University of Colorado Limb Girdle Muscular Dystrophies Diagnosis and Treatment in the Genetic Era Matthew P. Wicklund, MD University of Colorado

Disclosure Information Matthew P. Wicklund, MD Disclosure of Relevant Financial Relationships I have the following financial relationships to disclose: Scientific Advisory Board for: In-Depth Genomics Speaker’s Bureau for: None Grant/Research support from: Sanofi-Genzyme, Sarepta Research Collaboration sans compensation: Jain Foundation, Athena Diagnostics Stockholder in: None Honoraria from: Sanofi-Genzyme, MDA Employee of: None Disclosure of Off-Label and/or investigative Uses I may discuss the following off label use and/or investigational use in my presentation: Corticosteroids and genetic-based therapies in muscular dystrophies.

Learning Objectives Illustrate the genetic variability of limb girdle muscular dystrophies (LGMDs). Delineate optimal, cost effective strategies for diagnosis of LGMDs. Develop an understanding of genetic therapies for LGMDs, understanding translatability of these techniques across disease. Introduce future paradigms related to management of muscle disorders.

Introduction

History 1954 - Walton and Nattrass Proposed LGMD as a distinct clinical entity Initially distinguished cases from the 3 most common muscular dystrophies…

“Limb Girdle Muscle Weakness” “Post-natal onset of progressive weakness and muscle atrophy affecting proximal muscles of the upper and lower extremities”

Variability Genetic Pathogenic Regional/Ethnic Phenotypic

Limb Girdle Weakness 15 autosomal recessive LGMDs 3 autosomal dominant LGMDs

Limb Girdle Weakness 9 distal myopathies 15 autosomal recessive LGMDs 3 autosomal dominant LGMDs 9 distal myopathies

Limb Girdle Weakness 6 Emery Dreifuss muscular dystrophies 15 autosomal recessive LGMDs 3 autosomal dominant LGMDs 9 distal myopathies 6 Emery Dreifuss muscular dystrophies

Limb Girdle Weakness 26+ autosomal recessive LGMDs 10+ autosomal dominant LGMDs 9+ distal myopathies (1A, 1E, 2B, 2L) 7+ EDMD (1B) 13+ myofibrillar myopathies (1A, 1E) 7+ metabolic myopathies 3+ myotonic disorders 2 dystrophinopathies (Becker & carriers) 2 FSHD 1 lysosomal storage disease 80+ genes in total

LGMD and Other Muscular Dystrophies FSHD1 FSHD2 DM2 DM1