Prospective and longitudinal natural history study of patients with Type 2 and 3 spinal muscular atrophy: Baseline data NatHis-SMA study

Abstract

Spinal muscular atrophy (SMA) is a monogenic disorder caused by loss of function mutations in the survival motor neuron 1 gene, which results in a broad range of disease severity, from neonatal to adult onset. There is currently a concerted effort to define the natural history of the disease and develop outcome measures that accurately capture its complexity. As several therapeutic strategies are currently under investigation and both the FDA and EMA have recently approved the first medical treatment for SMA, there is a critical need to identify the right association of responsive outcome measures and biomarkers for individual patient follow-up. As an approved treatment becomes available, untreated patients will soon become rare, further intensifying the need for a rapid, prospective and longitudinal study of the natural history of SMA Type 2 and 3. Here we present the baseline assessments of 81 patients aged 2 to 30 years of which 19 are non-sitter SMA Type 2, 34 are sitter SMA Type 2, 9 non-ambulant SMA Type 3 and 19 ambulant SMA Type 3. Collecting these data at nine sites in France, Germany and Belgium established the feasibility of gathering consistent data from numerous and demanding assessments in a multicenter SMA study. Most assessments discriminated between the four groups well. This included the Motor Function Measure (MFM), pulmonary function testing, strength, electroneuromyography, muscle imaging and workspace volume. Additionally, all of the assessments showed good correlation with the MFM score. As the untreated patient population decreases, having reliable and valid multi-site data will be imperative for recruitment in clinical trials. The pending two-year study results will evaluate the sensitivity of the studied outcomes and biomarkers to disease progression.

Trial registration: ClinicalTrials.gov (NCT02391831).

Conflict of interest statement

CV has received travel grants from Allergan and Roche for participation at meetings and has consultancy activities for Biogen and F. Hoffmann-La Roche; LV has served on scientific advisory board for Biogen and F. Hoffmann-La Roche; US has served on scientific advisory boards for Biogen, Novartis and F. Hoffmann-La Roche; JYH is co-inventor of the MyoGrip and MyoPinch devices; JYH and LS are co-inventors of the MoviPlate device; LPL is co-inventor of the ACTIVE system; PYB is employee of CRIS; TS, NH and ET are employees of Roche Group; LS is co-inventor of the ActiMyo device and has served on scientific advisory boards for AveXis, Biogen and F. Hoffmann-La Roche. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. CONSORT diagram.

1 As this manuscript was limited to baseline data, there were no withdrawal of participants. 2 To be defined as “sitter” the patient must have a score ≥ 1 on item 9 of the MFM (“with support of one or both upper limbs maintain the seated position for 5 seconds”). For 3 patients the MFM could not be performed at baseline. 2 were classified as sitters since they had a score of 3 at the 6-month follow-up visit and 1 was retrospectively classified as a non-sitter according to patient files. 3 To be defined as “Ambulant” the patient must be able to walk 10 meters without human assistance or use of an ambulation device such as a cane or a walker.

Fig 2. Psychomotor development of patients with SMA type 2 and 3.

A: General motor development; B: Fine motor development; Values for ages displayed on histograms are median (min-max); * p ≤ 0.05.

Fig 3. Example of MRI images of patients with SMA type 2 and 3.

A. Example of Dixon images and water T2 map in mildly (upper panel; non-ambulant SMA type 3) and more severely (lower panel; non-sitter SMA type 2) infiltrated patient forearms; B. Example of Dixon images and water T2 map in mildly (upper panel) and more severely (lower panel) infiltrated ambulant patient thighs; C. Example of series of spin echo images at increasing TEs (10 ms steps) in the forearm of a patient and the water T2 map reconstructed from this series using the tri-exp fitting method.

Fig 4. Correlation matrix between motor function (MFM) total score and other outcome measures.

Abbreviations: FVC: Forced Vital Capacity; MEP: Maximum Expiratory Pressure; MIP: Maximum Inspiratory Pressure; PCF: Peak Cough Flow; SNIP: Sniff Nasal Inspiratory Pressure; 6MWT: 6-Minutes-Walk Test; 10MWT: 10-Meters-Walk Test; nGyr: norm of the angular velocity of the wrist; nAcc: norm of the acceleration of the wrist; zAcc: vertical acceleration of the wrist; ADM: Abductor Digiti Minimi; CMAP: Compound Muscle Action Potentials; C-CSA: Contractile-Cross Section Area; Abnormal T2: percentage of voxels with abnormal T2 Values in red: Spearman’s correlation test with p ≤ 0.05.