Abstract
BackgroundPathogenic variants in the FKRP gene cause impaired glycosylation of α-dystroglycan in muscle, producing a limb-girdle muscular dystrophy with cardiomyopathy. Despite advances in understanding the pathophysiology of FKRP-associated myopathies, clinical research in the limb-girdle muscular dystrophies has been limited by the lack of normative biomarker data to gauge disease progression.MethodsParticipants in a phase 2 clinical trial were evaluated over a 4-month, untreated lead-in period to evaluate repeatability and to obtain normative data for timed function tests, strength tests, pulmonary function, and body composition using DEXA and whole-body MRI. Novel deep learning algorithms were used to analyze MRI scans and quantify muscle, fat, and intramuscular fat infiltration in the thighs. T-tests and signed rank tests were used to assess changes in these outcome measures.ResultsNineteen participants were observed during the lead-in period for this trial. No significant changes were noted in the strength, pulmonary function, or body composition outcome measures over the 4-month observation period. One timed function measure, the 4-stair climb, showed a statistically significant difference over the observation period. Quantitative estimates of muscle, fat, and intramuscular fat infiltration from whole-body MRI corresponded significantly with DEXA estimates of body composition, strength, and timed function measures.ConclusionsWe describe normative data and repeatability performance for multiple physical function measures in an adult FKRP muscular dystrophy population. Our analysis indicates that deep learning algorithms can be used to quantify healthy and dystrophic muscle seen on whole-body imaging.Trial registrationThis study was retrospectively registered in clinicaltrials.gov (NCT02841267) on July 22, 2016 and data supporting this study has been submitted to this registry.
Highlights
Pathogenic variants in the Fukutin-related protein (FKRP) gene cause impaired glycosylation of α-dystroglycan in muscle, producing a limb-girdle muscular dystrophy with cardiomyopathy
Pathogenic variants in FKRP cause an autosomal recessive muscular dystrophy that is most commonly known as limb-girdle muscular dystrophy 2I (LGMD2I), emerging classification schemes refer to this disease as LGMD R9 [2]
Pulmonary function testing using a bedside spirometer was performed by the clinical evaluator and forced vital capacity (FVC), forced expiratory volume (FEV1), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) measurements were obtained
Summary
Pathogenic variants in the FKRP gene cause impaired glycosylation of α-dystroglycan in muscle, producing a limb-girdle muscular dystrophy with cardiomyopathy. Despite advances in understanding the pathophysiology of FKRP-associated myopathies, clinical research in the limb-girdle muscular dystrophies has been limited by the lack of normative biomarker data to gauge disease progression. The limb-girdle muscular dystrophies are a class of genetic muscle diseases that are characterized by progressive muscle weakness. Several limb-girdle muscular dystrophies are caused by pathogenic variants in genes that regulate glycosylation of α-dystroglycan in the sarcolemma. Pathogenic variants in FKRP cause an autosomal recessive muscular dystrophy that is most commonly known as limb-girdle muscular dystrophy 2I (LGMD2I), emerging classification schemes refer to this disease as LGMD R9 [2]. There is currently no curative medical treatment for LGMD2I, and the management is primarily supportive
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