We didn't experience a potential enrollment bias due to the opportunity to enroll in therapeutic trials as none were available at the beginning of this study. The enrollment number was higher than initially expected in this challenging and vulnerable population. Given that there was no direct benefit for patients in our study, this highlighted the enthusiasm of patients and families to embrace clinical research opportunities and to contribute their time and effort.

In conclusion, our cross-sectional results demonstrate that these outcome measures and biomarkers (pulmonary function and strength tests, upper limb function and abilities, compound muscle action potentials and muscle imaging) were able to differentiate non-sitter patients with SMA Type 2, sitter patients with SMA Type 2, non-ambulant patients with SMA Type 3 and ambulant patients. The majority of the measures also demonstrated a good correlation with the MFM score. The incomplete cross correlations between these tools suggest that including these additional measures in a therapeutic trial could provide a more comprehensive functional, anatomical and physiological evaluation of patients with SMA.

The objective of the longitudinal data analysis will be to identify if these outcome measures can capture even more discrete changes over time and show possible differences in disease progression between the three functional patient groups.

**Supporting information**

**S1 Checklist.**

(PDF)

**S1 Protocol.**

(PDF)

**S1 Statistical Analysis Plan.**

(PDF)

**S1 Table. Baseline characteristics and medical history of enrolled patients.** Abbreviations: bpm: breath per minute, BPAP: Bi-level positive airway pressure, CPAP: Continuous Positive Airway Pressure, IPV: Intrapulmonary Percussive Ventilation, NPV: Negative Pressure Ventilation, IPPV: Intermittent Positive Pressure Ventilation, AFO: Ankle and Foot Orthosis; Values are median (IQR) and overall population size is n = 81 unless otherwise indicated;

* 0.001 < p ≤ 0.05; ** p ≤ 0.001;

□ Application conditions of the Chi-square test not fully verified (theoretical effect ≤ 5, too small effectives);

a, b, c Subscript letters represent Post-hoc tests results. In a row, a same subscript letter indicates a subset of categories (non-sitter SMA type 2, sitter SMA type 2, non-ambulant SMA type 3 and ambulant SMA type 3) which column proportions do not differ significantly from each other at level 0.05.

(DOCX)

**S2 Table. Psychomotor development of patients with SMA type 2 and 3.** Values are effectives per motor skill;

* 0.001 < p ≤ 0.05; ** p ≤ 0.001;

□ Application conditions of the Chi-square test not fully verified (theoretical effect ≤ 5, too small effectives);

a, b, c Subscript letters represent Post-hoc tests results. In a row, a same subscript letter indicates a subset of categories (non-sitter SMA type 2, sitter SMA type 2, non-ambulant SMA type 3 and ambulant SMA type 3) which do not differ significantly from each other at level 0.05.

(DOCX)
S1 Fig. MFM scores in patients with SMA type 2 and 3.
(TIF)

**Acknowledgments**

Firstly, the authors thank the patients and families and caregivers for their participation in this study. The authors also thank the NatHis-SMA study group for data collection and protocol organization (numbers in bracket refer to authors affiliations): Elena Gargaun¹, Marianne Hezode¹, Charlotte Lilien¹, Valérie Decostre¹, Aurélie Phelep¹, Mélanie Villeret¹, Arnaud Jol-let¹, Rose-Diana Ho¹, Isabelle Ledoux¹, Amélie Moraux¹, Pauline Hivert¹, Aurélie Canal¹, Severine Denis², Stéphanie Delstanche², Armelle Magot³, Christelle Peseux³, Pascal Cintas⁴, Valérie Bellio⁴, Stéphanie Fontaine⁶, Véronique Manel⁶, Nathalie Goemans⁷, Marleen Van Den Hauwe⁷, Stéphanie Coopman⁹, Perrine Bocquillon⁹, Olivier Blouet¹¹, Jean Baptiste Chan-son¹¹, Heike Kölbel¹² and Andrea Gangfuβ¹². The lead author for this group is Laurent Ser-vais¹, ², ¹⁷. The authors thank the Strasbourg In Vivo Platform of the ICube laboratory, UMR 7357 Strasbourg University/CNRS for NMR images acquisition. The authors thank Christian Czech¹⁵ and Ricardo Hermosilla¹ for their contributions to study design, biomarkers analysis, interpretation of data, writing of the report. Finally, the authors thank Amy Whereat (Speak the Speech consulting, Paris) for providing medical writing assistance and help editing the manuscript.

