Benign or not benign? Deep phenotyping of liver Glycogen Storage Disease IX

Fernandes, Samuela A.; Cooper, Gabrielle E.; Gibson, Rebecca A.; Kishnani, Priya S.

doi:10.1016/j.ymgme.2020.10.004

Cited by 22 publications

(34 citation statements)

References 19 publications

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“…All relevant clinical data were extracted from the collected literature. In order to compare findings from GSD VI patients with those recently published for GSD IX patients [9], the datasets were organized and evaluated according to Fernandes et al [9]. Briefly, all the cases were evaluated and analyzed with a special focus on demographic information; the clinical course, including the age at diagnosis and presenting symptoms; biochemical laboratory, enzymatic and genetic data; liver biopsy findings; hepatic adenoma; transplantation; and pregnancies.…”

Section: Data Collectionmentioning

confidence: 99%

“…Patients with documented hepatomegaly, growth retardation, delayed growth or short stature were reported according to published criteria [9]. All the information on neurologic outcomes or neurologic symptoms was collected from the case reports.…”

Section: Hepatomegaly Growth and Developmentmentioning

confidence: 99%

“…Fernandes et al recently published a review on all genetically proven cases of GSD type IX, a very similar disorder of glycogen metabolism due to phosphorylase kinase deficiency [9]. Phosphorylase kinase catalyzes the phosphorylation and thereby activation of glycogen phosphorylase as a crucial regulatory enzyme in glycogenolysis.…”

Section: Introductionmentioning

confidence: 99%

“…Phosphorylase kinase catalyzes the phosphorylation and thereby activation of glycogen phosphorylase as a crucial regulatory enzyme in glycogenolysis. The authors analyzed the data of 230 patients with different subtypes of GSD IX, with a special focus on age at diagnosis, presenting symptoms, laboratory findings, liver biopsy results, liver transplant and genetic findings [9]. GSD VI and IX are usually considered disorders that cannot be distinguished by clinical or laboratory findings other than by enzymatic or genetic analyses.…”

Section: Introductionmentioning

confidence: 99%

“…With the aim of facilitating the distinction of GSD VI and GSD IX, this review integrates findings from all published cases of genetically proven GSD VI. In order to be able to compare our data on GSD VI to the data for GSD IX provided by Fernandes et al [9], we chose a very similar approach of literature search and evaluation.…”

Section: Introductionmentioning

confidence: 99%

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The Phenotypic and Genetic Spectrum of Glycogen Storage Disease Type VI

Grünert

Hannibal

Spiekerkoetter

2021

Genes

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Glycogen storage disease type VI (GSD VI) is an autosomal recessive disorder of glycogen metabolism due to mutations in the glycogen phosphorylase gene (PYGL), resulting in a deficiency of hepatic glycogen phosphorylase. We performed a systematic literature review in order to collect information on the clinical phenotypes and genotypes of all published GSD VI patients and to compare the data to those for GSD IX, a biochemically and clinically very similar disorder caused by a deficiency of phosphorylase kinase. A total of 63 genetically confirmed cases of GSD VI with clinical information were identified (median age: 5.3 years). The age at presentation ranged from 5 weeks to 38 years, with a median of 1.8 years. The main presenting symptoms were hepatomegaly and poor growth, while the most common laboratory findings at initial presentation comprised elevated activity of liver transaminases, hypertriglyceridemia, fasting hypoglycemia and postprandial hyperlactatemia. Liver biopsies (n = 37) showed an increased glycogen content in 89.2%, liver fibrosis in 32.4% and early liver cirrhosis in 10.8% of cases, respectively. No patient received a liver transplant, and one successful pregnancy was reported. Our review demonstrates that GSD VI is a disorder with broad clinical heterogeneity and a small number of patients with a severe phenotype and liver cirrhosis. Neither clinical nor laboratory findings allow for a differentiation between GSD VI and GSD IX. Early biochemical markers of disease severity or clear genotype phenotype correlations are missing. Given the overall benign and unspecific phenotype and the need for enzymatic or genetic analyses for confirmation of the diagnosis, GSD VI is likely underdiagnosed. With new treatment approaches in sight, early, pre-symptomatic diagnosis, especially with respect to hepatic cirrhosis, will become even more important.

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Section: Data Collectionmentioning

confidence: 99%

Section: Hepatomegaly Growth and Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Phenotypic and Genetic Spectrum of Glycogen Storage Disease Type VI

Grünert

Hannibal

Spiekerkoetter

2021

Genes

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Gene therapy for glycogen storage diseases

Koeberl

Koch

Lim

et al. 2023

J of Inher Metab Disea

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Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long‐term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose‐6‐phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/− cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno‐associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. Gene therapy for the glycogen storage diseases is under development, addressing an unmet need for specific, stable therapy for these conditions.

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