[en] OBJECTIVE: To understand the natural disease upper limb progression over 3 years of ambulatory and non-ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors. METHODS: Forty boys with DMD (22 non-ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53-skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly. RESULTS: In the whole population, there were strong nonlinear correlations between outcome measures. In non-ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI-based FF, hand grip and key pinch, and MFM. Boys who presented with a FF<20% and a grip strength >27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF <10% retained ambulation 3 years later. INTERPRETATION: We demonstrate that continuous decline in upper limb strength, function, and MRI measured muscle structure can be reliably measured in ambulatory and non-ambulatory boys with DMD with high SRM and strong correlations between outcomes. Our results suggest that a combination of grip strength and FF can be used to predict important motor milestones.
Disciplines :
Pediatrics Neurology
Author, co-author :
Lilien, Charlotte
Reyngoudt, Harmen
Seferian, Andreea Mihaela
Gidaro, Teresa
Annoussamy, Mélanie
Chê, Virginie
Decostre, Valérie
Ledoux, Isabelle
Le Louër, Julien
Guemas, Eric
Muntoni, Francesco
Hogrel, Jean-Yves
Carlier, Pierre Georges
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
Crisafulli S, Sultana J, Fontana A, et al. Global epidemiology of Duchenne muscular dystrophy: an updated systematic review and meta-analysis. Orphanet J Rare Dis 2020;15:141.
Bello L, Gordish-Dressman H, Morgenroth LP, et al. Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne Natural History Study. Neurology 2015;85:1048–1055.
Brogna C, Coratti G, Pane M, et al. Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53. PLoS One 2019;14:e0218683.
Connolly AM, Malkus EC, Mendell JR, et al. Outcome reliability in non-ambulatory boys/men with Duchenne muscular dystrophy. Muscle Nerve 2015;51:522–532.
Mayer OH, Leinonen M, Rummey C, Meier T, Buyse GM; Group DS. Efficacy of idebenone to preserve respiratory function above clinically meaningful thresholds for forced vital capacity (FVC) in patients with Duchenne muscular dystrophy. J Neuromusc Dis 2017;4:189–198.
Hogrel J-Y, Wary C, Moraux A, et al. Longitudinal functional and NMR assessment of upper limbs in Duchenne muscular dystrophy. Neurology 2016;86:1022–1030.
Ricotti V, Evans MRB, Sinclair CDJ, et al. Upper limb evaluation in Duchenne muscular dystrophy: fat-water quantification by MRI, muscle force and function define endpoints for clinical trials. PLoS One 2016;11:e0162542.
Vuillerot C, Girardot F, Payan C, et al. Monitoring changes and predicting loss of ambulation in Duchenne muscular dystrophy with the Motor Function Measure. Dev Med Child Neurol 2010;52:60–65.
Servais L, Deconinck N, Moraux A, et al. Innovative methods to assess upper limb strength and function in non-ambulant Duchenne patients. Neuromuscul Disord 2013;23:139–148.
Seferian AM, Moraux A, Annoussamy M, et al. Upper limb strength and function changes during a one-year follow-up in non-ambulant patients with Duchenne Muscular Dystrophy: an observational multicenter trial. PLoS One 2015;10:e0113999.
Seferian AM, Moraux A, Canal A, 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:e0121799.
Pane M, Coratti G, Brogna C, et al. Upper limb function in Duchenne muscular dystrophy: 24 month longitudinal data. PLoS One 2018;13:e0199223.
Mayhew AG, Coratti G, Mazzone ES, et al. Performance of Upper Limb module for Duchenne muscular dystrophy. Dev Med Child Neurol 2020;62:633–639.
Connolly AM, Florence JM, Zaidman CM, et al. Clinical trial readiness in non-ambulatory boys and men with Duchenne muscular dystrophy: MDA-DMD network follow-up. Muscle Nerve 2016;54:681–689.
Le Moing A-G, Seferian AM, Moraux A, 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:e0156696.
Lee HN, Sawnani H, Horn PS, et al. The Performance of the Upper Limb scores correlate with pulmonary function test measures and Egen Klassifikation scores in Duchenne muscular dystrophy. Neuromuscul Disord 2016;26:264–271.
Steffensen B, Hyde S, Lyager S, Mattsson E. Validity of the EK scale: a functional assessment of non-ambulatory individuals with Duchenne muscular dystrophy or spinal muscular atrophy. Physiother Res Int 2001;6:119–134.