**Author Contributions**

**Conceptualization:** Jean-Yves Hogrel, Timothy Seabrook, Elie Toledano, Mélanie Annous-samy, Laurent Servais.

**Data curation:** Aurélie Chabanon, Jean-Yves Hogrel, Emmanuel Fournier, Linda Pax Lowes.

**Formal analysis:** Mélanie Annoussamy.

**Funding acquisition:** Timothy Seabrook, Elie Toledano, Mélanie Annoussamy, Laurent Servais.

**Investigation:** Andreea Mihaela Seferian, Aurore Daron, Yann Péréon, Claude Cances, Carole Vuillerot, Liesbeth De Waele, Jean-Marie Cuisset, Vincent Laugel, Ulrike Schara, Teresa Gidaro, Stéphanie Gilabert, Pierre Carlier, Emmanuel Fournier, Laurent Servais.

**Methodology:** Aurélie Chabanon, Jean-Yves Hogrel, Pierre Carlier, Emmanuel Fournier, Linda Pax Lowes, Nicole Hellbach, Timothy Seabrook, Elie Toledano, Mélanie Annous-samy, Laurent Servais.

**Project administration:** Aurélie Chabanon, Mélanie Annoussamy.

**Resources:** Andreea Mihaela Seferian, Aurore Daron, Yann Péréon, Claude Cances, Carole Vuillerot, Liesbeth De Waele, Jean-Marie Cuisset, Vincent Laugel, Ulrike Schara, Teresa Gidaro, Jean-Yves Hogrel, Pierre-Yves Baudin, Pierre Carlier, Linda Pax Lowes, Nicole Hellbach, Laurent Servais.

**Supervision:** Timothy Seabrook, Elie Toledano, Mélanie Annoussamy, Laurent Servais.

**Visualization:** Aurélie Chabanon.

**Writing – original draft:** Aurélie Chabanon.

**Writing – review & editing:** Aurélie Chabanon, Andreea Mihaela Seferian, Aurore Daron, Yann Péréon, Claude Cances, Carole Vuillerot, Liesbeth De Waele, Jean-Marie Cuisset,
S1 Fig. MFM scores in patients with SMA type 2 and 3.
(TIF)

**Acknowledgments**

Firstly, the authors thank the patients and families and caregivers for their participation in this study. The authors also thank the NatHis-SMA study group for data collection and protocol organization (numbers in bracket refer to authors affiliations): Elena Gargaun¹, Marianne Hezode¹, Charlotte Lilien¹, Valérie Decostre¹, Aurélie Phelep¹, Mélanie Villeret¹, Arnaud Jol-let¹, Rose-Diana Ho¹, Isabelle Ledoux¹, Amélie Moraux¹, Pauline Hivert¹, Aurélie Canal¹, Severine Denis², Stéphanie Delstanche², Armelle Magot³, Christelle Peseux³, Pascal Cintas⁴, Valérie Bellio⁴, Stéphanie Fontaine⁶, Véronique Manel⁶, Nathalie Goemans⁷, Marleen Van Den Hauwe⁷, Stéphanie Coopman⁹, Perrine Bocquillon⁹, Olivier Blouet¹¹, Jean Baptiste Chan-son¹¹, Heike Kölbel¹² and Andrea Gangfuβ¹². The lead author for this group is Laurent Ser-vais¹, ², ¹⁷. The authors thank the Strasbourg In Vivo Platform of the ICube laboratory, UMR 7357 Strasbourg University/CNRS for NMR images acquisition. The authors thank Christian Czech¹⁵ and Ricardo Hermosilla¹ for their contributions to study design, biomarkers analysis, interpretation of data, writing of the report. Finally, the authors thank Amy Whereat (Speak the Speech consulting, Paris) for providing medical writing assistance and help editing the manuscript.

