Laura E. Case

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management

Duchenne muscular dystrophy (DMD) is a severe, progressive disease that affects 1 in 3600-6000 live male births. Although guidelines are available for various aspects of DMD, comprehensive clinical care recommendations do not exist. The US Centers for Disease Control and Prevention selected 84 clinicians to develop care recommendations using the RAND Corporation-University of California Los Angeles Appropriateness Method. The DMD Care Considerations Working Group evaluated assessments and interventions used in the management of diagnostics, gastroenterology and nutrition, rehabilitation, and neuromuscular, psychosocial, cardiovascular, respiratory, orthopaedic, and surgical aspects of DMD. These recommendations, presented in two parts, are intended for the wide range of practitioners who care for individuals with DMD. They provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care. In part 1 of this Review, we describe the methods used to generate the recommendations, and the overall perspective on care, pharmacological treatment, and psychosocial management.

Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care

Optimum management of Duchenne muscular dystrophy (DMD) requires a multidisciplinary approach that focuses on anticipatory and preventive measures as well as active interventions to address the primary and secondary aspects of the disorder. Implementing comprehensive management strategies can favourably alter the natural history of the disease and improve function, quality of life, and longevity. Standardised care can also facilitate planning for multicentre trials and help with the identification of areas in which care can be improved. Here, we present a comprehensive set of DMD care recommendations for management of rehabilitation, orthopaedic, respiratory, cardiovascular, gastroenterology/nutrition, and pain issues, as well as general surgical and emergency-room precautions. Together with part 1 of this Review, which focuses on diagnosis, pharmacological treatment, and psychosocial care, these recommendations allow diagnosis and management to occur in a coordinated multidisciplinary fashion.

Pompe disease diagnosis and management guideline

Disclaimer: ACMG standards and guidelines are designed primarily as an educational resource for physicians and other health care providers to help them provide quality medical genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient’s record the rationale for any significant deviation from these standards and guidelines.

Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease

Purpose:Infantile Pompe disease resulting from a deficiency of lysosomal acid α-glucosidase (GAA) requires enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Cross-reactive immunologic material negative (CRIM-negative) Pompe patients develop high-titer antibody to the rhGAA and do poorly. We describe successful tolerance induction in CRIM-negative patients.Methods:Two CRIM-negative patients with preexisting anti-GAA antibodies were treated therapeutically with rituximab, methotrexate, and gammaglobulins. Two additional CRIM-negative patients were treated prophylactically with a short course of rituximab and methotrexate, in parallel with initiating rhGAA.Results:In both patients treated therapeutically, anti-rhGAA was eliminated after 3 and 19 months. All four patients are immune tolerant to rhGAA, off immune therapy, showing B-cell recovery while continuing to receive ERT at ages 36 and 56 months (therapeutic) and 18 and 35 months (prophylactic). All patients show clinical response to ERT, in stark contrast to the rapid deterioration of their nontolerized CRIM-negative counterparts.Conclusion:The combination of rituximab with methotrexate ± intravenous gammaglobulins (IVIG) is an option for tolerance induction of CRIM-negative Pompe to ERT when instituted in the naïve setting or following antibody development. It should be considered in other conditions in which antibody response to the therapeutic protein elicits robust antibody response that interferes with product efficacy.Genet Med 2012:14(1):135–142

