Observational Study

. 2021 Jan 26;96(4):e587-e599.

doi: 10.1212/WNL.0000000000011051. Epub 2020 Oct 16.

Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study

Federica Trucco¹, Deborah Ridout¹, Mariacristina Scoto¹, Giorgia Coratti¹, Marion L Main¹, Robert Muni Lofra¹, Anna G Mayhew¹, Jacqueline Montes¹, Marika Pane¹, Valeria Sansone¹, Emilio Albamonte¹, Adele D'Amico¹, Enrico Bertini¹, Sonia Messina¹, Claudio Bruno¹, Deepak Parasuraman¹, Anne-Marie Childs¹, Vasantha Gowda¹, Tracey Willis¹, Min Ong¹, Chiara Marini-Bettolo¹, Darryl C De Vivo¹, Basil T Darras¹, John Day¹, Elizabeth A Kichula¹, Oscar H Mayer¹, Aledie A Navas Nazario¹, Richard S Finkel¹, Eugenio Mercuri¹, Francesco Muntoni²; International SMA Consortium (iSMAc)

Collaborators, Affiliations

Collaborators

International SMA Consortium (iSMAc):
Roberto De Sanctis, Alice Pirola, Antonella Longo, Maria Sframeli, Marina Pedemonte, Lindsey Pallant, Elizabeth Wraige, Sarah Turner, Kay White, Allan M Glanzman, Matthew Civitello, Angela Berardinelli, Giovanni Baranello, Stefan Spinty, Anirban Majumbdar, Imelda Huges, Deepa Krishnakumar, Gabriel Chow, Neil Thomas, Sithara Ramdas

Affiliations

¹ From the Dubowitz Neuromuscular Centre (F.T., M.S., M.L.M., F.M.) and Population, Policy and Practice Programme (D.R.), UCL GOS Institute of Child Health, London, UK; DINOGMI, University of Genoa (F.T.), IRCCS Istituto G. Gaslini, Italy; NIHR Great Ormond Street Hospital Biomedical Research Centre (D.R., F.M.), Great Ormond Street Institute of Child Health, University College London, and Great Ormond Street Hospital Trust, UK; Paediatric Neurology (G.C., M.P., E.M.), Catholic University; Centro Clinico Nemo (G.C., M.P., E.M.), Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy; John Walton Muscular Dystrophy Research Centre (R.M.L., C.M.-B.), Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; Departments of Neurology and Pediatrics (J.M., D.C.D.V.) and Departments of Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Paediatric Neurology and Centro Clinico Nemo (V.S., E.A.), Milan; Unit of Neuromuscular and Neurodegenerative Disorders (A.D., E.B.), Post-Graduate Bambino Gesù Children's Research Hospital, IRCCS, Rome; Department of Clinical and Experimental Medicine (S.M.), University of Messina Paediatric Neurology and Nemo Sud Clinical Centre; Center of Translational and Experimental Myology (C.B.), IRCCS Istituto Giannina Gaslini, Genova, Italy; University Hospitals Birmingham NHSFT (D.P.); Leeds Children Hospital (A.