**Author Contributions**

**Conceptualization:** Jean-Yves Hogrel, Timothy Seabrook, Elie Toledano, Mélanie Annous-samy, Laurent Servais.

**Data curation:** Aurélie Chabanon, Jean-Yves Hogrel, Emmanuel Fournier, Linda Pax Lowes.

**Formal analysis:** Mélanie Annoussamy.

**Funding acquisition:** Timothy Seabrook, Elie Toledano, Mélanie Annoussamy, Laurent Servais.

**Investigation:** Andreea Mihaela Seferian, Aurore Daron, Yann Péréon, Claude Cances, Carole Vuillerot, Liesbeth De Waele, Jean-Marie Cuisset, Vincent Laugel, Ulrike Schara, Teresa Gidaro, Stéphanie Gilabert, Pierre Carlier, Emmanuel Fournier, Laurent Servais.

**Methodology:** Aurélie Chabanon, Jean-Yves Hogrel, Pierre Carlier, Emmanuel Fournier, Linda Pax Lowes, Nicole Hellbach, Timothy Seabrook, Elie Toledano, Mélanie Annous-samy, Laurent Servais.

**Project administration:** Aurélie Chabanon, Mélanie Annoussamy.

**Resources:** Andreea Mihaela Seferian, Aurore Daron, Yann Péréon, Claude Cances, Carole Vuillerot, Liesbeth De Waele, Jean-Marie Cuisset, Vincent Laugel, Ulrike Schara, Teresa Gidaro, Jean-Yves Hogrel, Pierre-Yves Baudin, Pierre Carlier, Linda Pax Lowes, Nicole Hellbach, Laurent Servais.

**Supervision:** Timothy Seabrook, Elie Toledano, Mélanie Annoussamy, Laurent Servais.

**Visualization:** Aurélie Chabanon.

**Writing – original draft:** Aurélie Chabanon.

**Writing – review & editing:** Aurélie Chabanon, Andreea Mihaela Seferian, Aurore Daron, Yann Péréon, Claude Cances, Carole Vuillerot, Liesbeth De Waele, Jean-Marie Cuisset,
Vincent Laugel, Ulrike Schara, Teresa Gidaro, Stéphanie Gilabert, Jean-Yves Hogrel, Pierre Carlier, Emmanuel Fournier, Linda Pax Lowes, Nicole Hellbach, Timothy Seabrook, Elie Toledano, Mélanie Annoussamy, Laurent Servais.

References

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2. Covert DD, Le TT, McAndrew PE, Strasswimmer J, Crawford TO, Mendell JR, et al. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet. 1997; 6(8):1205-14. PMID: 9259265

3. Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992; 2(5-6):423-8. PMID: 1300191

4. Zerres K, Rudnik-Schoneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol. 1995; 52 (5):518-23. PMID: 7733848

5. Russman BS, Buncher CR, White M, Samaha FJ, Iannaccone ST. Function changes in spinal muscular atrophy II and III. The DCN/SMA Group. Neurology. 1996; 47(4):973-6. PMID: 8857729

6. Wirth B, Garbes L, Riessland M. How genetic modifiers influence the phenotype of spinal muscular atro-phy and suggest future therapeutic approaches. Curr Opin Genet Dev. 2013; 23(3):330-8. https://doi.org/10.1016/j.gde.2013.03.003 PMID: 23602330

7. Czech C, Tang W, Bugawan T, Mano C, Horn C, Iglesias VA, et al. Biomarker for Spinal Muscular Atro-phy: Expression of SMN in Peripheral Blood of SMA Patients and Healthy Controls. PLoS One. 2015; 10(10):e0139950. https://doi.org/10.1371/journal.pone.0139950 PMID: 26468953

8. Kaufmann P, McDermott MP, Darras BT, Finkel RS, Sproule DM, Kang PB, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012; 79(18):1889-97. https://doi.org/10.1212/WNL.0b013e318271f7e4 PMID: 23077013

9. Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014; 83(9):810-7. https://doi.org/10.1212/WNL.000000000000741 PMID: 25080519

10. Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB, et al. Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol. 2016; 3(2):132-45. https://doi.org/10.1002/acn3.283 PMID: 26900585

