- GSDs are a group of metabolic disorders that are inherited, caused by deficiency in enzymes that are needed for either glycogen synthesis or glycogen degradation. There is a very broad spectrum on how GSDs present – they can either affect a single tissue type like the muscles or can involve multiple systems.
1 The GSDs have historically been diagnosed by a combination of pathology findings, biochemical results and clinical symptoms. Findings from muscle or liver histology and enzyme deficiency studies are relied upon. The main technique for diagnosing glycogen storage disease over the past ten years is DNA mutation analysis.
1 Common types of GSD are depicted in Table 1.
2,3,4,5,6 Other phosphokinase deficiency diseases range from GSD type VIa to VIII to IX.
The GSD Type III is caused by a deficiency of glycogen debranching enzyme (GDE) which is located on chromosome 1p21.
6 It has a variable presentation depending upon the severity which makes diagnosis difficult. In GSD III often presenting features are hepatomegaly, growth retardation, hypoglycemia, hyperlipidemia, transaminase elevation.
In GSD IIIa individuals have deficient GDE enzyme activity in both liver and muscle, whereas those with GSD IIIb have enzyme deficiency limited to the liver.
6 Thus in Individuals with GSD IIIa along with hepatic manifestations they, may have variable myopathy and ventricular hypertrophy or cardiomyopathy. Muscle weakness in GSDIII can be both proximal and distal along with hypoglycemia or hepatomegaly but does not affect respiratory muscles.
6
Hypoglycemia is a feared symptom, however it is not as frequent in GSD type I. In GSD III there may be elevated creatine kinase, ketosis on fasting but normal lactate and uric acid.
7 Hence these patients need regular monitoring of blood
Glucose (preprandial), liver function studies, lipid profile, lactate, creatine kinase and cardiac functions. Presence of myopathy may be evaluated using electromyogram and nerve conduction studies.
Liver (and or muscle) histology in GSD III demonstrate a vacuolar accumulation of non-membrane bound glycogen primarily located in cytoplasm, which is Periodic Acid Schiff (PAS) positive and diastase sensitive. Lipid vacuoles are less frequent in GSD III than in GSD I, presence of fibrosis, ranging from minimal periportal fibrosis to micronodular cirrhosis is noted in GSD III not in GSD I. For definitive diagnosis either molecular genetics or enzymatic testing is necessary.
6
GSD III being multisystem disorder needs a multidisciplinary team for its best management by experienced physician along with occupational therapist, genetic counsellor, metabolic dietitian along with emotional and psychological support provided to patients and their families.
6 Prevention of hypoglycemia in infants and young child with GSD is the initial focus of management. Small frequent feeding and avoidance of fasting is the initial step. Bed time snack, corn starch and/continuous enteral feedings may be needed for overnight fast.
6 High carbohydrate intake is avoided. Cornstarch is given with a typical starting dose of 1 g/kg enterally to prevent hypoglycemia. Recommended protein intake is 3 g/kg (25% of total calorie intake); additional protein supplementation may be required. Vitamin D and calcium supplementation might also be indicated. The last resort of liver transplantation is only reserved for patients with severe hepatic dysfunction or cirrhosis.
6,7 Because gluconeogenesis is intact in GSD III, sucrose, fructose, lactose are not restricted as they are for individuals with GSD I.
6
Liver ultrasound is done every 6-12 months in children and 12-24 months in adults to evaluate the liver size, structure or complications like hepatic cirrhosis with manifestations of portal hypertension, adenomas, if any, liver MRI as needed. Yearly measurements of serum calcium and 25(OH)-vitamin are advised due to associated risk of osteoporosis, regular monitoring of growth parameters are necessary on follow up.
6,7
Routine evaluation of cardiac status with ECG and echocardiogram is recommended in GSD IIIa at the time of diagnosis and then 1-2 yearly until there is abnormality in echo or if there is clinical symptoms of cardiac involvement. For GSD IIIb evaluation of cardiac status at the time of diagnosis, later on every 5 yearly is reasonable.
7 The long-term results for GSD patients primarily hinge on effective dietary management tailored to each specific GSD type and patient adherence to these protocols.
8
The identification of biallelic pathogenic variants in AGL confirms the diagnosis of GSD III in a proband. Once the AGL pathogenic variants in an affected family member have been identified, prenatal testing for a high-risk pregnancy and preimplantation genetic testing for GSD III are options.
7
[Table1]
| References : |
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- Schreuder AB, Rossi A, Grünert SC, et al. Glycogen Storage Disease Type III. 2010 Mar 9 [Updated 2022 Jan 6]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26372/
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