Correlation between quantitative whole-body muscle magnetic resonance imaging and clinical muscle weakness in Pompe disease.
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IntroductionPrevious examination of whole-body muscle involvement in Pompe disease has been limited to physical examination and/or qualitative magnetic resonance imaging (MRI). In this study we assess the feasibility of quantitative proton-density fat-fraction (PDFF) whole-body MRI in late-onset Pompe disease (LOPD) and compare the results with manual muscle testing.
MethodsSeven LOPD patients and 11 disease-free controls underwent whole-body PDFF MRI. Quantitative MR muscle group assessments were compared with physical testing of muscle groups.
ResultsThe 95% upper limits of confidence intervals for muscle groups were 4.9-12.6% in controls and 6.8-76.4% in LOPD patients. LOPD patients showed severe and consistent tongue and axial muscle group involvement, with less marked involvement of peripheral musculature. MRI was more sensitive than physical examination for detection of abnormality in multiple muscle groups.
ConclusionThis integrated, quantitative approach to muscle assessment provides more detailed data than physical examination and may have clinical utility for monitoring disease progression and treatment response.
Published Version (Please cite this version)
Horvath, Jeffrey J, Stephanie L Austin, Laura E Case, Karla B Greene, Harrison N Jones, Brian J Soher, Priya S Kishnani, Mustafa R Bashir, et al. (2015). Correlation between quantitative whole-body muscle magnetic resonance imaging and clinical muscle weakness in Pompe disease. Muscle & nerve, 51(5). pp. 722–730. 10.1002/mus.24437 Retrieved from https://hdl.handle.net/10161/27309.
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Laura E Case, PT, DPT, MS, PCS, C/NDT is a board-certified clinical specialist in pediatric physical therapy. She has dedicated her career to teaching, research in childhood-onset neuromusculoskeletal disorders, and to the lifelong treatment of people with childhood-onset neurological and neuromuscular disorders such as cerebral palsy, traumatic brain injury, Duchenne muscular dystrophy, spinal muscular atrophy, Pompe disease, myelodysplasia, juvenile rheumatoid arthritis, and brachial plexus injury.
She has been involved in numerous clinical trials for the treatment of disorders including Pompe disease and other metabolic disorders, cerebral palsy, Duchenne muscular dystrophy, and spinal muscular atrophy. Dr. Case has participated in the development of international guidelines for the management of Duchenne muscular dystrophy, Pompe disease, and other glycogen storage diseases.
She teaches and consults internationally, has worked on a number of Center for Disease Control (CDC) task forces, has served on numerous committees and task forces in the pediatric section of APTA, served two terms as NC State Representative to the APTA Section on Pediatrics, and is a member of the North American Pompe Registry Board of Advisors.
My research focuses on the development and clinical translation of quantitative, multi-parametric MRI and MR spectroscopy (MRS) data acquisition and analysis techniques. These methods are applicable to the characterization of both chronic and focal pathologies, originally in the brain, but more recently in other organs such as liver and muscle. The overarching goals of these investigations are 1) to improve acquired data quality, 2) to obtain the maximum amount of useful information and/or to exclude confounding signals, and 3) to acquire additional a priori information that can make a given analysis more robust. My practical goals are to develop flexible, reusable and user-friendly tools and techniques, primarily through open source software packages, that can be applied in a robust manner for clinical investigative and diagnostic use.
My early research aimed at developing robust quantitation methods for spectroscopic imaging (SI) data analysis in the brain. As part of a multi-disciplinary team I helped develop a cross-platform GUI-driven suite of spectral processing/analysis tools to simplify the use of SI in clinical research. Throughout my career, I have continued work to expand spatial coverage, to create simulations of metabolic data acquisition to extend the accuracy of the models used to fit the SI data, and to develop acquisition and post-processing algorithms to remove unwanted water and lipid signals. This work led up to the idea for which I received my first R01. It has also resulted in two open-source software packages, MIDAS and Vespa (http://mrir.med.miami.edu:8000/midas and https://vespa-mrs.github.io/vespa.io/) that have received wide acceptance by many researchers and groups.
