This document provides information on various types of glycogen storage diseases (GSDs) that affect the liver. It discusses the underlying genetic defects, characteristic features, diagnosis, and management of different types of liver GSDs. The main types covered are GSD types I, III, IV, VI, IX, and 0. The text explains that liver GSDs result from enzymatic defects in glycogen synthesis or breakdown in the liver, leading to an accumulation of glycogen. Clinical manifestations vary depending on the specific enzyme deficiency but often include hepatomegaly, hypoglycemia, and lactic acidosis. Diagnosis involves genetic testing, enzyme assays, and liver biopsies. Management focuses on dietary measures and supplementation

1. GLYCOGEN STORAGE DISEASE –
LIVER GLYCOGENOSES
Nibin

5. • Glycogen storage disease is a group of genetic causes , that results
from a defect In enzyme or protein required for either glycogen
synthesis or degradation
• Characterised by deposition of either normal or abnormal glycogen in
the specific tissues
• GSDs are categorized by numerical type in accordance with the
chronological order in which these enzymatic defects were identified
• GSDs can also be classified by major organ involvement into liver and
muscle glycogenoses

6. • glucose-6-phosphatase deficiency (type I )
• Debranching enzyme deficiency (type III )
• Branchingenzyme deficiency (type IV )
• Liver phosphorylase deficiency (type VI )
• Phosphorylase kinase deficiency (type IX , formerly GSD VIa)
• Glycogen synthase deficiency (type 0 )

7. Type I Glycogen Storage Disease (Glucose-6-
Phosphatase or Translocase Deficiency, Von
Gierke Disease)
• AR
• 2 subtypes:
• Type Ia - glucose-6-phosphatase is deficient
• Type Ib - translocase that transports glucose-6-phosphate across the
microsomal membrane is deficient

8. • CLINICAL FEATURES
• NEWBORN – hypoglycaemia and lactic acidosis
• 3- 4 months – hepatomegaly and hypoglycemic seizures

10. Diagnosis
• Lactic acidosis
• Hypoglycemia
• Hyperuricemia
• Hyperlipedemia
• Neutropenia
• Genetic testing

12. Type III Glycogen Storage Disease (Debrancher
Deficiency, Limit Dextrinosis)
• Debranching enzyme is deficient
• glycogen breakdown is incomplete, glycogen with short outer-branch
chains accumaulates , which resemble limit dextrin
• hepatomegaly, hypoglycemia, short stature, variable skeletal
myopathy, and variable cardiomyopathy
• AR
• 2 types
IIIA – Liver and muscles involved
IIIB – Liver only

13. • overlapping features with GSD1 ,hepatomegaly, hypoglycemia,
hyperlipidemia, and growth retardation
Blood lactate and uric acid level NORMAL

15. • Universal distension of hepatocytes by glycogen and presence of
fibrous septa
• Enzyme assay in muscle and liver
• Gene sequencing

16. • MANAGEMENT
• Dietary management ; avoid simple sugars , hypoglycaemia treated
with small frequent meals with complex carbohydrates such as corn
starch , supplements , nasogastric drip
• Liver transplantation
• cardiac transplantation

17. TYPE IV GSD /ANDERSON DISEASE
• Deficiency of branching enzyme activity
• Accumulation of abnormal glycogen , amylopectin like substrate , polyglucosan
• AR
• Unlike patients with the other liver GSDs (I, III, VI, IX), those with GSD IV do not
have hypoglycemia
CLASSIC FORM
• Manifest as hepatosplenomegaly and FTT , Progressive cirrhosis
• Liver failure and death by 5 year of age
• Extrahepatic involvement – cardiac , skeletal, CNS

18. NEUROMUSCULAR FORM – 4 Variants
• Perinatal form- fetal akinesia deformation sequence and death
• Congenital form – severe hypotonia, muscle atrophy , neuronal
involvement , death
• Childhood form – myopathy or cardiomyopathy
• Adult form – adult polyglucosan body disease
Isolated myopathy , diffuse PNS and CNS dysfunction

19. • DIAGNOSIS
• Distinct staining properties of the cytoplasmic inclusions & EM
• Liver histology-micronodular cirrhosis and basophilic
inclusions in the hepatocytes(PAS positive and partially resistant to
diastase digestion)
• Definitive diagnosis- deficient branching enzyme
• Genetic study identification of pathogenic variants in the GBE gene

20. • No specific treatment for type IV GSD
• Nervous system involvement requires supportive, symptomatic
management.
• Liver transplantation has been performed for patients with
progressive liver disease

21. TYPE VI GLYCOGEN STORAGE DISEASE (LIVER
PHOSPHORYLASE DEFICIENCY, HERS DISEASE)
• GSD VI is an autosomal recessive disease
• Type VI GSD is caused by deficiency of liver glycogen phosphorylase
• Early childhood- hepatomegaly and growth retardation
• Hypoglycemia, hyperlipidemia, and hyperketosis are of variable
severity
• Lactic acid and uric acid levels are normal
• Focal nodular hyperplasia  hepatocellular adenoma malignant
transformation into carcinoma

22. • Diagnosis can be confirmed molecular testing of the liver
phosphorylase gene (PYGL)
• A liver biopsy showing elevated glycogen content and decreased
hepatic phosphorylase enzyme activity
• Treatment is symptomatic and aims to prevent hypoglycemia
• adequate nutrition
• A high-carbohydrate, high-protein diet and frequent feeding
are effective in preventing hypoglycemia.