11. Cano SJ, Mayhew A, Glanzman AM, Krosschell KJ, Swoboda KJ, Main M, et al. Rasch analysis of clini-cal outcome measures in spinal muscular atrophy. Muscle Nerve. 2014; 49(3):422-30. https://doi.org/10.1002/mus.23937 PMID: 23836324

12. Bonati U, Holiga S, Hellbach N, Risterucci C, Bergauer T, Tang W, et al. Longitudinal characterization of biomarkers for spinal muscular atrophy. Ann Clin Transl Neurol. 2017; 4(5):292-304. https://doi.org/10.1002/acn3.406 PMID: 28491897

13. Lowes LP, Alfano LN, Crawfis R, Berry K, Yin H, Dvorchik I, et al. Reliability and validity of active-seated: An outcome in dystrophinopathy. Muscle Nerve. 2015; 52(3):356-62. https://doi.org/10.1002/mus.24557 PMID: 25641021

14. Le Moing AG, Seferian AM, Moraux A, Annoussamy M, Dorveaux E, Gasnier E, et al. A Movement Monitor Based on Magneto-Inertial Sensors for Non-Ambulant Patients with Duchenne Muscular Dys-trophy: A Pilot Study in Controlled Environment. PLoS One. 2016; 11(6):e0156696. https://doi.org/10.1371/journal.pone.0156696 PMID: 27271157

15. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016; 86(10):890-7. https://doi.org/10.1212/WNL.0000000000002445 PMID: 26865511

16. Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016; 388(10063):3017-26. https://doi.org/10.1016/S0140-6736(16)31408-8 PMID: 27939059

17. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017; 377(18):1723-32. https://doi.org/10.1056/NEJMoa1702752 PMID: 29091570

18. Berard C, Payan C, Hodgkinson I, Fermanian J, Group MFMCS. A motor function measure for neuro-muscular diseases. Construction and validation study. Neuromuscul Disord. 2005; 15(7):463-70. PMID: 16106528
Vincent Laugel, Ulrike Schara, Teresa Gidaro, Stéphanie Gilabert, Jean-Yves Hogrel, Pierre Carlier, Emmanuel Fournier, Linda Pax Lowes, Nicole Hellbach, Timothy Seabrook, Elie Toledano, Mélanie Annoussamy, Laurent Servais.

## References

1. 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(1):155-65. PMID: 7813012

2. Covert DD, Le TT, McAndrew PE, Strasswimmer J, Crawford TO, Mendell JR, et al. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet. 1997; 6(8):1205-14. PMID: 9259265

3. Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992; 2(5-6):423-8. PMID: 1300191

4. Zerres K, Rudnik-Schoneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol. 1995; 52 (5):518-23. PMID: 7733848

5. Russman BS, Buncher CR, White M, Samaha FJ, Iannaccone ST. Function changes in spinal muscular atrophy II and III. The DCN/SMA Group. Neurology. 1996; 47(4):973-6. PMID: 8857729

6. Wirth B, Garbes L, Riessland M. How genetic modifiers influence the phenotype of spinal muscular atrophy and suggest future therapeutic approaches. Curr Opin Genet Dev. 2013; 23(3):330-8. https://doi.org/10.1016/j.gde.2013.03.003 PMID: 23602330

7. Czech C, Tang W, Bugawan T, Mano C, Horn C, Iglesias VA, et al. Biomarker for Spinal Muscular Atrophy: Expression of SMN in Peripheral Blood of SMA Patients and Healthy Controls. PLoS One. 2015; 10(10):e0139950. https://doi.org/10.1371/journal.pone.0139950 PMID: 26468953

8. Kaufmann P, McDermott MP, Darras BT, Finkel RS, Sproule DM, Kang PB, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012; 79(18):1889-97. https://doi.org/10.1212/WNL.0b013e318271f7e4 PMID: 23077013

9. Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014; 83(9):810-7. https://doi.org/10.1212/WNL.000000000000741 PMID: 25080519

10. Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB, et al. Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol. 2016; 3(2):132-45. https://doi.org/10.1002/acn3.283 PMID: 26900585

11. Cano SJ, Mayhew A, Glanzman AM, Krosschell KJ, Swoboda KJ, Main M, et al. Rasch analysis of clinical outcome measures in spinal muscular atrophy. Muscle Nerve. 2014; 49(3):422-30. https://doi.org/10.1002/mus.23937 PMID: 23836324