Glycogen Storage Disease Type III diagnosis and management guidelines

Purpose: Glycogen storage disease type III is a rare disease of variable clinical severity affecting primarily the liver, heart, and skeletal muscle. It is caused by deficient activity of glycogen debranching enzyme, which is a key enzyme in glycogen degradation. Glycogen storage disease type III manifests a wide clinical spectrum. Individuals with glycogen storage disease type III present with hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation. Those with type IIIa have symptoms related to liver disease and progressive muscle (cardiac and skeletal) involvement that varies in age of onset, rate of disease progression, and severity. Those with type IIIb primarily have symptoms related to liver disease. This guideline for the management of glycogen storage disease type III was developed as an educational resource for health care providers to facilitate prompt and accurate diagnosis and appropriate management of patients.Methods: An international group of experts in various aspects of glycogen storage disease type III met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.Results: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (cardiovascular, gastrointestinal/nutrition, hepatic, musculoskeletal, and neuromuscular) involved in glycogen storage disease type III. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic transplantation, and prenatal diagnosis, are addressed.Conclusions: A guideline that will facilitate the accurate diagnosis and appropriate management of individuals with glycogen storage disease type III was developed. This guideline will help health care providers recognize patients with all forms of glycogen storage disease type III, expedite diagnosis, and minimize stress and negative sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.

Pompe disease: Design, methodology, and early findings from the Pompe Registry

Pompe disease is an autosomal recessive, progressive, debilitating, and often fatal neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA). It is characterized by the accumulation of glycogen in muscle tissue that leads to progressive muscle weakness and loss of function. It presents as a broad spectrum of clinical phenotypes, with varying rates of progression, symptom onset, degree of organ involvement, and severity. The Pompe Registry represents worldwide data collection on this rare and clinically heterogeneous disease. This report describes the design, methodology, and early findings from the Registry and presents an overview of the Registry population over a five-year period from its inception in September 2004 through September 2009. Among the 742 patients from 28 countries in the Registry, 70% (517/742) reported symptom onset >12 months of age and 23% (170/742) reported symptom onset ≤12 months of age. Seventy-eight percent (582/742) of registry patients have received enzyme replacement therapy. Overall, Registry data appear to be consistent with smaller natural history studies in terms of symptoms and disease course in classical infantile Pompe disease (≤12 months of age with cardiomyopathy) and late-onset Pompe disease (>12 months of age). In addition, a subset of patients with symptom onset ≤12 months of age do not have cardiomyopathy (14.7%); these patients appear to have a later age at first symptoms and diagnosis than their peers with cardiomyopathy. As the largest dataset on Pompe disease to date, the Pompe Registry will serve to improve recognition of the disease, enhance understanding of the variable disease course, and offer insights into treated and untreated disease course.

The emerging phenotype of long-term survivors with infantile Pompe disease

Purpose:Enzyme replacement therapy with alglucosidase alfa for infantile Pompe disease has improved survival creating new management challenges. We describe an emerging phenotype in a retrospective review of long-term survivors.Methods:Inclusion criteria included ventilator-free status and age ≤6 months at treatment initiation, and survival to age ≥5 years. Clinical outcome measures included invasive ventilator-free survival and parameters for cardiac, pulmonary, musculoskeletal, gross motor, and ambulatory status; growth; speech, hearing, and swallowing; and gastrointestinal and nutritional status.Results:Eleven of 17 patients met study criteria. All were cross-reactive immunologic material-positive, alive, and invasive ventilator-free at most recent assessment, with a median age of 8.0 years (range: 5.4–12.0 years). All had marked improvements in cardiac parameters. Commonly present were gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and four required the use of assistive ambulatory devices. All long-term survivors had low or undetectable anti-alglucosidase alfa antibody titers.Conclusion:Long-term survivors exhibited sustained improvements in cardiac parameters and gross motor function. Residual muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, dysphagia with risk for aspiration, and osteopenia were commonly observed findings.Genet Med 2012:14(9):800–810.

