PracticeUpdate: Neurology - Winter 2018

CONFERENCE COVERAGE 24

Next-Generation Sequencing Can Be Helpful in Diagnosing and Characterizing Limb Girdle Muscular Dystrophy Rare and subject to misdiagnosis, limb girdle muscular dystrophy needs clinical evaluation

N ext-generation sequencing has been found to be helpful in diagnosing and characteriz- ing limb girdle muscular dystrophy (LGMD), a disease for which clinical trials are needed, accord- ing to two presentations at ICNMD 2018. Clinical trials are needed in LGMD Corrado Angelini, MD, of the Istituto di Ricovero e Cura a Carattere Scientifico San Camillo Hospi- tal in Venice, Italy, told Elsevier’s PracticeUpdate , “Patients affected by LGMD are awaiting clinical treatment. Future developments may include the discovery of adeno-associated viral gene therapy or drugs able to counteract muscle atrophy.” Dr. Angelini explained that LGMD is progressive weakness with onset in the proximal limb girdle mus- cles. Age of onset varies from early childhood (not congenital) to late adulthood. Progression of muscle weakness is usually symmetrical and varies among individuals and genetic type. These disorders present a wide spectrum of muscle involvement and wasting, spanning from very severe forms with childhood onset and rapid progression to relatively benign forms with late onset. A consortium meeting under the auspices of the European Neuromuscular Center, introduced a classification of LGMD based on molecular/genetic criteria. Autosomal-dominant loci were designated as LGMD 1, autosomal-recessive loci as LGMD 2. LGMD nomenclature adopted a progressive alpha- betical letter indicating the order of gene mapping identification. A new classification was proposed in a 2017 Euro- pean Neuromuscular Center meeting, where autosomal-dominant LGMD and recessive forms were named and numbered. This new classification includes dystrophies with proximal or disto-proximal features and high creatine kinase presentation with histopathological evidence at biopsy of fiber degeneration/regeneration, fiber splitting, MRI imaging consistent with degenerative changes, and fibro-fatty infiltration. Inflammatory myopathies, myofibrillar myopathies, and metabolic myopathies are differential diagnoses that can be excluded on the basis of clinical features, muscle histopathology, and laboratory exams. It is important that inflammatory and metabolic disorders be classified to inform differential diagnosis because many of these diseases are treatable.

Dr. Corrado Angelini

LGMDs constitute a considerable fraction of all dystrophic individuals. Prevalence ranges from approximately eight to 70 cases per million inhabit- ants (1:123,000–1:14,500) depending on geographical area and ethnic origin. The frequency of each form of LGMD varies among populations. Clinical phenotypes due to LGMD gene mutations include severe childhood onset forms, distal and proximal myopathies, pseudometabolic myopathies, eosinophilic myositis, and hyperCKemia. Identifying suitable selection criteria is crucial in tri- als where participants are treated after identifying defective genes responsible for LGMD. Therapy is still unresolved in LGMD and care is mostly limited to rehabilitation, clinical follow-up of cardiac and res- piratory complications. Several drugs have been tested, including corti- costeroids and myostatin inhibitors with variable success. New drugs are pursued actively as well as genetic and cell therapies. A number of clinical trials are being developed. Dr. Angelini concluded that though LGMDs are rela- tively rare, clinical trials are needed in homogeneous individual groups. Approximately 8% of individuals misdiagnosed with LGMD may actually suffer from facioscapulohumeral muscular dystrophy. Muscle (CT and MR) imaging may be helpful to char- acterize severity and the pattern and distribution of muscle wasting. Outcome measures for each clinical

Dr. Vincenzo Nigro

PRACTICEUPDATE NEUROLOGY