12. Bonati U, Holiga S, Hellbach N, Risterucci C, Bergauer T, Tang W, et al. Longitudinal characterization of biomarkers for spinal muscular atrophy. Ann Clin Transl Neurol. 2017; 4(5):292-304. https://doi.org/10.1002/acn3.406 PMID: 28491897

13. Lowes LP, Alfano LN, Crawfis R, Berry K, Yin H, Dvorchik I, et al. Reliability and validity of active-seated: An outcome in dystrophinopathy. Muscle Nerve. 2015; 52(3):356-62. https://doi.org/10.1002/mus.24557 PMID: 25641021

14. Le Moing AG, Seferian AM, Moraux A, Annoussamy M, Dorveaux E, Gasnier E, et al. A Movement Monitor Based on Magneto-Inertial Sensors for Non-Ambulant Patients with Duchenne Muscular Dystrophy: A Pilot Study in Controlled Environment. PLoS One. 2016; 11(6):e0156696. https://doi.org/10.1371/journal.pone.0156696 PMID: 27271157

15. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016; 86(10):890-7. https://doi.org/10.1212/WNL.0000000000002445 PMID: 26865511

16. Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016; 388(10063):3017-26. https://doi.org/10.1016/S0140-6736(16)31408-8 PMID: 27939059

17. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017; 377(18):1723-32. https://doi.org/10.1056/NEJMoa1702752 PMID: 29091570

18. Berard C, Payan C, Hodgkinson I, Fermanian J, Group MFMCS. A motor function measure for neuro-muscular diseases. Construction and validation study. Neuromuscul Disord. 2005; 15(7):463-70. PMID: 16106528
19. Seferian AM, Moraux A, Canal A, Decostre V, Diebate O, Le Moing AG, et al. Upper limb evaluation and one-year follow up of non-ambulant patients with spinal muscular atrophy: an observational multicenter trial. PLoS One. 2015; 10(4):e0121799. https://doi.org/10.1371/journal.pone.0121799 PMID: 25861036

20. Iannaccone ST, Hynan LS, American Spinal Muscular Atrophy Randomized Trials G. Reliability of 4 outcome measures in pediatric spinal muscular atrophy. Arch Neurol. 2003; 60(8):1130–6. https://doi.org/10.1001/archneur.60.8.1130 PMID: 12925371

21. Neve V, Cuisset JM, Edme JL, Carpentier A, Howsam M, Leclerc O, et al. Sniff nasal inspiratory pressure in the longitudinal assessment of young Duchenne muscular dystrophy children. Eur Respir J. 2013; 42(3):671–80. https://doi.org/10.1183/09031936.00127712 PMID: 23258781

22. Dunaway Young S, Montes J, Kramer SS, Marra J, Salazar R, Cruz R, et al. Six-minute walk test is reliable and valid in spinal muscular atrophy. Muscle Nerve. 2016; 54(5):836–42. https://doi.org/10.1002/mus.25120 PMID: 27015431

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27. Servais L, Deconinck N, Moraux A, Benali M, Canal A, Van Parys F, et al. Innovative methods to assess upper limb strength and function in non-ambulant Duchenne patients. Neuromuscul Disord. 2013; 23(2):139–48. https://doi.org/10.1016/j.nmd.2012.10.022 PMID: 23219352

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19. Seferian AM, Moraux A, Canal A, Decostre V, Diebate O, Le Moing AG, et al. Upper limb evaluation and one-year follow up of non-ambulant patients with spinal muscular atrophy: an observational multicenter trial. PLoS One. 2015; 10(4):e0121799. https://doi.org/10.1371/journal.pone.0121799 PMID: 25861036

20. Iannaccone ST, Hynan LS, American Spinal Muscular Atrophy Randomized Trials G. Reliability of 4 outcome measures in pediatric spinal muscular atrophy. Arch Neurol. 2003; 60(8):1130–6. https://doi.org/10.1001/archneur.60.8.1130 PMID: 12925371

