TY - JOUR

T1 - Natural history of limb girdle muscular dystrophy R9 over 6 years

T2 - searching for trial endpoints

AU - Murphy, Alexander P

AU - Morrow, Jasper

AU - Dahlqvist, Julia R

AU - Stojkovic, Tanya

AU - Willis, Tracey A

AU - Sinclair, Christopher D J

AU - Wastling, Stephen

AU - Yousry, Tarek

AU - Hanna, Michael S

AU - James, Meredith K

AU - Mayhew, Anna

AU - Eagle, Michelle

AU - Lee, Laurence E

AU - Hogrel, Jean-Yves

AU - Carlier, Pierre G

AU - Thornton, John S

AU - Vissing, John

AU - Hollingsworth, Kieren G

AU - Straub, Volker

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

U2 - 10.1002/acn3.774

DO - 10.1002/acn3.774

M3 - Journal article

C2 - 31211167

VL - 6

SP - 1033

EP - 1045

JO - Annals of Clinical and Translational Neurology

JF - Annals of Clinical and Translational Neurology

SN - 2328-9503

IS - 6

ER -