Glycogen Storage Disorders (GSDs)😊

Glycogen

Glucose is stored as glycogen because

it is compact
Has solubility

Stored only in the liver and skeletal muscle.

Only site where Glycogen synthesis and glycogenolysis happens

Has the most branched structure.

Glucose linked by α-1,4 linkage in straight chains.
α-1,6 linkage forms branch points.

Glycogen Storage Disorders (GSDs)

Mnemonic

Andersen – Branching enzyme defect

Cori – Debranching enzyme defect - limitless

von Gierkes → Glucose 6 phosphatase

Hers → Hepatic phosporylase

Fasting hypoglycemia - vaishna (0136)

During Exercise - count 3, 5, 7 (0357)

Counter Regulatory Hormones

Includes

Glucagon
Growth hormone
Nor-epinephrine
Cortisol

They increase the rate of gluconeogenesis if glycogenolysis does not work.

A three month old newborn, who was healthy at birth develops chronic liver failure and muscle weakness. On examinations, serum glucose is low, associated with ketoacidosis and reduced pH. The ALT and AST levels rise. Uric acid and lactate levels in the blood are normal. When administered intravenously, glucagon elevates blood sugar levels after meals but not after an overnight fast. Liver biopsy shows increased glycogen in liver. Which enzyme in this youngster is most likely to be defective?

Glucose-6-phosphatase

Muscle phosphorylase

Branching enzyme

Debranching enzyme

ANS

Debranching enzyme

GSD Type	Key Features	Investigations
Type Ia Glucose-6-phosphatase	Von Gierke's disease (Type Ia) • Protruding abdomen • severe fasting hypoglycemia • ketosis • prominent buccal fat • thin extremities • convulsions/coma on fasting • massive hepatomegaly • enlarged kidneys • growth retardation	• S. Glucose ↓ • Rothera's test: Positive • S. Uric acid ↑↑ • S. Lactate ↑↑ (lactic acidosis) • Hyperlipidemia • Hypertriglyceridemia • Fatty liver • AST & ALT: Normal Liver biopsy: • Normal glycogen accumulation
Type Ib Glu-6-PO₄ transporter (SER)	• Similar to Type Ia + neutropenia	ㅤ
Type III Debranching enzyme (α-1,6-glucosidase and 4-α-D-glucanotransferase)	Cori/Forbes disease (Limit Dextrinosis) • Like Von Gierke but milder • Early morning hypoglycemia • not fatal • hepatomegaly • muscle weakness (IIIa) • cardiomyopathy (IIIa) • (Coriii - threee)	• S. Glucose ↓ • Rothera's test: Negative • S. Uric acid: Normal • S. Lactate: Normal • AST & ALT: ↑ Liver biopsy: • Limit dextrin accumulation
Type IV Branching enzyme	Andersen’s disease (Amylopectinoses) • Fasting hypoglycemia • portal hypertension • hepatosplenomegaly • progressive liver cirrhosis • fatal ↳ (death within 5 yrs due to liver failure) • hypotonia	• S. Glucose ↓ • Rothera's test: Negative • S. Uric acid: Normal • S. Lactate: Normal • AST & ALT: ↑↑ Liver biopsy: • Amylopectin accumulation Genetic testing • GBE1 gene ↳ (Branching Enzyme 1 gene)
Type VI Hepatic glycogen phosphorylase	Hers’ disease • Mild hypoglycemia • hepatomegaly • growth retardation • hyperlipidemia	• Normal lactate/uric acid Genetic testing • PYGL gene • Hers → PY Girl (PYGL)

GSD Type	Key Features	Investigations
Type II Lysosomal Acid α-1,4-glucosidase / Acid maltase	Pompe disease • With Hypertrophic HCM • Floppy infant • generalized hypotonia • fatal ↳ death within 2 yrs ↳ due to cardiac failure • enlarged tongue • enlarged liver • A glucose (α glucosidase) pump and acid (acid maltase)	Chest X-ray: • Massive cardiomegaly • Elevated CK • glycogen in lysosomes • no hypoglycemia/ lactic acidosis • enzyme analysis ↳ from cultured fibroblasts
Type V Muscle glycogen phosphorylase (myophosphorylase)	McArdle disease (most common) • Adolescent male • Calf muscle pain on exercise • Exercise intolerance ———————————————— • No hemolysis • Second wind phenomenon • LDH levels are normal. • (Mc Adle - Muscle in Adoloscent)	• Glucose ↓ (during exercise) • S. Lactate ↓ • AST & ALT: Normal • Creatine kinase ↑↑ • Burgundy coloured urine ↳ myoglobinuria Genetic testing • (PYGM gene) (”GYM”)
Type VII Muscle + erythrocyte PFK 1	Tarui’s disease • Like McArdle • Exercise intolerance • muscle cramps ———————————————— Difference • Myoglobinuria • No 2nd wind phenomenon • Hemolysis • LDH levels are high. • Fructose (PFK) thinnapo Blood (hemolysis) tuuri (Tauris)	• S. Glucose ↓ (during exercise) • S. Lactate ↓ • Creatine kinase ↑ • elevated CK/bilirubin Genetic testing • PFKM gene