-M.C.); Evelina Children's Hospital (V.G.), London; The Robert Jones and Agnes Hunt Orthopaedic Hospital (T.W.), Oswestry; Sheffield Children's Hospital (M.O.), UK; Department of Neurology (B.T.D.), Boston Children's Hospital and Harvard Medical School, MA; Stanford University (J.D.), Medical Centre, Palo Alto, CA; Divisions of Pediatric Neurology (E.A.K.), Pulmonology (O.H.M.) and Physical Therapy (A.M.G.), The Children's Hospital of Philadelphia, and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia; and Divisions of Neurology (R.S.F.) and Pulmonary Medicine (A.A.N.N.), Department of Pediatrics, Nemours Children's Hospital, Orlando, FL.
² From the Dubowitz Neuromuscular Centre (F.T., M.S., M.L.M., F.M.) and Population, Policy and Practice Programme (D.R.), UCL GOS Institute of Child Health, London, UK; DINOGMI, University of Genoa (F.T.), IRCCS Istituto G. Gaslini, Italy; NIHR Great Ormond Street Hospital Biomedical Research Centre (D.R., F.M.), Great Ormond Street Institute of Child Health, University College London, and Great Ormond Street Hospital Trust, UK; Paediatric Neurology (G.C., M.P., E.M.), Catholic University; Centro Clinico Nemo (G.C., M.P., E.M.), Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy; John Walton Muscular Dystrophy Research Centre (R.M.L., C.M.-B.), Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; Departments of Neurology and Pediatrics (J.M., D.C.D.V.) and Departments of Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Paediatric Neurology and Centro Clinico Nemo (V.S., E.A.), Milan; Unit of Neuromuscular and Neurodegenerative Disorders (A.D., E.B.), Post-Graduate Bambino Gesù Children's Research Hospital, IRCCS, Rome; Department of Clinical and Experimental Medicine (S.M.), University of Messina Paediatric Neurology and Nemo Sud Clinical Centre; Center of Translational and Experimental Myology (C.B.), IRCCS Istituto Giannina Gaslini, Genova, Italy; University Hospitals Birmingham NHSFT (D.P.); Leeds Children Hospital (A.-M.C.); Evelina Children's Hospital (V.G.), London; The Robert Jones and Agnes Hunt Orthopaedic Hospital (T.W.), Oswestry; Sheffield Children's Hospital (M.O.), UK; Department of Neurology (B.T.D.), Boston Children's Hospital and Harvard Medical School, MA; Stanford University (J.D.), Medical Centre, Palo Alto, CA; Divisions of Pediatric Neurology (E.A.K.), Pulmonology (O.H.M.) and Physical Therapy (A.M.G.), The Children's Hospital of Philadelphia, and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia; and Divisions of Neurology (R.S.F.) and Pulmonary Medicine (A.A.N.N.), Department of Pediatrics, Nemours Children's Hospital, Orlando, FL. f.muntoni@ucl.ac.uk.

