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Pediatric Oncall Journal

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Glycogen Storage Disease - Type 3

Glycogen Storage Disease - Type 3

04/11/2023 https://www.pediatriconcall.com/Journal/images/journal_cover.jpg
Suhani Jain1, Ira Shah2.
1Grant Government Medical College, Sir JJ Group of Hospitals, Mumbai, India,
2Consultant in Pediatric Infectious Diseases, Levioza Health Care, Mumbai, India.

ADDRESS FOR CORRESPONDENCE
Suhani Jain , Flat number 402, Ramdeo Arise, Behind Hotel Airport Centre Pt, Wardha Road, Nagpur-440025.
Email: suhani2208@gmail.com
Keywords
Glycogen Storage disease, Hepatomegaly, Glycogen debranching enzyme

Clinical Problem
A 9-month-old female child was referred for asymptomatic hepatomegaly detected by the local physician. Her birth history was normal and she had achieved milestones as per her age. The child had no family history of jaundice and had received all doses for Hepatitis B vaccine. On examination, weight was 6.5 kg (Less than 3rd centile as per WHO growth charts), height was 66 cm (Less than 3rd centile as per WHO growth charts) and she had hepatomegaly with a liver span of 13 cm. Other examination findings were normal. On investigation, serum bilirubin was 1.2 mg/dl, SGOT was 144 IU/L, SGPT was 160 IU/L, total proteins were 6.3 gm/dl, albumin was 4.2 gm/dl, GGTP was 98 IU/L, alkaline phosphatase was 320 IU/L, cholesterol was 201 mg/dl (Normal range: 100-220 mg/dl) and triglycerides were 607 mg/dl (Normal Range: 30-100 mg/dl). Prothrombin time was 15 sec and INR was 1.2. Complete blood count was normal. Venous blood gas (VBG) showed ph of 7.4 and bicarbonate of 23.4 meq/L. Serum lactate was 2.2 mmol/L. CPK was 24 U/L. Serum uric acid was 3.5 mg/dl. Ultrasound abdomen showed hepatomegaly with coarse echotexture. There was no splenomegaly or nephromegaly. Doppler of the portal system was normal. Ophthalmological evaluation were normal. Histological examination of liver biopsy was suggestive of glycogen storage disease (GSD) Type 3 in view of fibrotic septae with plant like appearance and ballooned hepatocytes. Genetic testing showed the patient to be homozygous for C.1081C>T in exon 8 and C.1883A>G in exon 14 in AGL gene suggestive of GSD type 3.
 

How to diagnose and manage glycogen storage disease?
 
Discussion
- 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

Table 1. Common types of GSD2,3,4,5,6
Type of GSD Deficiency of enzyme Treatment Outcomes
Type 0 glycogen synthethase deficiency Symptoms are alleviated by frequent protein-rich meals and night time feedings of uncooked cornflour (UCCS) Liver not enlarged
Type I - Von Gierke Disease (subtypes Ia, Ib, Ic, Id) Glucose-6-phosphatase Treatment: frequent oral glucose/cornstarch; avoidance of fructose and galactose. Increased Glycogen in liver and kidneys, increased blood lactate, increased triglycerides, increased uric acid.
Liver and Kidney enlarged
Type II - Pompe's Disease Lysosomal acid a-1,4- glucosidase (acid maltase) Enzyme replacement therapy (ERT) is currently the most reliable treatment. Cardiomyopathy, hypotonia, exercise intolerance and systemic findings lead to early death.
Type III - Cori's Disease
(subtypes-IIIa, IIIb, IIIC, IIId)
Debranching enzymes (a-1,6-glucosidase and 4-a-d-glucanotransferase). Treatment focussed on diet , with the goal of maintaining normoglycemia. Frequent carbohydrate-rich meals along with proteins and cornflour supplements, either alone or in conjunction with gastric tube feedings. Milder symptoms as compared to Von Gierke but normal blood lactate levels.
Can lead to cardiomyopathy based on the subtype.
Type IV - Anderson's Disease Branching enzyme. Liver transplantation is the only treatment option for individuals Hepatosplenomegaly and failure to thrive are the most common symptoms in early infancy.
Infantile cirrhosis, muscular weakness, hypotonia, cardiomyopathy, and early childhood death are among the other findings.
Type V – Mc Ardles disease Skeletal muscle glycogen phosphorylase (myophosphorylase). Painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities. Liver is not involved, so Blood glucose levels typically unaffected.
Type VI - Her's Disease Liver glycogen phosphorylase Mostly a mild manifestation, so no treatment required.
Avoid prolonged periods of fasting .
Gross hepatomegaly; patient is largely asymptomatic without hypoglycemia.
 
Compliance with ethical standards
Funding:  None  
Conflict of Interest:  None

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DOI:  https://doi.org/10.7199/ped.oncall.2024.8
 
Cite this article as:
Jain S, Shah I. Glycogen Storage Disease - Type 3. Pediatr Oncall J. 2024;21. doi: 10.7199/ped.oncall.2024.8
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