Review Article 04/25/2018 on mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== by https://journals.lww.com/continuum from Downloaded Downloaded from Address correspondence to https://journals.lww.com/continuum Dr Stanley Jones P. Iyadurai, Ohio State University, Wexner The Limb-Girdle Medical Center, Department of Neurology, 395 W 12th Ave, Columbus, OH 43210, Muscular Dystrophies and [email protected]. Relationship Disclosure: by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== Dr Iyadurai has received the Dystrophinopathies personal compensation for serving on the advisory boards of Allergan; Alnylam Stanley Jones P. Iyadurai, MSc, PhD, MD; John T. Kissel, MD, FAAN Pharmaceuticals, Inc; CSL Behring; and Pfizer, Inc. Dr Kissel has received personal ABSTRACT compensation for serving on a consulting board of AveXis, Purpose of Review: The classic approach to identifying and accurately diagnosing limb- Inc; as journal editor of Muscle girdle muscular dystrophies (LGMDs) relied heavily on phenotypic characterization and & Nerve; and as a consultant ancillary studies including muscle biopsy. Because of rapid advances in genetic sequencing for Novartis AG. Dr Kissel has received research/grant methodologies, several additional LGMDs have been molecularly characterized, and the funding as principal investigator diagnostic approach to these disorders has been simplified. This article summarizes the of a study from the National epidemiology, clinical features, and genetic defects underlying the LGMDs. Institutes of Health and has received funding for clinical Recent Findings: In recent years, the advent of next-generation sequencing has heralded trials from AveXis, Inc; an era of molecular diagnosis in conjunction with physical characterization. Inadvertently, AxelaCare Health Solutions, this process has also led to the ‘‘next-generation aftermath,’’ whereby variants of unknown LLC; BioMarin; CSL Behring; Cytokinetics, Inc; Ionis significance are identified in most patients. Similar to the published diagnostic and treat- Pharmaceuticals; and Quintiles, ment guidelines for Duchenne muscular dystrophy, diagnostic and treatment guidelines Inc; and receives publishing have recently been published for LGMDs. In addition, the first medication (based on the royalties from Oxford University Press. exon-skipping strategy) for treatment of patients with a subset of Duchenne muscular Unlabeled Use of dystrophy has been recently approved by the US Food and Drug Administration (FDA). Products/Investigational Summary: The LGMDs are a heterogeneous group of hereditary, progressive, and Use Disclosure: Drs Iyadurai and Kissel degenerative neuromuscular disorders that present with primary symptoms of shoulder discuss the unlabeled/ girdle and pelvic girdle weakness. Although a combination of clinical and molecular genetic investigational use of evaluations may be sufficient for accurate diagnosis of LGMDs in many cases, the corticosteroids to treat Duchenne muscular dystrophy. contribution of imaging and histopathologic correlations still remains a critical, if not a * 2016 American Academy necessary, component of evaluation in some cases. of Neurology. Continuum (Minneap Minn) 2016;22(6):1954–1977. INTRODUCTION tities (eg, Emery-Dreifuss muscular dys- The limb-girdle muscular dystrophies trophy) and with entities not necessarily (LGMDs) are a heterogeneous group of presenting in a limb-girdle pattern of genetic disorders generally characterized weakness (eg, dysferlinopathies). by weakness of the shoulder and the pelvic The dawn of molecular genetics in the girdle muscles. Based on the inheritance 1990s and, more recently, the increasing patterns, autosomal dominant (LGMD application of next-generation massive type 1), autosomal recessive (LGMD parallel-sequencing technologies have type 2), and X-linked forms of LGMD resulted in a fundamental change in how Supplemental digital content: have been described. Successive letters of these disorders are defined, identified, Videos accompanying this article are cited in the text as thealphabethavebeenusedtonamethe diagnosed, and managed. For example, Supplemental Digital Content. LGMDs according to the chronology of in the traditional approach, muscle bi- on 04/25/2018 Videos may be accessed by clicking on links provided in the identification of the genetic locus. While opsies were performed routinely on es- HTML, PDF, and app versions straightforward and convenient, this sys- sentially all patients with LGMD as part of this article; the URLs are pro- vided in the print version. Video tem