AANEM PRACTICE TOPIC CONSENSUS TREATMENT RECOMMENDATIONS FOR LATE-ONSET POMPE DISEASE EDWARD J. CUPLER, MD,1 KENNETH I. BERGER, MD,2 ROBERT T. LESHNER, MD,3 GIL I. WOLFE, MD,4 JAY J. HAN, MD,5 RICHARD J. BAROHN, MD,6 and JOHN T. KISSEL, MD,7 of the AANEM CONSENSUS COMMITTEE ON LATE-ONSET POMPE DISEASE 1 Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine and Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York, USA 3 Department of Neurosciences, University of California San Diego, San Diego, California, USA 4 Department of Neurology, University of Texas Southwestern Medical School, Dallas, Texas, USA 5 Department of Physical Medicine and Rehabilitation, University of California Davis, Sacramento, California, USA 6 Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA 7 Department of Neurology, Division of Neuromuscular Medicine, Ohio State University, Columbus, Ohio, USA Accepted 14 October 2011 ABSTRACT: Introduction: Pompe disease is a rare, autosomal use of ERT. After 1 year of ERT, patients’ condition should be recessive disorder caused by deficiency of the glycogen-degrad- reevaluated to determine whether ERT should be continued. ing lysosomal enzyme acid alpha-glucosidase. Late-onset Pompe Muscle Nerve 45: 319–333, 2012 disease is a multisystem condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders. Meth- ods: Objective is to propose consensus-based treatment and Consensus statements are important for developing management recommendations for late-onset Pompe disease. treatment recommendations when evidence-based Methods: A systematic review of the literature by a panel of spe- cialists with expertise in Pompe disease was undertaken. Conclu- medical guidelines and treatment recommendations sions: A multidisciplinary team should be involved to properly based on controlled trials are sparse or nonexistent. In treat the pulmonary, neuromuscular, orthopedic, and gastrointesti- the case of late-onset Pompe disease, it is an appropri- nal elements of late-onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and atetimetoassembleagroupofexpertsinthefieldto patients symptomatic at diagnosis) should begin treatment with review and analyze the medical literature and create enzyme replacement therapy (ERT) immediately; presymptomatic recommendations for disease management (based patients without symptoms or signs should be observed without on the best available evidence) until additional data Abbreviations: 6MWT, 6-minute walk test; AANEM, American Associa- from controlled studies become available to enable tion of Neuromuscular & Electrodiagnostic Medicine; AFOs, ankle-foot further recommendations. The American Associa- orthoses; BiPAP, bilevel positive airway pressure; CPAP, continuous posi- tive airway pressure; DEXA, dual-energy X-ray absorptiometry; EMBASSY, tion of Neuromuscular & Electrodiagnostic Medicine Exploratory Muscle Biopsy, Biomarker, and Imaging Assessment Study; (AANEM) convened a consensus committee of spe- EMG, electromyography; ERT, enzyme replacement therapy; FDA, Food and Drug Administration; FVC, forced vital capacity; GAA, acid alpha-glu- cialists with expertise in the diagnosis and treatment cosidase; LOTS, Late-Onset Treatment Study; MEP, maximal expiratory of Pompe disease and, using a modified consensus pressure; MIP, maximal inspiratory pressure; rhGAA, recombinant human 1 acid alpha-glucosidase; SDB, sleep-disordered breathing; SF-36; 36-item development conference method, the committee Short Form Health Survey Questionnaire worked to create consensus-based recommendations Key words: acid alpha-glucosidase; acid maltase deficiency; lysosomal storage disorder; neuromuscular disease; Pompe disease for the treatment of late-onset Pompe disease. Disclaimer: This article was prepared and reviewed by the AANEM and did not undergo the separate review process of Muscle & Nerve. OVERVIEW OF POMPE DISEASE Approved by the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Board, September 2011. History of Pompe Disease. Pompe disease, also Disclosures: Task force co-chairs: Dr. Barohn has nothing to disclose. referred to as acid maltase deficiency, is a rare, auto- Dr. Kissel serves as a consultant for Alexion Pharmaceuticals for a clinical trial in myasthenia gravis. Task force members: Dr. Han has somal recessive disorder that was first described in nothing to disclose. Dr. Berger has served as a consultant to Genzyme 1932 in a 7-month-old girl who died of cardiomyopa- Corporation for clinical trials in MPS I and Pompe disease, and he has served as a consultant to BioMarin Corporation for clinical trials in MPS thy. The