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Ann Clin Transl Neurol. 2019 May 16;6(6):1033-1045. doi: 10.1002/acn3.774. eCollection 2019 Jun.

Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints.

Author information

1
The John Walton Muscular Dystrophy Research Centre Institute of Genetic Medicine Newcastle University Newcastle Hospitals NHS Foundation Trust Central Parkway Newcastle Upon Tyne United Kingdom NE1 4EP.
2
Department of Molecular Neurosciences MRC Centre for Neuromuscular Diseases UCL Institute of Neurology London United Kingdom.
3
Department of Neurology Copenhagen Neuromuscular Center Rigshospitalet University of Copenhagen Blegdamsvej 9 2100 Copenhagen Denmark.
4
Institute of Myology AP6HP, G-H Pitié-Salpêtrière 47-83 boulevard de l'hôpital 75651 Paris Cedex 13 France.
5
The Robert Jones and Agnes Hunt Orthopaedic Hospital Oswestry Shropshire United Kingdom.
6
Institute of Myology Neuromuscular Investigation Center Pitié-Salpêtrière Hospital Paris France.
7
Newcastle Magnetic Resonance Centre Institute of Cellular Medicine Newcastle University Newcastle upon Tyne United Kingdom.

Abstract

Objective:

Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years.

Methods:

Twenty-three participants with LGMD R9, previously assessed over a 1-year period, were re-enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups.

Results:

At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1-year follow-up study. In direct contrast to the 1-year follow-up, the 6-min walk test, 10-m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1- and 6-year studies.

Interpretation:

These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression.

Conflict of interest statement

APM, JM, JD, TS, CS, SW, MH, LL, JVH, and PC report no conflict of interest. Professor Willis has served on advisory boards for PTC pharmaceuticals, Genzyme Sanofi, Sarepta and Biogen and has received honorariums for lectures and symposium from PTC pharmaceuticals, Genzyme Sanofi and Biogen. Yousry has received honoraria and travel expenses for advisory committee work from Bayer Schering, Biogen Idec, and Novartis; and research grants (held by University College London) from Biogen Idec, GlaxoSmithKline, Novartis, and Schering AG for analysis of data from MS trials. James performs consultancy work (training physiotherapists) for: Roche, Pfizer, PTC, Summit, Sarepta, Santhera, Italfarmaco, Amicus and has participated in advisory boards for PTC Therapeutics. Mayhew performs consultancy work (training physiotherapists) for: Roche, Avexis, Biogen, Pfizer, PTC, Summit, Sarepta, Santhera, Italfarmaco, Amicus, Tamoxifen noncommercial study for DMD and has participated in advisory boards for: PTC, AMO Pharma, Roche, Summit, Biogen, Modus, Novartis. Eagle performs consultancy work for: Biomarin, GSK, Prosensa, Italfarmaco, Amicus, Capricor, Catabasis, Eli Lilly, Fibrogen, MNK, PTC, Santhera, Solid, Summit, Sarepta, Theracon, Reveragen and Wave. Thornton has received research support from GlaxoSmithKline, Medtronic, and Siemens. Vissing has received research and travel support, and speaker honoraria from Sanofi Genzyme, Ultragenyx Pharmaceuticals, Santhera Pharmaceuticals and aTyr Pharma, and served as consultant on advisory boards for Sanofi/Genzyme, aTyr pharma, Ultragenyx Pharmaceuticals, Santhera Pharmaceuticals, Sarepta Therapeutics, Audentes Therapeutics and Stealth Biotherapeutics within the last 3 years. Hollingsworth reports grants from the United Kingdom Medical Research Council, Diabetes UK, the European Union (H2020, 667078) and the Newcastle Healthcare Charity, consultancy for Summit pharmaceuticals and trial support from ImagingDMD outside the submitted work. All reimbursements were received by Newcastle University, no personal benefits were received. Straub has or had been a chief/principal investigator for trials sponsored by Sanofi Genzyme, GSK, Prosensa/Biomarin, Ionis Pharmceuticals, and Sarepta and a subinvestigator for many other commercial studies. He received speaker honoraria from Sanofi Genzyme and is or has been on advisory boards for Audentes Therapeutics, Biogen, Biomarin, Bristol‐Myer Squibb, Exonics Therapeutics, Italfarmaco S.p.A., Nicox, Sanofi Genzyme, Santhera Pharmaceuticals, Sarepta Therapeutics, Summit Therapeutics, Tivorsan, TrophyNOD, and Wave Therapeutics. He received funding for research collaboration with Ultragenyx and Sanofi Genzyme.

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