PMID: 33067401
PMCID: PMC7905794
DOI: 10.1212/WNL.0000000000011051

Observational Study

Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study

Federica Trucco et al. Neurology. 2021.

. 2021 Jan 26;96(4):e587-e599.

doi: 10.1212/WNL.0000000000011051. Epub 2020 Oct 16.

Authors

Collaborators

International SMA Consortium (iSMAc):
Roberto De Sanctis, Alice Pirola, Antonella Longo, Maria Sframeli, Marina Pedemonte, Lindsey Pallant, Elizabeth Wraige, Sarah Turner, Kay White, Allan M Glanzman, Matthew Civitello, Angela Berardinelli, Giovanni Baranello, Stefan Spinty, Anirban Majumbdar, Imelda Huges, Deepa Krishnakumar, Gabriel Chow, Neil Thomas, Sithara Ramdas

Affiliations

¹ From the Dubowitz Neuromuscular Centre (F.T., M.S., M.L.M., F.M.) and Population, Policy and Practice Programme (D.R.), UCL GOS Institute of Child Health, London, UK; DINOGMI, University of Genoa (F.T.), IRCCS Istituto G. Gaslini, Italy; NIHR Great Ormond Street Hospital Biomedical Research Centre (D.R., F.M.), Great Ormond Street Institute of Child Health, University College London, and Great Ormond Street Hospital Trust, UK; Paediatric Neurology (G.C., M.P., E.M.), Catholic University; Centro Clinico Nemo (G.C., M.P., E.M.), Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy; John Walton Muscular Dystrophy Research Centre (R.M.L., C.M.-B.), Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; Departments of Neurology and Pediatrics (J.M., D.C.D.V.) and Departments of Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Paediatric Neurology and Centro Clinico Nemo (V.S., E.A.), Milan; Unit of Neuromuscular and Neurodegenerative Disorders (A.D., E.B.), Post-Graduate Bambino Gesù Children's Research Hospital, IRCCS, Rome; Department of Clinical and Experimental Medicine (S.M.), University of Messina Paediatric Neurology and Nemo Sud Clinical Centre; Center of Translational and Experimental Myology (C.B.), IRCCS Istituto Giannina Gaslini, Genova, Italy; University Hospitals Birmingham NHSFT (D.P.); Leeds Children Hospital (A.-M.C.); Evelina Children's Hospital (V.G.), London; The Robert Jones and Agnes Hunt Orthopaedic Hospital (T.W.), Oswestry; Sheffield Children's Hospital (M.O.), UK; Department of Neurology (B.T.D.), Boston Children's Hospital and Harvard Medical School, MA; Stanford University (J.D.), Medical Centre, Palo Alto, CA; Divisions of Pediatric Neurology (E.A.K.), Pulmonology (O.H.M.) and Physical Therapy (A.M.G.), The Children's Hospital of Philadelphia, and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia; and Divisions of Neurology (R.S.F.) and Pulmonary Medicine (A.A.N.N.), Department of Pediatrics, Nemours Children's Hospital, Orlando, FL.
² From the Dubowitz Neuromuscular Centre (F.T., M.S., M.L.M., F.M.) and Population, Policy and Practice Programme (D.R.), UCL GOS Institute of Child Health, London, UK; DINOGMI, University of Genoa (F.T.), IRCCS Istituto G. Gaslini, Italy; NIHR Great Ormond Street Hospital Biomedical Research Centre (D.R., F.M.), Great Ormond Street Institute of Child Health, University College London, and Great Ormond Street Hospital Trust, UK; Paediatric Neurology (G.C., M.P., E.M.), Catholic University; Centro Clinico Nemo (G.C., M.P., E.M.), Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy; John Walton Muscular Dystrophy Research Centre (R.M.L., C.M.-B.), Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; Departments of Neurology and Pediatrics (J.M., D.C.D.V.) and Departments of Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Paediatric Neurology and Centro Clinico Nemo (V.S., E.A.), Milan; Unit of Neuromuscular and Neurodegenerative Disorders (A.D., E.B.), Post-Graduate Bambino Gesù Children's Research Hospital, IRCCS, Rome; Department of Clinical and Experimental Medicine (S.M.), University of Messina Paediatric Neurology and Nemo Sud Clinical Centre; Center of Translational and Experimental Myology (C.B.), IRCCS Istituto Giannina Gaslini, Genova, Italy; University Hospitals Birmingham NHSFT (D.P.); Leeds Children Hospital (A.-M.C.); Evelina Children's Hospital (V.G.), London; The Robert Jones and Agnes Hunt Orthopaedic Hospital (T.W.), Oswestry; Sheffield Children's Hospital (M.O.), UK; Department of Neurology (B.T.D.), Boston Children's Hospital and Harvard Medical School, MA; Stanford University (J.D.), Medical Centre, Palo Alto, CA; Divisions of Pediatric Neurology (E.A.K.), Pulmonology (O.H.M.) and Physical Therapy (A.M.G.), The Children's Hospital of Philadelphia, and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia; and Divisions of Neurology (R.S.F.) and Pulmonary Medicine (A.A.N.N.), Department of Pediatrics, Nemours Children's Hospital, Orlando, FL. f.muntoni@ucl.ac.uk.

PMID: 33067401
PMCID: PMC7905794
DOI: 10.1212/WNL.0000000000011051

Abstract

Objective: To describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA).

Methods: This was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy.

Results: There were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8-16.6) and 15.1 (13.8-16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes.

Conclusions: In SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.