21. Neve V, Cuisset JM, Edme JL, Carpentier A, Howsam M, Leclerc O, et al. Sniff nasal inspiratory pressure in the longitudinal assessment of young Duchenne muscular dystrophy children. Eur Respir J. 2013; 42(3):671–80. https://doi.org/10.1183/09031936.00127712 PMID: 23258781

22. Dunaway Young S, Montes J, Kramer SS, Marra J, Salazar R, Cruz R, et al. Six-minute walk test is reliable and valid in spinal muscular atrophy. Muscle Nerve. 2016; 54(5):836–42. https://doi.org/10.1002/mus.25120 PMID: 27015431

23. Roelants M, Hauspie R, Hoppenbrouwers K. References for growth and pubertal development from birth to 21 years in Flanders, Belgium. Ann Hum Biol. 2009; 36(6):680–94. https://doi.org/10.3109/03014460903049074 PMID: 19919503

24. de Lattre C, Payan C, Vuillerot C, Rippert P, de Castro D, Berard C, et al. Motor function measure: validation of a short form for young children with neuromuscular diseases. Arch Phys Med Rehabil. 2013; 94(11):2218–26. https://doi.org/10.1016/j.apmr.2013.04.001 PMID: 23602884

25. Vuillerot C, Payan C, Iwaz J, Ecochard R, Berard C, Group MFMSMAS. Responsiveness of the motor function measure in patients with spinal muscular atrophy. Arch Phys Med Rehabil. 2013; 94(8):1555–61. https://doi.org/10.1016/j.apmr.2013.01.014 PMID: 23380348

26. Bertini E, Dessaud E, Mercuri E, Muntoni F, Kirschner J, Reid C, et al. Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017.

27. Servais L, Deconinck N, Moraux A, Benali M, Canal A, Van Parys F, et al. Innovative methods to assess upper limb strength and function in non-ambulant Duchenne patients. Neuromuscul Disord. 2013; 23(2):139–48. https://doi.org/10.1016/j.nmd.2012.10.022 PMID: 23219352

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44. Dunaway S, Montes J, McDermott MP, Martens W, Neisen A, Glanzman AM, et al. Physical therapy services received by individuals with spinal muscular atrophy (SMA). J Pediatr Rehabil Med. 2016; 9 (1):35-44. https://doi.org/10.3233/PRM-160360 PMID: 26966799

45. Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007; 22(8):1027-49. https://doi.org/10.1177/0883073807305788 PMID: 17761659

46. Finkel R, Bertini E, Muntoni F, Mercuri E, Group ESWS. 209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7-9 November 2014, Heemskerk, The Netherlands. Neuromuscul Disord. 2015; 25(7):593-602. https://doi.org/10.1016/j.nmd.2015.04.009 PMID: 26045156

47. Ramsey D, Scoto M, Mayhew A, Main M, Mazzone ES, Montes J, et al. Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool. PLoS One. 2017; 12(2): e0172346. https://doi.org/10.1371/journal.pone.0172346 PMID: 28222119

48. Mercuri E, Finkel R, Montes J, Mazzone ES, Sormani MP, Main M, et al. Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials. Neuromuscul Disord. 2016; 26(2):126-31. https://doi.org/10.1016/j.nmd.2015.10.006 PMID: 26776503

49. Mazzone E, De Sanctis R, Fanelli L, Bianco F, Main M, van den Hauwe M, et al. Hammersmith Functional Motor Scale and Motor Function Measure-20 in non ambulant SMA patients. Neuromuscul Disord. 2014; 24(4):347-52. https://doi.org/10.1016/j.nmd.2014.01.003 PMID: 24491485

50. Khirani S, Colella M, Caldarelli V, Aubertin G, Boule M, Forin V, et al. Longitudinal course of lung function and respiratory muscle strength in spinal muscular atrophy type 2 and 3. Eur J Paediatr Neurol. 2013; 17(6):552-60. https://doi.org/10.1016/j.ejpn.2013.04.004 PMID: 23672834

51. Montes J, McDermott MP, Martens WB, Dunaway S, Glanzman AM, Riley S, et al. Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy. Neurology. 2010; 74(10):833-8. https://doi.org/10.1212/WNL.0b013e3181d3e308 PMID: 20211907

