A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III.

Abstract

Introduction

A deficiency of glycogen debrancher enzyme in patients with glycogen storage disease type III (GSD III) manifests with hepatic, cardiac, and muscle involvement in the most common subtype (type a), or with only hepatic involvement in patients with GSD IIIb.

Objective and methods

To describe longitudinal biochemical, radiological, muscle strength and ambulation, liver histopathological findings, and clinical outcomes in adults (≥18 years) with glycogen storage disease type III, by a retrospective review of medical records.

Results

Twenty-one adults with GSD IIIa (14 F & 7 M) and four with GSD IIIb (1 F & 3 M) were included in this natural history study. At the most recent visit, the median (range) age and follow-up time were 36 (19-68) and 16 years (0-41), respectively. For the entire cohort: 40% had documented hypoglycemic episodes in adulthood; hepatomegaly and cirrhosis were the most common radiological findings; and 28% developed decompensated liver disease and portal hypertension, the latter being more prevalent in older patients. In the GSD IIIa group, muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device. Older individuals tended to show more severe muscle weakness and mobility limitations, compared with younger adults. Asymptomatic left ventricular hypertrophy (LVH) was the most common cardiac manifestation, present in 43%. Symptomatic cardiomyopathy and reduced ejection fraction was evident in 10%. Finally, a urinary biomarker of glycogen storage (Glc4) was significantly associated with AST, ALT and CK.

Conclusion

GSD III is a multisystem disorder in which a multidisciplinary approach with regular clinical, biochemical, radiological and functional (physical therapy assessment) follow-up is required. Despite dietary modification, hepatic and myopathic disease progression is evident in adults, with muscle weakness as the major cause of morbidity. Consequently, definitive therapies that address the underlying cause of the disease to correct both liver and muscle are needed.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1016/j.ymgmr.2021.100821

Publication Info

Hijazi, Ghada, Anna Paschall, Sarah P Young, Brian Smith, Laura E Case, Tracy Boggs, Sathya Amarasekara, Stephanie L Austin, et al. (2021). A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III. Molecular genetics and metabolism reports, 29. p. 100821. 10.1016/j.ymgmr.2021.100821 Retrieved from https://hdl.handle.net/10161/26688.

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Scholars@Duke

Young

Sarah Phyllis Young

Professor of Pediatrics

As a clinical biochemical geneticist and a director of the Duke Biochemical Genetics laboratory, my research interests are focused on improving laboratory diagnostics for rare inherited disorders of metabolism. I am actively involved in the development of assays using mass spectrometry and other analytical techniques. My current research on biomarkers for lysosomal storage disorders, such as Fabry and Pompe disease and the mucopolysaccharidoses includes monitoring the response to novel therapies in patients. I also have an interest in neurometabolic disorders such as the creatine deficiency syndromes and sulfite oxidase and molybdenum cofactors. These disorders can be diagnosed using liquid chromatography-tandem mass spectrometric assays that measure biomarkers in urine. Guanidinoacetate methyltransferase deficiency is a disorder that can be detected in the newborn period and is amenable to dietary therapy, and is thus a good candidate for newborn screening.

Case

Laura Elizabeth Case

Associate Professor in Orthopaedic Surgery

Laura E Case, PT, DPT, MS, PhD, 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.

El-Gharbawy

Areeg Hassan El-Gharbawy

Associate Professor of Pediatrics

I am an Associate Professor in the Department of Pediatrics, Division of Medical Genetics at Duke University; pursuing a career in clinical/translational research with 70% protected time for research. My clinical background is broad encompassing residency and fellowship training in internal medicine, endocrinology, diabetes, nutrition, metabolism, and clinical and biochemical genetics. This uniquely positioned me to evaluate and study pediatric and adult patients with inborn errors of metabolism, mitochondrial disorders, and lysosomal storage diseases. I transitioned from clinical medicine to a career in translational research to address the needs of patients with rare inherited metabolic disorders due to the paucity of therapies and biomarkers. My strength comes from my experience in managing patients with different inborn errors of metabolism and optimizing their treatment based on their underlying clinical, molecular, and biochemical phenotypes. In the era of precision medicine and big data analysis, my aim is to utilize my clinical skills and available tools at Duke University to conduct studies with implications for new drug, mechanism, and biomarker discovery. Studies are and will be conducted at Duke clinical research center in collaboration with clinical and basic scientists including Priya Kishnani, MD, Dwight Koeberl MD, Ph.D., and Karl-Dimiter Bissig MD, Ph.D. who are well established and funded clinical and basic science investigators at Duke. This collaboration allows me to integrate clinical data generated from natural history studies, with result from animal models, and metabolomics. This has implications for discovering innovative therapies, mechanisms, and biomarkers that serve and optimize patient care. I am currently analyzing metabolomics data on patients with Glycogen storage diseases and new therapeutics. I hold an IND on a PI initiated (industry-funded) clinical trial (pilot study) for using triheptanoin an anaplerotic compound that promotes energy through the Krebs cycle in patients with glycogen storage disease type 1.

Deak

Kristen Lee Deak

Assistant Professor of Pathology

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