has sometimes generated confusion of the characterization and diagnostic legends begin on page 1976. in regard to more traditionally named en- process. However, the lack of specificity 1954 www.ContinuumJournal.com December 2016 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS and significant overlap in biopsy find- shoulder girdle muscles, although specific h Limb-girdle muscular ings among the various LGMDs (eg, the disorders may initially manifest more dystrophies have an presence of inflammatory cells) have prominently in one region (eg, hips) com- estimated incidence of rendered this invasive technique less pared to the shoulders. With progression, 1 to 6 out of 100,000. useful and necessary in this day of readily weakness may spread outside of the h Limb-girdle muscular available genetic testing. However, some pelvic and the shoulder girdle to more dystrophies are of muscle biopsy findings are fairly charac- distal groups, the neck and axial muscles, dominant, recessive, or teristic of certain LGMDs (eg, the pres- or both. Depending on the type of LGMD, X-linked forms. ence of eosinophils in calpainopathy) and the pulmonary musculature and heart h The typical pattern of are useful diagnostic tools in some cases may also be involved. Creatine kinase weakness in limb-girdle when next-generation sequencing analysis (CK) levels may be normal, mildly elevated muscular dystrophies of a patient with LGMD fails to establish (usually in LGMD1s), or highly elevated involves the shoulder a genetic diagnosis. Similarly, ultrasound (usually in LGMD2s or X-linked LGMD) girdle and the pelvic girdle muscles, with or MRI of the muscle may be helpful in depending on the disorder. Extraocular variable involvement of providing data about the pattern of in- muscles are usually spared, as are cranial the cardiac and volved muscles and serve as a useful guide muscles, except in certain disorders where pulmonary musculature. for the appropriate muscle for biopsy or the facial muscles may be involved. h The combination of to help guide focused genetic testing. The current diagnostic approach still phenotypic evaluation, relies on careful phenotypic delineation electrodiagnostic and EPIDEMIOLOGY of the pattern of weakness, a search for muscle biopsy features, The LGMDs have a general estimated in- other associated features (eg, contractures, and gene panel testing cidence of 1 to 6 out of 100,000. How- heart involvement), distinctive EMG find- are helpful in diagnosis ever, this is likely an underestimate ings (including abnormal spontaneous of the limb-girdle muscular dystrophies. given that significant genetic, phenotypic, activity, complex repetitive discharges, h and regional variability confound these myotonic discharges), and focused genetic Contractures and figures, as do variable and incomplete testing for suspected causative gene de- scoliosis are common in limb-girdle muscular penetrance, and care access. While fects. Currently, multigene next-generation dystrophies. population-based whole-genome sequenc- panels are commercially available and ing strategies may be helpful in estimating permit testing of a large number of genes the prevalence more accurately, this in one step. For example, specific LGMD approach is currently not practical be- panels may evaluate 25 to 35 genes, or cause of the cost and labor intensiveness a general myopathy panel may evaluate of the current whole-genome sequenc- 180 genes in a single pass. Although pow- ing technologies. In the United States, erful, the process of screening multiple calpainopathy, dysferlinopathy, and genes at the same time (multigene panel dystrophinopathies are the most com- testing) for LGMDs typically results in mon forms of LGMD. identification of multiple so-called vari- ants of unknown significance. These may CLINICAL FEATURES AND include novel variants not reported in DIAGNOSIS disease or population databases, which Although the LGMDs are, by definition, in many cases are not causative. When var- congenital disorders, clinical manifesta- iants of unknown significance (either tions can begin at almost any time from single or multiple) are identified, family early childhood to late adulthood. Most of testing to establish segregation as well as the disorders, in fact, manifest in adult- additional muscle biopsy studies (such as hood with a range of presentation as immunostaining) may help establish the late as the seventies and eighties. LGMDs diagnosis, at least in some cases. While often manifest with the simultaneous intuitively and intellectually appealing, onset of