GSD Type	Glucose	Lactate	Uric Acid	Ketosis	AST/ALT	Biopsy Finding
I (Ia)	↓↓↓	↑↑	↑↑	Positive	Normal	Normal glycogen
Ib	↓↓↓	↑↑	↑↑	Positive	Normal	Same as Ia
III	↓	Normal	Normal	Negative	↑	Limit dextrin
IV	↓	Normal	Normal	Negative	↑↑	Amylopectin
VI	↓ (mild)	Normal	Normal	—	Mild ↑	Normal glycogen

Feature	Pompe (II)	McArdle (V)	Tarui (VII)
CK	↑	↑↑	↑
HCM	Yes	no	no
Lactate (exercise)	Normal	↓	↓
Myoglobinuria	No	Yes	Yes
Hemolysis	No	No	Yes
Second wind	no	yes	no
Hypoglycemia	No	No	No
Genetic Test	–	PYGM	PFKM

GSD Type	Key Features	Investigations
Type 0	• Glycogen synthase defect • No glycogen storage • No hepatomegaly • Hypoglycemia • Ketosis • Postprandial hyperglycemia	Genetic testing
Fanconi–Bickel syndrome	• GLUT2 defect • Glycogen accumulation disorder • Hepatomegaly absent	ㅤ
GSD IX	• Phosphorylase Kinase Deficiency • Hepatomegaly • Mild Hypoglycemia • Growth retardation • Variable muscle involvement	Genetic testing • PHKA1 • PHKA2 • PHKB • PHKG2 genes

NOTE: Different Fanconis

ㅤ	ㅤ
Fanconi disease/syndrome	• Proximal tubular reabsorption problem → Type 2 RTA • Glycosuria, aminoaciduria
Fanconi anemia (Not syndrome)	• Pancytopenia + radial ray
Fanconi Bickel syndrome	• Mutation in GLUT-2 • Bickel → Bi → 2 (GLUT 2) Defect in glucose sensing → ↓ insulin release • Postprandial Hyperglycemia. • Fasting Hypoglycemia • Glycogen accumulation disorder

VACTERAL
Holt - Oram (ASD + Radial Ray)
TAR (thrombocytopenia + absent radius)
Congenital torticollis → Cock robin position — VACTERAL
Holt - Oram (ASD + Radial Ray)
**TAR** (thrombocytopenia + absent radius)
Congenital torticollis → **Cock robin position**

Stranger things characters

Dustin (Cleido cranial dysplasia)

Robin (Cock robin position)

Ray (Radial Ray) Hopper (Holt Oram ASD)

Glycogen synthase deficiency (Type 0)

It is a GSD without glycogen storage.

Liver biopsy shows 0 glycogen in the liver.

Presents with fasting hypoglycemia and exercise intolerance.

Type I Von Gierke's Disease

Defect in Glucose-6-phosphatase.

Causes severe fasting hypoglycemia.

Both gluconeogenesis and liver glycogenolysis cannot increase blood glucose.

Does not respond to counter-regulatory hormone administration.

Glucose-6-phosphatase is present only in the liver.

It was the first GSD to be detected.

Complications

Renal failure

Pancreatitis

PCOD

Hepatic adenoma

PAH

Osteopenia

Except Cardiomyopathy

Type II Pompe's Disease

Mnemonic:

Pompe

Pump Problem → Heart (HCM) + Lysosomal enzyme defect
Pump () cheyyan glucose thinnunna alpha (alpha glucosidase) ne vilikkanam, maltase (Acid maltase) thinnunna ale vilichalum mathi

Glucose thinnunna Beta (Beta glucosidase) ye → Gotcha (Gauchers)

Both Glucosidase defects have ERT
A glucose (Alpha glucosidase) pump

McArdle

McArdle = Muscle cramps + Myoglobinuria + 2nd wind → Teen Gym

Tarui

McArdle + Hemolysis, but no 2nd wind → Fructose problem = PFK deficiency

It is the only lysosomal storage disorder that is also a GSD.

Involves a defect in Acid maltase or alpha glucosidase.

Affects cardiac and skeletal muscle.

Clinical Features:

Cardiomegaly,

Cardiomyopathy,

Respiratory distress,

d/t floppy diaphragm

Hypotonia/floppy baby,

Failure to thrive.

Death usually occurs within 2 years.

Enzyme replacement therapy is available.

Type III Cori's Disease

Defect in the de-branching enzyme.

Liver biopsy reveals abnormal glycogen with multiple branch points (Alpha dextrin).

Also called Limit dextrinosis.

Presents with fasting hypoglycemia and exercise intolerance.

Type V McArdle's Disease

Defect in Muscle Phosphorylase.

Presents with exercise intolerance, particularly to anaerobic exercises (e.g., weightlifting).

Due to ATP depletion, there is no relaxation, leading to painful muscle cramps.

Blood from the exercising arm shows low glucose and low lactate.

LDH levels are normal.

Type VI Her's Disease

Defect in Liver phosphorylase.

Presents with fasting hypoglycemia.

Responds to counter-regulatory hormones.

Type VII Tarui's Disease

A glycolytic enzyme defect (PFK 1).

RBCs affected: Leads to hemolytic anemia.

ATP is not generated, the Na-K ATPase pump fails, RBCs swell and rupture.

White muscle fibers affected: Leads to exercise intolerance (anaerobic).

LDH levels are high.

Anderson's Disease (Type IV)

Deficiency of the branching enzyme.

Abnormal glycogen without branch points accumulates.

Presents with hepatomegaly, then progresses to liver cirrhosis.

It is a GSD with neither fasting hypoglycemia nor exercise intolerance.