Physical therapy management of Pompe disease

Pompe disease (Glycogen storage disease type II, GSDII, or acid maltase deficiency) is an autosomal recessive disorder characterized by deficiency of acid α-glucosidase resulting in intra-lysosomal accumulation of glycogen and leading to progressive muscle dysfunction. The natural history of infantile-onset Pompe disease is characterized by hypertrophic cardiomyopathy and profound generalized weakness presenting in the first few months of life, with rapid progression and death usually occurring by one year of age. Late-onset Pompe disease is characterized by onset of symptoms after one year of age, less severe or absence of cardiac involvement and slower progression, with symptoms primarily related to progressive dysfunction of skeletal muscles and respiratory muscle involvement. Recent clinical trials of enzyme replacement therapy have begun to allow greater opportunity for potential improvement in motor status, function, and survival than ever before, with hopes of moving toward maximizing physical function for individuals with Pompe disease. Children are living longer with some achieving independent sitting, creeping, and walking–milestones typically never achieved in the untreated natural history of the disorder. With increased survival, clinical management based on an understanding of the pathology and pathokinesiology of motor function gains importance. This article reviews current knowledge regarding the motor system in Pompe disease and provides an overview of physical therapy management of Pompe disease, including management strategies for individuals on enzyme replacement therapy.

The impact of antibodies in late-onset Pompe disease: A case series and literature review

Pompe disease (glycogen storage disease type II, GSD II) is an autosomal recessive disease caused by a deficiency of acid α-glucosidase (GAA), leading to lysosomal glycogen accumulation in various tissues, most notably cardiac, skeletal and smooth muscle. While both infantile and late-onset patients have benefited greatly from alglucosidase alfa (Myozyme®) enzyme replacement therapy (ERT), a subgroup of patients does not demonstrate as pronounced a response as others. Various factors have been identified which may help predict the response to ERT in infantile Pompe disease patients. High, sustained antibody titers (HSAT) have been correlated with poor response to ERT in infantile Pompe cases. However, the literature on the role of antibodies in the late-onset Pompe disease (LOPD) population is limited. Our literature review highlights the need for studies to explore the potential impact of antibodies in LOPD. Further supporting the importance of this issue, our retrospective chart review of sixty LOPD patients revealed that six of these sixty (10%) LOPD patients developed HSAT of ≥1:51,200 on two or more occasions at or beyond 6 months on ERT. Here, we present a series of three of these six LOPD patients for whom detailed antibody data and clinical data were available for greater than 1 year on ERT. These three patients developed HSAT corresponding with clinical decline as demonstrated by pulmonary function, quality of life, and motor function testing, affirming the development of HSAT in a subset of patients with LOPD, and its potentially negative impact on clinical response to ERT. The findings of our study and literature review lead us to conclude that there is a strong indication for systematic studies to accurately delineate the potential impact of antibodies in LOPD.

Infantile Pompe disease on ERT: update on clinical presentation, musculoskeletal management, and exercise considerations.

Enzyme replacement therapy (ERT) with alglucosidase alpha, approved by the FDA in 2006, has expanded possibilities for individuals with Pompe disease (glycogen storage disease type II, GSDII, or acid maltase deficiency). Children with infantile Pompe disease are surviving beyond infancy, some achieving independent walking and functional levels never before possible. Individuals with late‐onset Pompe disease are experiencing motor and respiratory improvement and/or stabilization with slower progression of impairments. A new phenotype is emerging for those with infantile Pompe disease treated with ERT. This new phenotype appears to be distinct from the late‐onset phenotype rather than a shift from infantile to late‐onset phenotype that might be expected from a simple diminution of symptoms with ERT. Questions arise regarding the etiology of the distinct distribution of weakness in this new phenotype, with increasing questions regarding exercise and musculoskeletal management. Answers require an increased understanding of the muscle pathology in Pompe disease, how that muscle pathology may be impacted by ERT, and the potential impact of, and need for, other clinical interventions. This article reviews the current state of knowledge regarding the pathology of muscle involvement in Pompe disease and the potential change in muscle pathology with ERT; the newly emerging musculoskeletal and gross motor phenotype of infantile Pompe disease treated with ERT; updated recommendations regarding musculoskeletal management in Pompe disease, particularly in children now surviving longer with residual weakness impacting development and integrity of the musculoskeletal system; and the potential impact and role of exercise in infantile Pompe survivors treated with ERT.