Longitudinal Analysis of Respiratory Function of Different Types of Limb Girdle Muscular Dystrophies Reveals Independent Trajectories

Robert Muni-Lofra; Eduard Juanola-Mayos; Marianela Schiava; Dionne Moat; Maha Elseed; Jassi Michel-Sodhi; Elizabeth Harris; Michelle McCallum; Ursula Moore; Mark Richardson; Christina Trainor; Karen Wong; Monika Malinova; Carla Bolano-Diaz; Michael John Keogh; Elisabetta Ghimenton; Jose Verdu-Diaz; Anna Mayhew; Michela Guglieri; Volker Straub; Meredith K James; Chiara Marini-Bettolo; Jordi Diaz-Manera

doi:10.1212/NXG.0000000000200084

Longitudinal Analysis of Respiratory Function of Different Types of Limb Girdle Muscular Dystrophies Reveals Independent Trajectories

Neurol Genet. 2023 Jul 10;9(4):e200084. doi: 10.1212/NXG.0000000000200084. eCollection 2023 Aug.

Authors

Robert Muni-Lofra¹, Eduard Juanola-Mayos¹, Marianela Schiava¹, Dionne Moat¹, Maha Elseed¹, Jassi Michel-Sodhi¹, Elizabeth Harris¹, Michelle McCallum¹, Ursula Moore¹, Mark Richardson¹, Christina Trainor¹, Karen Wong¹, Monika Malinova¹, Carla Bolano-Diaz¹, Michael John Keogh¹, Elisabetta Ghimenton¹, Jose Verdu-Diaz¹, Anna Mayhew¹, Michela Guglieri¹, Volker Straub¹, Meredith K James¹, Chiara Marini-Bettolo¹, Jordi Diaz-Manera¹

Affiliation

¹ From the John Walton Muscular Dystrophy Research Centre (R.M.-L., M.S., D.M., M.E., J.M.-S., E.H., M. McCallum, U.M., M.R., C.T., K.W., M. Malinova, C.B.-D., M.J.K., E.G., J.V.-D., A.M., M.G., V.S., M.K.J., C.M.-B., J.D.-M.), Translational and Clinical Research Institute, Newcastle University, UK; Highly Specialized Service for Rare Neuromuscular Disorders (R.M.-L., M.S., D.M., M.E., J.M.-S., E.H., M. McCallum, U.M., M.R., C.T., K.W., M. Malinova, C.B.-D., M.J.K., E.G., J.V.-D., A.M., M.G., V.S., M.K.J., C.M.-B., J.D.-M.), Limb Girdle Muscular Dystrophies, Genetics Department, Integrated Laboratory Medicine, Newcastle Upon Tyne Hospitals NHS Foundation Trust, United Kingdom; and Neuromuscular Diseases Unit, Neurology Department, Hospital Germans Tries I Pujol (E.J.-M.), Badalona, Spain.

Abstract

Background and objectives: The prevalence and progression of respiratory muscle dysfunction in patients with limb girdle muscular dystrophies (LGMDs) has been only partially described to date. Most reports include cross-sectional data on a limited number of patients making it difficult to gain a wider perspective on respiratory involvement throughout the course of the disease and to compare the most prevalent LGMD subtypes.

Methods: We reviewed the results of spirometry studies collected longitudinally in our cohort of patients in routine clinical visits from 2002 to 2020 along with additional clinical and genetic data. A linear mixed model was used to investigate the factors associated with the progression of respiratory dysfunction.

Results: We followed up 156 patients with 5 different forms of LGMDs for a median of 8 years (range 1-25 years). Of them, 53 patients had pathogenic variants in the Capn3 gene, 47 patients in the Dysf gene, 24 patients in the Fkrp gene, 19 in the Ano5 gene, and 13 in one of the sarcoglycan genes (SCG). At baseline, 58 patients (37.1%) had a forced vital capacity percentage predicted (FVCpp) below 80%, while 14 patients (8.9%) had peak cough flow (PCF) values below 270 L/min. As a subgroup, FKRP was the group with a higher number of patients having FVC <80% and/or PCF <270 L/min at initial assessment (66%). We observed a progressive decline in FVCpp and PCF measurements over time, being age, use of wheelchair, and LGMD subtype independent factors associated with this decline. Fkrp and sarcoglycan patients had a quicker decline in their FVC (Kaplan-Meier curve, F test, p < 0.001 and p = 0.02, respectively). Only 7 of the 58 patients with low FVCpp values reported symptoms of respiratory dysfunction, which are commonly reported by patients with FVCpp below 50%-60%. The number of patients ventilated increased from 2 to 8 during follow-up.

Discussion: Respiratory dysfunction is a frequent complication of patients with LGMDs that needs to be carefully studied and has direct implications in the care offered in daily clinics. Respiratory dysfunction is associated with disease progression because it is especially seen in patients who are full-time wheelchair users, being more frequent in patients with mutations in the Fkrp and sarcoglycan genes.