Szigyarto CA, Spitali P. Biomarkers of Duchenne muscular dystrophy: current findings. Degener Neurol Neuromuscul Dis 2018;8:1–13.
Ropars J, Gravot F, Ben Salem D, et al. Muscle MRI: a biomarker of disease severity in Duchenne muscular dystrophy? A systematic review. Neurology 2020;94:117–133.
Willcocks RJ, Rooney WD, Triplett WT, et al. Multicenter prospective longitudinal study of magnetic resonance biomarkers in a large Duchenne muscular dystrophy cohort. Ann Neurol 2016;79:535–547.
Silva EC, Machado DL, Resende MB, et al. Motor function measure scale, steroid therapy and patients with Duchenne muscular dystrophy. Arq Neuropsiquiatr 2012;70:191–195.
Killian M, Buchowski MS, Donnelly T, et al. Beyond ambulation: measuring physical activity in youth with Duchenne muscular dystrophy. Neuromuscul Disord 2020;30:277–282.
Servais L, Montus M, Guiner CL, et al. Non-ambulant Duchenne patients theoretically treatable by exon 53 skipping have severe phenotype. J Neuromusc Dis 2015;2:269–279.
Le Guiner C, Montus M, Servais L, et al. Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients. Mol Ther 2014;22:1923–1935.
Frank DE, Schnell FJ, Akana C, et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology 2020;94:e2270–e2282.
Scaglioni D, Catapano F, Ellis M, et al. The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy. Acta Neuropathol Commun 2021;9:7.
Arora H, Willcocks RJ, Lott DJ, et al. Longitudinal timed function tests in Duchenne muscular dystrophy: ImagingDMD cohort natural history. Muscle Nerve 2018;58:631–638.
Bulut N, Gurbuz I, Yilmaz O, et al. The association of hand grip strength with functional measures in non-ambulatory children with Duchenne muscular dystrophy. Arq Neuropsiquiatr 2019;77:792–796.
Demir G, Bulut N, Yılmaz Ö, et al. Manual ability and upper limb performance in nonambulatory stage of Duchenne muscular dystrophy. Arch Pediatr 2020;27:304–309.
Forbes SC, Arora H, Willcocks RJ, et al. Upper and lower extremities in Duchenne muscular dystrophy evaluated with quantitative MRI and proton MR spectroscopy in a Multicenter Cohort. Radiology 2020;295:616–625.
Annoussamy M, Seferian AM, Daron A, et al. Natural history of Type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study. Ann Clin Transl Neurol 2021;8:359–373.
Hogrel J-Y, Decostre V, Ledoux I, et al. Normalized grip strength is a sensitive outcome measure through all stages of Duchenne muscular dystrophy. J Neurol 2020;267:2022–2028.
Naarding KJ, Reyngoudt H, van Zwet EW, et al. MRI vastus lateralis fat fraction predicts loss of ambulation in Duchenne muscular dystrophy. Neurology 2020;94:e1386–e1394.
Rooney WD, Berlow YA, Triplett WT, et al. Modeling disease trajectory in Duchenne muscular dystrophy. Neurology 2020;94:e1622–e1633.
Brooke MH, Griggs RC, Mendell JR, et al. Clinical trial in Duchenne dystrophy. I. The design of the protocol. Muscle Nerve 1981;4:186–197.
Mercuri E, McDonald C, Mayhew A, et al. International workshop on assessment of upper limb function in Duchenne Muscular Dystrophy: Rome, 15–16 February 2012. Neuromuscul Disord 2012;22:1025–1028.
Dangouloff T, Servais L. Clinical evidence supporting early treatment of patients with spinal muscular atrophy: current perspectives. Ther Clin Risk Manag 2019;15:1153–1161.
Muntoni F, Domingos J, Manzur AY, et al. Categorising trajectories and individual item changes of the North Star Ambulatory Assessment in patients with Duchenne muscular dystrophy. PLoS One 2019;14:e0221097.
Mayhew A, Mazzone ES, Eagle M, et al. Development of the performance of the upper limb module for Duchenne muscular dystrophy. Dev Med Child Neurol 2013;55:1038–1045.
Bylo M, Farewell R, Coppenrath VA, Yogaratnam D. A review of deflazacort for patients with Duchenne muscular dystrophy. Ann Pharmacother 2020;54:788–794.
Schreiber A, Brochard S, Rippert P, et al. Corticosteroids in Duchenne muscular dystrophy: impact on the motor function measure sensitivity to change and implications for clinical trials. Dev Med Child Neurol 2018;60:185–191.