52. Pereira AC, Ribeiro MG, Araujo AP. Timed motor function tests capacity in healthy children. Arch Dis Child. 2016; 101(2):147-51. https://doi.org/10.1136/archdischild-2014-307396 PMID: 26566688

53. Yonekawa T, Komaki H, Saito Y, Sugai K, Sasaki M. Peripheral nerve abnormalities in pediatric patients with spinal muscular atrophy. Brain Dev. 2013; 35(2):165-71. https://doi.org/10.1016/j.braindev.2012.03.009 PMID: 22512990

54. Kang PB, Gooch CL, McDermott MP, Darras BT, Finkel RS, Yang ML, et al. The motor neuron response to SMN1 deficiency in spinal muscular atrophy. Muscle Nerve. 2014; 49(5):636-44. https://doi.org/10.1002/mus.23967 PMID: 23893312

55. Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC, Reyna SP, et al. Natural history of dener- vation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol. 2005; 57(5):704-12. https://doi.org/10.1002/ana.20473 PMID: 15852397

56. Farrar MA, Vucic S, Johnston HM, du Sart D, Kiernan MC. Pathophysiological insights derived by natu- ral history and motor function of spinal muscular atrophy. J Pediatr. 2013; 162(1):155-9. https://doi.org/10.1016/j.jpeds.2012.05.067 PMID: 22809660

57. Lewelt A, Krosschell KJ, Scott C, Sakonju A, Kissel JT, Crawford TO, et al. Compound muscle action potential and motor function in children with spinal muscular atrophy. Muscle Nerve. 2010; 42(5):703-8. https://doi.org/10.1002/mus.21838 PMID: 20737553

58. Wadman RI, Vrancken AF, van den Berg LH, van der Pol WL. Dysfunction of the neuromuscular junct- ion in spinal muscular atrophy types 2 and 3. Neurology. 2012; 79(20):2050-5. https://doi.org/10.1212/WNL.0b013e3182749eca PMID: 23115209

59. Kobayashi DT, Shi J, Stephen L, Ballard KL, Dewey R, Mapes J, et al. SMA-MAP: a plasma protein panel for spinal muscular atrophy. PLoS One. 2013; 8(4):e60113. https://doi.org/10.1371/journal.pone.0060113 PMID: 23565191
40. Geiger R, Strasak A, Treml B, Gasser K, Kleinsasser A, Fischer V, et al. Six-minute walk test in children and adolescents. J Pediatr. 2007; 150(4):395-9, 9 e1-2. https://doi.org/10.1016/j.jpeds.2006.12.052 PMID: 17382117

41. Gibbons WJ, Fruchter N, Sloan S, Levy RD. Reference values for a multiple repetition 6-minute walk test in healthy adults older than 20 years. J Cardiopulm Rehabil. 2001; 21(2):87-93. PMID: 11314289

42. Kaufmann P, McDermott MP, Darras BT, Finkel R, Kang P, Oskoui M, et al. Observational study of spinal muscular atrophy type 2 and 3: functional outcomes over 1 year. Arch Neurol. 2011; 68(6):779-86. https://doi.org/10.1001/archneurol.2010.373 PMID: 21320981

43. Fujak A, Ingenhorst A, Heuser K, Forst R, Forst J. Treatment of scoliosis in intermediate spinal muscular atrophy (SMA type II) in childhood. Ortop Traumatol Rehabil. 2005; 7(2):175-9. PMID: 17615511

44. Dunaway S, Montes J, McDermott MP, Martens W, Neisen A, Glanzman AM, et al. Physical therapy services received by individuals with spinal muscular atrophy (SMA). J Pediatr Rehabil Med. 2016; 9 (1):35-44. https://doi.org/10.3233/PRM-160360 PMID: 26966799

45. Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007; 22(8):1027-49. https://doi.org/10.1177/0883073807305788 PMID: 17761659

46. Finkel R, Bertini E, Muntoni F, Mercuri E, Group ESWS. 209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7-9 November 2014, Heemskerk, The Netherlands. Neuromuscul Disord. 2015; 25(7):593-602. https://doi.org/10.1016/j.nmd.2015.04.009 PMID: 26045156