disease was identified as a glycogen storage IV and MPS VI. Dr. Cupler is a member of the speaker bureau for disorder in which glycogen had accumulated within Genzyme Corporation and for Athena Diagnostics, Inc., and is a member 2,3 of the Pompe Registry North American Board of Advisors for Genzyme vacuoles of all the examined tissue. In 1954, the Corporation. Dr. Leshner is a member of the Genzyme Global Advisory disease was classified as glycogen storage disease type II,4 Board for Pompe disease and has received honoraria for speaking engagements and research support from Genzyme Corporation. Dr. and in 1963 it became the first identified lysosomal Wolfe has served on the speaker bureau for Genzyme Corporation. storage disorder.5,6 During the 1960s and 1970s, None of the authors of this article is an inventor, and no authors are receiving royalty payments. All authors received travel support and cases of a milder phenotype that occurred in older honoraria for the initial consensus development meeting from MedLogix patients (late-onset Pompe disease) were described Communications, LLC, and the AANEM, through an educational grant 7 from Genzyme Corporation. by Engel and colleagues. The reported frequency Correspondence to: C. French, AANEM, 2621 Superior Drive NW, of infantile-onset Pompe disease ranges from Rochester, MN 55901 approximately 1 in 35,000 to 1 in 138,000 among VC 2011 Wiley Periodicals, Inc. 8,9 Published online 15 December 2011 in Wiley Online Library Taiwanese and Dutch populations, respectively. (wileyonlinelibrary.com). DOI 10.1002/mus.22329 The estimated frequency of late-onset Pompe AAEM Practice Topic: Late-Onset Pompe Disease MUSCLE & NERVE March 2012 319 FIGURE 1. Timeline for Pompe disease: 75 years from description to availability of disease-modifying agent. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] disease is 1 in 57,000.10 The actual frequency of late- mandated postmarketing surveillance of alglucosi- onset Pompe disease in the USA is not known, but dase alfa. The manufacturer will conduct studies to one study suggested that the frequency of all forms evaluate the tests used for drug profiling and moni- may be as high as 1 in 40,000.11 toring and for qualification, quantification, specifica- There was no disease-specific treatment for Pompe tion, and stability of alglucosidase alfa. Moreover, the disease until enzyme replacement therapy (ERT) was FDA required that additional immunogenicity, safety, first attempted in 1973. Highly purified, placenta- efficacy, pharmacokinetics, and long-term follow-up derived acid alpha-glucosidase (GAA) enzyme was studies be conducted to better understand the role administered by intravenous infusion, taking advant- of alglucosidase alfa in the treatment of Pompe dis- age of the ability of lysosomes to internalize exoge- ease. These studies are currently ongoing. nous proteins by endocytosis.12 Initial attempts at Pathophysiology of Pompe Disease. Lysosomal GAA ERT encountered problems of immunogenicity, and catalyzes the breakdown of glycogen into glucose. there was limited availability of purified GAA for Acid alpha-glucosidase deficiency in Pompe disease enzyme delivery.13,14 In 1979, the 28-kb gene for GAA results in the accumulation of lysosomal and was identified on chromosome 17,15 and in the 1990s new recombinant technology became available, ena- bling the production of enough recombinant human acid alpha-glucosidase (rhGAA) to allow ERT clinical trials to be conducted. Figure 1 show the timeline for the development of ERT for Pompe disease. In 2006, alglucosidase alfa (Myozyme; Genzyme Corporation, Cambridge, Massachusetts)16 was approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency and became the first disease-specific treatment for Pompe disease. The approval was based on the results of a pivotal trial of ERT with alglucosidase alfa in 18 infants.17 The results of the first randomized, dou- ble-blind, placebo-controlled study of ERT, known as the Late-Onset Treatment Study (LOTS),18 led to FIGURE 2. Pathophysiology of Pompe disease. GAA, acid the approval in 2010 of Lumizyme (Genzyme Corpo- 19 alpha-glucosidase; UDP, uridine diphosphate. Based on Raben ration) for the treatment of late-onset Pompe dis- et al.108 with permission. [Color figure can be viewed in the ease in the USA. Along with its approval, the FDA online issue, which is available at wileyonlinelibrary.com.] 320 AAEM Practice Topic: Late-Onset Pompe Disease MUSCLE & NERVE March 2012 nonlysosomal glycogen in multiple tissues20–22 been observed.30,31 Clinical myotonia is absent, but (Fig. 2). In infantile-onset