The latest versions of these tools are in active use in CAMRD studies investigating 1) volumetric changes in physiologic biomarkers of cellular breakdown in the brain due to high grade glioma progression, 2) changes in liver energy homeostasis due to a challenge using injected fructose, 3) spectral analysis and quantitation of edited single-voxel MRS method such as MEGA-PRESS and MEGA-sLASER to isolate small metabolite signals like GABA and 2HG. I also work actively to educate my colleagues as to the existence and applicability of these and other tools that I have access to due to my contacts in the MR research community.
More recently, I have developed a number of research projects in the rapidly changing area of body MR. Initial projects were to characterize the use of high-speed 3D MR imaging sequences to characterize the presence of water and fat in various organs. Standard in- and opposed-phase techniques were compared with newer fat-water separated imaging techniques. Fat-water separation imaging methods create individual water and fat images that maintain useful anatomic references while allowing both fat and water signals to be viewed separately. In parallel with our technique development for water-far imaging techniques, I developed and patented a novel technique for utilizing the heat insensitive nature of fat to non-invasively map temperature changes during the application of hyperthermia treatments for sarcomas.
Currently, I am investigating the use of tissue modelling to estimate absolute tissue fat fractions to provide a normalization technique for comparing in- and opposed-phase measures across platforms, sequences and field strengths. I am also working on an R01 that measures dynamic liver energy metabolism to help detect and stage NASH patients.
A multidisciplinary approach to care of individuals with genetic disorders in conjunction with clinical and bench research that contributes to:
1) An understanding of the natural history and delineation of long term complications of genetic disorders with a special focus on liver Glycogen storage disorders, lysosomal disorders with a special focus on Pompe disease, Down syndrome and hypophosphatasia
2) ) The development of new therapies such as AAV gene therapy, enzyme therapy, small molecule and other approaches for genetic disorders through translational research
3) The development and execution of large multicenter trials to confirm safety and efficacy of potential therapies
4) Role of antibodies/immune response in patients on therapeutic proteins and AAV gene therapy
. Glycogen Storage Disease (GSD): We are actively following subjects with all types of Glycogen Storage Disease, with particular emphasis on types I, II, III, IV, VI and IX. The goal of the treatment team is to better determine the clinical phenotype and long term complications of these diseases. Attention to disease manifestations observed in adulthood, such as adenomas and risk for HCC, is of paramount importance in monitoring and treating these chronic illnesses. We are establishing clinical algorithms for managing adenomas, and the overall management of these patients including cardiac, bone, muscle and liver issues. A special focus is biomarker discovery, an Omics approach including metabolomics and immune phenotyping. We are working on AAV gene therapy for several hepatic GSDs
.Lysosomal Storage Disease: The Duke Lysosomal Storage Disease (LSD) treatment center follows and treats patients with Pompe, Gaucher, Fabry, Mucopolysaccharidosis, Niemann Pick, LAL-D and other LSD's. The Duke Metabolism Clinical Research Team is exploring many aspects of enzyme replacement therapy (ERT), including impact on different systems, differential response, and long term effects. Other symptomatic and treatment interventions for this category of diseases are also being explored in the context of clinical care.
. Pompe Disease: The care team has extensive experience in the care of infants and adults with Pompe disease and was instrumental in conducting clinical trials and the bench to bedside work that led to the 2006 FDA approval of alglucosidase alfa, the first treatment for this devastating disease. We are currently focusing on role of antibodies/immune response on patient outcome and role of immune modulation/immune suppression as an adjunct to ERT. Our team is also working on AAV gene therapy for Pompe disease. A focus is on newborn screening (NBS) and understanding the clinical phenotype and management approaches for babies identified via NBS
. Hypophosphatasia: We follow a large cohort of patients with HPP. The goal is to understand the features of the disease beyond bone disease, development of biomarkers, role of ERT and immune responses in HPP
. Neuromuscular disorders: We are collaborating with neurologists, cardiologists and neuromuscular physicians to serve as a treatment site for clinical trials in these diseases. We are currently involved in trials of DMD and are working closely on setting up collaborations for studies in SMA.
Hepatobiliary and pancreatic imaging
Liver cancer (hepatocellular carcinoma)
Fatty liver, NAFLD, and NASH
Chronic liver disease and cirrhosis
Technical development in MRI
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