Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome.

Christiaan P Sentner,Pascal Laforêt,Terry G J Derks,Philippe Labrune,Ulrike Steuerwald,Irene J Hoogeveen,François M Petit,Joanna Taybert,Patrick J Mckiernan,G Peter A Smit,David A Weinstein,Nicholas J Beauchamp,Aurélie Hubert,Elaine Murphy,René Santer

doi:10.1007/s10545-016-9932-2

Abstract

Glycogen storage disease type III (GSDIII) is a rare disorder of glycogenolysis due to AGL gene mutations, causing glycogen debranching enzyme deficiency and storage of limited dextrin. Patients with GSDIIIa show involvement of liver and cardiac/skeletal muscle, whereas GSDIIIb patients display only liver symptoms and signs. The International Study on Glycogen Storage Disease (ISGSDIII) is a descriptive retrospective, international, multi-centre cohort study of diagnosis, genotype, management, clinical course and outcome of 175 patients from 147 families (86 % GSDIIIa; 14 % GSDIIIb), with follow-up into adulthood in 91 patients. In total 58 AGL mutations (non-missense mutations were overrepresented and 21 novel mutations were observed) were identified in 76 families. GSDIII patients first presented before the age of 1.5 years, hepatomegaly was the most common presenting clinical sign. Dietary management was very diverse and included frequent meals, uncooked cornstarch and continuous gastric drip feeding. Chronic complications involved the liver (hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma in 11 %), heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood), and muscle (pain in 34 %). Type 2 diabetes mellitus was diagnosed in eight out of 91 adult patients (9 %). In adult patients no significant correlation was detected between (non-) missense AGL genotypes and hepatic, cardiac or muscular complications. This study demonstrates heterogeneity in a large cohort of ageing GSDIII patients. An international GSD patient registry is warranted to prospectively define the clinical course, heterogeneity and the effect of different dietary interventions in patients with GSDIII.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9932-2) contains supplementary material, which is available to authorized users.

Highlights

Glycogen storage disease type III (GSDIII; OMIM #232400) is a rare inborn error of glycogen degradation with an incidence of 1:100,000 (Dagli et al 2010; Kishnani et al 2010; Laforêt et al 2012)
GSDIII is caused by mutations in the AGL gene and the subsequent deficiency of the glycogen debranching enzyme (GDE; EC no. 3.2.1.33 and 2.4.1.25, UniProt P35573)
The ISGSDIII cohort is still relatively young, and follow-up has not extended into adulthood for all patients

Summary

Introduction

Glycogen storage disease type III (GSDIII; OMIM #232400) is a rare inborn error of glycogen degradation with an incidence of 1:100,000 (Dagli et al 2010; Kishnani et al 2010; Laforêt et al 2012). GSDIII is caused by mutations in the AGL gene and the subsequent deficiency of the glycogen debranching enzyme Patients with GSDIII present clinically with hepatomegaly, failure to thrive and fasting intolerance, biochemically associated with ketotic hypoglycaemia. During longterm follow-up the clinical focus shifts to the prevention and management of progressive hepatic, cardiac and myopathic complications (Dagli et al 2009; Sentner et al 2012; Verbeek et al 2015)

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