 20%). Acquisition of head control in prone position and/or the ability to roll in SMA type 1 was associated with longer survival. The ability to stand in addition to sit in SMA type 2 was associated with better motor function, older age at the time of scoliosis surgery and fewer respiratory complications. Age at onset in patients with SMA type 3 correlated inversely with age at the time of losing ambulation, as reported before.2

SMN2 copy number may be additionally helpful to assess prognosis or the risk of complications, but only within the relevant clinical context. The overlap of SMN2 copy number between SMA types obviously precludes its use as a general prognostic biomarker. The presence of 1 SMN2 copy was associated with neonatal onset (SMA type 0/1a). In contrast, 21 patients with SMA type 1 who could lift the head in prone position or roll over, or had a preserved respiratory function and consequently a longer survival, had 3 SMN2 copies. Previously observed long survival in a case series of patients with infantile onset and 3 SMN2 copies is also in line with prognostic value of SMN2 copy number in SMA type 1.4 ,5 We also observed associations of SMN2 copy number with the need for scoliosis surgery, occurrence of respiratory failure and loss of ambulation in SMA types 2 and 3.

The strength of our study is the relatively large number of patients and the clinical and genetic detail. An inherent weakness of SMA cohort studies is the possibility of inclusion and selection bias due to the largely retrospective design of the study and voluntary enrolment. We attempted to reduce recall bias by using all available sources including family picture books and family care register data.


The authors are grateful to the patients and families who participated in this study, and to the Dutch patient organisation for neuromuscular diseases (SN) that supported its initiation and execution. The authors wish to thank Mrs Petra Grootscholten and Mrs Esther de Jong of the Department of Genetics at the University Medical Centre Groningen for excellent technical assistance in the measurement of SMN1 and SMN2 gene copy numbers. This study was made possible by referrals from members of the Dutch SMA study group (N van Alfen, L Bok, N Cobben, IFM de Coo, M Dousma, B GM van Engelen, JM Fock, IJM de Groot, WGM Janssen, M J Kampelmacher, R Koers, I Kortland, ET Kruitwagen, VJ Langenhorst, PWA Muitjens, J Nicolai, JMF Niermeijer, EH Niks, M Nuysink, RG van Ommen-Koolmees, EAJ Peeters, LTL Sie, MW van Steenbergen, MJ van Tol-Jager, AAPH Vaessen-Verberne, AD van Velzen, JJGM Verschuuren, M Vugts, MEJ Wegdam-den Boer, PJ Wijkstra, M Wohlgemuth).



  • Contributors RIW contributed to the drafting of the manuscript for content, study concept and design, analysis or interpretation of data, study supervision, acquisition of data, statistical analysis. HHL contributed to the revising of the manuscript for content, study concept or design and analysis of data. MS, MG, INS, CAW, MAGCS, KPJB, DD contributed to the revising of the manuscript for content and acquisition of data. LHvdB contributed to the revising of the manuscript for content, study concept and design and interpretation of data. W-LvdP contributed to the drafting and revising of the manuscript for content, including writing for content, analysis or interpretation of data revising of the manuscript for content, study concept and design, interpretation of data, statistical analysis, study supervision and obtaining funding. W-LvdP and RIW had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding This study was supported by grants from the Prinses Beatrix Spierfonds (WAR08-24) and the Stichting Spieren voor Spieren.

  • Disclaimer The funders had no role in study design, data collection, data analysis or interpretation, writing the report or decisions in submitting this manuscript.

  • Competing interests LHvdB serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen Idec and Cytokinetics; received an educational grant from Baxter International; serves on the editorial board of Amyotrophic Lateral Sclerosis and the Journal of Neurology, Neurosurgery and Psychiatry; and receives research support from the Prinses Beatrix Spierfonds, Netherlands ALS Foundation, the European Community's Health Seventh Framework Programme (grant agreement number 259867), the Netherlands Organization for Health Research and Development (Vici Scheme, JPND (SOPHIA, STRENGTH)). W-LvdP receives research support from the Prinses Beatrix Spierfonds, Netherlands ALS Foundation and Stichting Spieren voor Spieren.

  • Ethics approval Medical Ethical Committee of the University Medical Centre Utrecht.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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