Type I glycogen storage disease

In general there are characteristic history and physical exam findings. When GSD I is suspected, laboratory tests are performed and confirmation of a diagnosis is usually obtained by mutational analysis.

History

A diagnosis of GSD I is supported by an inability to tolerate fasting during infancy. Symptoms of hypoglycemia may appear when the length of time between feeds increases, which often manifests as failure to sleep through the night without feeding.[1]Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014 Nov;16(11):e1. https://www.gimjournal.org/article/S1098-3600(21)02651-4/fulltext http://www.ncbi.nlm.nih.gov/pubmed/25356975?tool=bestpractice.com ​ Episodes of irritability or lethargy that resolve after feeding also indicate GSD I as a possible diagnosis. In rare cases, symptoms of hypoglycemia are very mild, and as a consequence, GSD may only be diagnosed in adulthood.[1]Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014 Nov;16(11):e1. https://www.gimjournal.org/article/S1098-3600(21)02651-4/fulltext http://www.ncbi.nlm.nih.gov/pubmed/25356975?tool=bestpractice.com ​ A tendency to bleed during childhood and adulthood (e.g., epistaxis, ecchymoses, or prolonged bleeding after surgery) may be noted and is caused by impaired platelet function in GSD I.[1]Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014 Nov;16(11):e1. https://www.gimjournal.org/article/S1098-3600(21)02651-4/fulltext http://www.ncbi.nlm.nih.gov/pubmed/25356975?tool=bestpractice.com

Physical exam

Hepatomegaly with a distended abdomen on physical exam is a distinguishing feature. Enlarged kidneys also occur in a majority of patients, but may only be demonstrated by abdominal ultrasonography. Other physical findings may include hyperpnea from lactic acidosis. Faltering growth and delayed puberty may also be noted. Untreated or inadequately treated infants and children may have a cushingoid appearance, and eruptive xanthomata on extensor surfaces may be present in patients with extreme hyperlipidemia.[1]Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014 Nov;16(11):e1. https://www.gimjournal.org/article/S1098-3600(21)02651-4/fulltext http://www.ncbi.nlm.nih.gov/pubmed/25356975?tool=bestpractice.com ​ Attenuated phenotypes have been described, presenting during adulthood with liver adenomas, hepatocellular carcinoma, gout, or acute pancreatitis.[2]Xu N, Han X, Zhang Y, et al. Clinical features of gout in adult patients with type Ia glycogen storage disease: a single-centre retrospective study and a review of literature. Arthritis Res Ther. 2022 Feb 26;24(1):58. https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-021-02706-5 http://www.ncbi.nlm.nih.gov/pubmed/35219330?tool=bestpractice.com [3]Ai J, He W, Huang X, et al. A case report of acute pancreatitis with glycogen storage disease type IA in an adult patient and review of the literature. Medicine (Baltimore). 2020 Oct 16;99(42):e22644. https://journals.lww.com/md-journal/fulltext/2020/10160/a_case_report_of_acute_pancreatitis_with_glycogen.35.aspx http://www.ncbi.nlm.nih.gov/pubmed/33080702?tool=bestpractice.com

Initial laboratory tests

Initial investigations should include serum glucose, serum bicarbonate, serum lactic acid, serum triglycerides, and serum concentrations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). During infancy, blood glucose concentration typically falls to <40 mg/dL within 3 to 4 hours after a feed and is accompanied by hyperlacticacidemia and metabolic acidosis (suggested by a low serum bicarbonate). Serum may be cloudy or milky with very high triglyceride and moderately elevated cholesterol levels.[1]Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014 Nov;16(11):e1. https://www.gimjournal.org/article/S1098-3600(21)02651-4/fulltext http://www.ncbi.nlm.nih.gov/pubmed/25356975?tool=bestpractice.com ​ Serum uric acid is increased and usually serum AST and ALT levels are also increased.

Molecular genetic testing

Mutational analysis is recommended to confirm GSD I and is also available for all other GSD types.[1]Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014 Nov;16(11):e1. https://www.gimjournal.org/article/S1098-3600(21)02651-4/fulltext http://www.ncbi.nlm.nih.gov/pubmed/25356975?tool=bestpractice.com [10]Beyzaei Z, Geramizadeh B. Molecular diagnosis of glycogen storage disease type I: a review. EXCLI J. 2019 Jan 30:18:30-46. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449677 http://www.ncbi.nlm.nih.gov/pubmed/30956637?tool=bestpractice.com GeneTests Opens in new window

If there are existing genetic test results, do not order a duplicate test unless there is uncertainty about the existing result, e.g., the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[12]American College of Medical Genetics and Genomics. Five things physicians and patients should question. Choosing Wisely, an initiative of the ABIM Foundation. 2021 [internet publication]. https://web.archive.org/web/20230326143738/https://www.choosingwisely.org/societies/american-college-of-medical-genetics-and-genomics

Liver biopsy

A liver biopsy for measurement of glucose-6-phosphatase activity may be necessary in the small minority of patients who do not have an identifiable gene mutation. This highly specialized test is offered at a few academic centers. GeneTests Opens in new window PreventionGenetics Opens in new window

Functional in vivo tests

Functional in vivo tests (provocative and/or loading) for suspected GSD I are now rarely necessary due to the availability of genetic testing. If the test is performed, it should be done by an experienced metabolic team due to the severe hyperlactatemia and metabolic acidosis that can result from inducing hypoglycemia by fasting.