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Figures

**Figure 1. CONSORT Flowchart of Patients Included in the Final Analysis According to Inclusion and Exclusion Criteria**
Data were available for 673 patients in the whole cohort. Patients >18 years of age, patients enrolled in interventional clinical trial, and patients with spinal muscle atrophy (SMA) type 3 ambulant at the first recorded visit were excluded. The breakdown of patients (n = 437) included in the analysis refers to first visit. CONSORT = Consolidated Standards of Reporting Trials.

**Figure 2. Rate of Decline of FVC%P in SMA Type 2, SMA Type 2 Sitters, and SMA Type 3**
(A) Spinal muscle atrophy (SMA) type 2 (632 observations from 200 patients). The slope of forced vital capacity (FVC) percent predicted (FVC%P) at age 5 to 13 years was −4.2 (95% confidence interval [CI] −4.8 to −3.7, p < 0.01) and after age 13 years was −1.0 (95% CI −2.1 to 0.2, p = 0.1). The 2 slopes were significantly different (p < 0.001). (B) SMA type 2 sitters (565 observation from 165 patients). The slope of FVC%P at age 5 to 13 years was −4.1%/y (95% CI −4.7 to −3.5, p < 0.001) and after age 13 years was −1.3 (95% CI −2.5 to −0.04, p = 0.04). The 2 slopes were significantly different (p < 0.001). (C) SMA type 3 nonambulant (151 observations from 59 patients). FVC%P improved mildly from age 5 to 8 years by 11.8 (95% CI 4.5–19.1, p = 0.002) before declining from age 8 to 13 years by 6.3 (95% CI −8.7 to −3.8, p < 0.001). After age 13 years, FVC%P slope declined by 0.9 (95% CI −3.1 to 1.4, p = 0.46). The slopes for 5 to 8 and 8 to 13 years were significantly different (p < 0.001 and p < 0.01).

**Figure 3. Age at Clinically Meaningful Thresholds of FVC%P (60%, 40%, 20%) in SMA Type 2 and 3.**
(A) At age 9.5 years, 25% of patients with spinal muscle atrophy (SMA) type 2 had forced vital capacity percent predicted (FVC%P) below 60%. Median (50%) age at FVC%P <60% was 12.8 years for SMA type 2. Fewer than 25% of patients with SMA type 3 had FVC%P below 60% (p < 0.001). (B) At age 13.4 years, 25% of patients with SMA type 2 and <20% of patients with SMA type 3 had FVC%P below 40% predicted (p < 0.01). (C) Fewer than 25% of patients with SMA type 2 and none of those with SMA type 3 had FVC%P below 20%.

**Figure 4. Slope of FVC%P Before and After Spinal Surgery in SMA Types 2 and 3**
(A) Overall population. Forced vital capacity percent predicted (FVC%P) declined yearly by 2.7% before scoliosis surgery and declined by 3.6% afterward (p = 0.22). (B) Spinal muscle atrophy (SMA) type 2 nonsitters. FVC%P increased by 2.4%/y before scoliosis surgery and declined by 5.2% afterward (p = 0.19). (C) SMA 2 sitters. FVC%P declined yearly by 2.8% before scoliosis surgery and declined by 3.4% afterward (p = 0.49). (D) SMA 3 nonambulant. FVC%P declined by 1.3%/y before scoliosis surgery and declined by 4.2% afterward (p = 0.48).

**Figure 5. Correlation Between Respiratory and Motor Function in SMA Types 2 and 3 at First Available Visit**
(A) Correlation between forced vital capacity (FVC) percent predicted (FVC%P) and Hammersmith Functional Motor Scale (HFMS) score in spinal muscle atrophy (SMA) type 2 (r = 0.67, p < 0.001) and SMA type 3 nonambulant (r = 0.68, p < 0.001). (B) Correlation between FVC%P and revised Upper Limb Module (RULM) score in SMA type 2 (r = 0.61 p < 0.001) and SMA type 3 nonambulant (r = 0.61, p < 0.01).

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Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study

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Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study

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