47. Ramsey D, Scoto M, Mayhew A, Main M, Mazzone ES, Montes J, et al. Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool. PLoS One. 2017; 12(2): e0172346. https://doi.org/10.1371/journal.pone.0172346 PMID: 28222119

48. Mercuri E, Finkel R, Montes J, Mazzone ES, Sormani MP, Main M, et al. Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials. Neuromuscul Disord. 2016; 26(2):126-31. https://doi.org/10.1016/j.nmd.2015.10.006 PMID: 26776503

49. Mazzone E, De Sanctis R, Fanelli L, Bianco F, Main M, van den Hauwe M, et al. Hammersmith Functional Motor Scale and Motor Function Measure-20 in non ambulant SMA patients. Neuromuscul Disord. 2014; 24(4):347-52. https://doi.org/10.1016/j.nmd.2014.01.003 PMID: 24491485

50. Khirani S, Colella M, Caldarelli V, Aubertin G, Boule M, Forin V, et al. Longitudinal course of lung function and respiratory muscle strength in spinal muscular atrophy type 2 and 3. Eur J Paediatr Neurol. 2013; 17(6):552-60. https://doi.org/10.1016/j.ejpn.2013.04.004 PMID: 23672834

51. Montes J, McDermott MP, Martens WB, Dunaway S, Glanzman AM, Riley S, et al. Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy. Neurology. 2010; 74(10):833-8. https://doi.org/10.1212/WNL.0b013e3181d3e308 PMID: 20211907

52. Pereira AC, Ribeiro MG, Araujo AP. Timed motor function tests capacity in healthy children. Arch Dis Child. 2016; 101(2):147-51. https://doi.org/10.1136/archdischild-2014-307396 PMID: 26566688

53. Yonekawa T, Komaki H, Saito Y, Sugai K, Sasaki M. Peripheral nerve abnormalities in pediatric patients with spinal muscular atrophy. Brain Dev. 2013; 35(2):165-71. https://doi.org/10.1016/j.braindev.2012.03.009 PMID: 22512990

54. Kang PB, Gooch CL, McDermott MP, Darras BT, Finkel RS, Yang ML, et al. The motor neuron response to SMN1 deficiency in spinal muscular atrophy. Muscle Nerve. 2014; 49(5):636-44. https://doi.org/10.1002/mus.23967 PMID: 23893312

55. Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC, Reyna SP, et al. Natural history of dener- vation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol. 2005; 57(5):704-12. https://doi.org/10.1002/ana.20473 PMID: 15852397

56. Farrar MA, Vucic S, Johnston HM, du Sart D, Kiernan MC. Pathophysiological insights derived by natu- ral history and motor function of spinal muscular atrophy. J Pediatr. 2013; 162(1):155-9. https://doi.org/10.1016/j.jpeds.2012.05.067 PMID: 22809660

57. Lewelt A, Krosschell KJ, Scott C, Sakonju A, Kissel JT, Crawford TO, et al. Compound muscle action potential and motor function in children with spinal muscular atrophy. Muscle Nerve. 2010; 42(5):703-8. https://doi.org/10.1002/mus.21838 PMID: 20737553

58. Wadman RI, Vrancken AF, van den Berg LH, van der Pol WL. Dysfunction of the neuromuscular junct- ion in spinal muscular atrophy types 2 and 3. Neurology. 2012; 79(20):2050-5. https://doi.org/10.1212/WNL.0b013e3182749eca PMID: 23115209

59. Kobayashi DT, Shi J, Stephen L, Ballard KL, Dewey R, Mapes J, et al. SMA-MAP: a plasma protein panel for spinal muscular atrophy. PLoS One. 2013; 8(4):e60113. https://doi.org/10.1371/journal.pone.0060113 PMID: 23565191
60. Crawford TO, Paushkin SV, Kobayashi DT, Forrest SJ, Joyce CL, Finkel RS, et al. Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. PLoS One. 2012; 7(4):e33572. https://doi.org/10.1371/journal.pone.0033572 PMID: 22558076
60. Crawford TO, Paushkin SV, Kobayashi DT, Forrest SJ, Joyce CL, Finkel RS, et al. Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. PLoS One. 2012; 7(4):e33572. https://doi.org/10.1371/journal.pone.0033572 PMID: 22558076