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.

In glycogen storage disease type III (GSD III), deficiency of the debranching enzyme causes storage of an intermediate glycogen molecule (limit dextrin) in the affected tissues. In subtype IIIa hepatic tissue, skeletaland cardiac muscle tissue is affected, while in subtype IIIb only hepatic tissue is affected. Cardiac storage of limit dextrin causes a form of cardiomyopathy, which resembles primary hypertrophic cardiomyopathy on cardiac ultrasound. We present a 32-year-old GSD IIIa patient with severe left ventricular hypertrophy (LVH) first diagnosed at the age of 8 years. LVH remained stable and symptomless until the patient presented at age 25 years with increasing dyspnea, fatigue, obesity, and NYHA (New York Heart Association) functional classification two out of four. Dyspnea, fatigue, and obesity progressed, and at age 28 years she was severely symptomatic with NYHA classification 3+ out of 4. On echocardiogram and electrocardiogram, the LVH had progressed as well. Initially, she was rejected for cardiac transplantation because of severe obesity. Therefore, a 900 cal, high protein diet providing 37% of total energy was prescribed during 4 months on which 10 kg weight loss was achieved. However, her symptoms as well as the electrocardiographic and echocardiographic LVH indices had improved dramatically -ultimately deferring cardiac transplantation. Thereafter, the caloric intake was increased to 1,370 cal per day, and the high protein intake was continued providing 43% of total energy. After 3 years of follow-up, the patient remains satisfied with reasonable exercise tolerance and minor symptoms in daily life.

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