23. TYPE IX GLYCOGEN STORAGE DISEASE
(PHOSPHORYLASE KINASE DEFICIENCY)
• Type IX GSD represents a heterogeneous group of glycogenoses.
• Deficiency of the enzyme phosphorylase kinase (PhK), which is
involved in the rate-limiting step of glycogenolysis.
• Pathogenic variants
PHKA1 gene - muscle PhK deficiency
PHKA2 and PHKG2 genes- liver PhK deficiency
PHKB gene – PhK deficiency in liver and muscle.

24. • Clinical manifestations of liver PhK deficiency short stature and abdominal
distention
• Hyperketotic hypoglycemia.
• Some children may have mild delays in gross motor development and
hypotonia.
• liver fibrosis progressing to cirrhosis and HCC
• Progressive splenomegaly and portal hypertension are reported secondary
to Cirrhosis
• Mild cardiomyopathy has been reported in a patient with GSD IX (PHKB
variant)
• Renal tubular acidosis has been reported in rare cases.

25. X-Linked Liver Phosphorylase Kinase Deficiency
(From PHKA2 Variants)
• X-linked liver PhK deficiency is one of the most common forms of liver
glycogenosis in males.
• Growth retardation
• Incidental detected hepatomegaly
• Slight delay in motor development
• Cholesterol, triglycerides, and liver enzymes are mildly elevated
• Ketosis may occur after fasting.
• Lactate and uric acid levels are normal.
• Hypoglycemia is typically mild in nature
• The response in blood glucose to glucagon is normal

26. Autosomal Liver and Muscle Phosphorylase Kinase
Deficiency (From PHKB Variants)
• autosomal recessive
• Similar to the X-linked form, symptoms include hepatomegaly and
growth retardation, Some patients exhibit muscle hypotonia

27. Autosomal Liver Phosphorylase Kinase Deficiency (From
PHKG2 Variants)
• more severe phenotypes, with recurrent hypoglycemia, prominent
hepatomegaly, significant liver fibrosis, and progressive cirrhosis.
• Liver involvement may present with cholestasis, bile duct
proliferation, esophageal varices, and splenomegaly
• Other reported presentations include delayed motor milestones,
muscle weakness, and
• renal tubular damage.

28. Liver Glycogen Synthase Deficiency
• Liver glycogen synthase deficiency(GSD 0)-Deficiency of hepatic
glycogen synthase
(GYS2) activity
Leading to a marked decrease of glycogen stored in the liver.
• True sense, this is not a type of GSD because the deficiency of th
e enzyme leads to
decreased glycogen stores

29. Clinical presentation:
• Infancy- early-morning (prebreakfast) drowsiness, pallor, emesis,
and fatigue and convulsions associated with hypoglycemia and
hyperketonemia
• Blood lactate and alanine levels are low
• No hyperlipidemia or hepatomegaly.
• Prolonged hyperglycemia, glycosuria, lactic acidosis, and
hyperalaninemia, with normal insulin levels after administration of
glucose or a meal, suggest a deficiency of glycogen synthase

30. Definitive diagnosis
• Measure the enzyme activity
• Genetic study identification of pathogenic variants in GYS2
Treatment
• consists of frequent meals, rich in protein and night time
supplementation with uncooked cornstarch to prevent
hypoglycemia and hyperketonemia

31. Hepatic glycogenosis with Renal Franconi syndrome (Franconi
Bickel syndrome )
• AR
• Defects in facilitative glucose transport GLUT2
• Proximal tubular dysfunction, impaired glucose and galactose utilisation
, accumulation of glycogen in liver and kidney
• Children:failure to thrive, rickets, and a protuberant abdomen from
hepatomegaly and nephromegaly
• Adolescent:short stature, dwarfism, and excess fat in the abdomen and
shoulders,
Susceptible to fractures

32. Laboratory findings
• Glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate
wasting, hypophosphatemia, increased serum alkaline
phosphatase levels, and radiologic findings of rickets
• Mild fasting hypoglycemia and hyperlipidemia
• Liver transaminase, plasma lactate, and uric acid levels are usually
normal
• Oral glucose and galactose challenge test - intolerance
• Liver biopsy

33. • There is no specific treatment
• Symptom-dependent treatment with phosphate and bicarbonate
can result in growth improvement.

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