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Observational Study
. 2021 Feb;8(2):359-373.
doi: 10.1002/acn3.51281. Epub 2020 Dec 24.

Natural history of Type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study

Mélanie Annoussamy  1   2 , Andreea M Seferian  1 , Aurore Daron  3 , Yann Péréon  4 , Claude Cances  5   6 , Carole Vuillerot  7   8 , Liesbeth De Waele  9   10 , Vincent Laugel  11 , Ulrike Schara  12 , Teresa Gidaro  1 , Charlotte Lilien  1   13 , Jean-Yves Hogrel  1 , Pierre Carlier  1 , Emmanuel Fournier  1 , Linda Lowes  14 , Ksenija Gorni  15 , Myriam Ly-Le Moal  16 , Nicole Hellbach  17 , Timothy Seabrook  17 , Christian Czech  17   18 , Ricardo Hermosilla  17 , Laurent Servais  1   13   19 ; NatHis-SMA study group
Affiliations
Observational Study

Natural history of Type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study

Mélanie Annoussamy et al. Ann Clin Transl Neurol. 2021 Feb.

Erratum in

Abstract

Objective: To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials.

Methods: Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease-modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo® ), quantitative magnetic resonance imaging (fat fraction [FFT2 ] mapping and contractile cross-sectional area [C-CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels.

Results: MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FFT2 increased over 12 and 24 months, although not with statistical significance. A significant increase in C-CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months.

Interpretation: These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo® enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months.

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Conflict of interest statement

MA is an employee of Sysnav; AD received personal fees from AveXis for Scientific Advisory Boards (SAB) and is Principal Investigator for SMA trials for Hoffmann‐La Roche and AveXis; LDW attended SAB of F. Hoffmann‐La Roche Ltd, Biogen and AveXis and received consultancy fees from Biogen and AveXis; VL received consulting fees for Biogen, Roche, Avexis, PTC therapeutics, Sarepta; US received honoraria for participation in SAB and industry symposia from Biogen, Roche, and Avexis; CL attended SAB of Biogen and received consultancy fees from Biogen, Sysnav, and F. Hoffmann‐La Roche Ltd; JYH received consulting fees for Biogen and Sarepta. He is co‐inventor of Myogrip and Myopinch; KG and NH are employees of, and holds shares in F. Hoffmann‐La Roche Ltd; MLL is an employee of Institut Roche; TS, CC, and RH are former employees and hold shares in F. Hoffmann‐La Roche Ltd; LS is a principal investigator of SMA studies for F. Hoffmann‐La Roche Ltd, Biogen, and AveXis; he has attended SAB of F. Hoffmann‐La Roche Ltd, Biogen, and AveXis and received consultancy fees from Biogen; he serves on the board for Cytokinetics. He is co‐inventor in the patent 20190029605 (Method for estimating physical activity of the upper limb) from which he has not perceived any financial interest; CC, EF, YP, AMS, PC, CV, LL, and TG report no conflict of interest.

Figures

Figure 1
Figure 1
CONSORT diagram. Reasons for premature withdrawal include: (A) loss of follow‐up; (B) consent withdrawal; (C) physician decision; (D) enrollment into other clinical trials; (E) initiation of nusinersen treatment; (F) other; and (G) missed visit. SMA, spinal muscular atrophy.
Figure 2
Figure 2
MFM total scores from baseline to 24 months in individuals with SMA according to age and SMA type. MFM20 was used in patients < 6 years of age; MFM32 was used in patients ≥ 6 years of age. For patients aged 4–6 years old, the physiotherapist selected the most appropriate version based on the child's motor function abilities. Each line represents the trajectory of one patient over 24 months. Assessments were made at baseline, Month 6, 12, 18, and 24. MFM, motor function measure; MFM20, 20‐item MFM; MFM32, 32‐item MFM.
Figure 3
Figure 3
Change in grip strength over 24 months by (A) SMA type and (B) age. Grip strength was measured as a percentage of predictive values based on age using MyoGrip at baseline, Month 6, 12, 18, and 24 (Month 12, n = 38; Month 24, n = 27). Higher values reflect a higher level of upper arm strength. A) Closed circles represent outliers. B) Each line represents the trajectory of one patient over 24 months. SMA, spinal muscular atrophy.
Figure 4
Figure 4
Change in mean pinch strength over 24 months by (A) SMA type and (B) age. Pinch strength was measured as a percentage of predictive values based on age using MyoPinch at baseline, Month 6, 12, 18, and 24. (Month 12, n = 37; Month 24, n = 27). Higher values reflect a higher level of upper arm strength. A) Closed circles represent outliers and B) Each line represents the trajectory of one patient over 24 months. SMA, spinal muscular atrophy.
Figure 5
Figure 5
(A) Change in FVC over 24 months according to age. B–E) Change in FVC, MIP, MEP, and PCF over 24 months by SMA type. (A/B) FVC change was measured using the Vitalograph spirometer at baseline, Month 6, 12, 18, and 24 (Month 12, n = 40; Month 24, n = 27). Each line represents the trajectory of one patient over 24 months. (C) MIP was evaluated using the MicroRPM device at baseline, Month 6, 12, 18, and 24 (Month 12, n = 40; Month 24, n = 27). (D) MEP was evaluated using the MicroRPM device at baseline, Month 6, 12, 18, and 24 (Month 12, n = 40; Month 24, n = 27). (E) PCF was measured using the Vitalograph spirometer at baseline, Month 6, 12, 18, and 24 (Month 12, n = 40; Month 24, n = 26). Closed circles represent outliers. FVC, forced vital capacity; MEP, minimum expiratory pressure; MIP, minimum inspiratory pressure; PCF, peak cough flow; SMA, spinal muscular atrophy.
Figure 6
Figure 6
SMN protein levels over 24 months in individuals with SMA according to age and SMA type. Each line represents an individual with SMA. Assessments were made at baseline, Month 6, 12, 18, and 24 (Month 12, n = 69; Month 24, n = 35). SMA, spinal muscular atrophy; SMN, survival of motor neuron.
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