Diseases pertaining

to glycogen
storage
Aditya Rosalya
BS15B003
Introduction
 Glycogen:-Glycogen, an important energy source, is found in most
tissues, but is especially abundant in liver and muscle.
 In the liver, glycogen serves as a glucose reserve for the maintenance
of normoglycemia.
 In muscle, glycogen provides energy for muscle contraction.
GLYCOGEN SYNTHESIS
Glycogen storage diseases
 Glycogen storage disease is the result of defects in the processing of
glycogen synthesis or breakdown within muscles, liver, and other cell
types
 There are about eleven known types of GSD, which are classified by
a number, by the name of the defective enzyme, or by the name
of the doctor who first described the condition

The GSDs can be divided in three main groups:

A) Those affecting liver,
B) Those affecting muscle,
C) and those which are generalized.
The liver glycogenoses Affect Muscles

GSD I GSD II
GSD V
GSD III GSD VII
GSD IV
GSD VI
GSD IX
GSD 0.
Glycogen Storage Disaease Type Enzyme Deficiency Prevalence
less than 20,000 people in US
I Von Geirke's disease Glucose 6 phosphatase
population
II Pompe's disease acid maltase 1 in 40000
III Cori's disease glycogen debrancher 1 in every 100000 live birth
IV Andersen disease glycogen branching enzyme ????
V McArdle disease muscle glycogen phosphorylase 1 in 100000
VI Hers' disease liver glycogen phosphorylase ????
VII Tarui's disease muscle phosphofructokinase 100 reported cases
Glycogen-storage diseases
GSD l(Von Gierke Disease)

 caused
by deficiency of the of glucose-6-
phosphatase (G6Pase)
 people with Type I GSD are able to store glucose
as glycogen but not able to release it normally,
with time the stores of glycogen build up in the
liver causing the liver to swell (hepatomegaly).
Glycogen G1P G6P
G6Pase
Glucose
Von Gierke described the first patient with GSD type I in 1929 under the name
hepatonephromegalia glycogenica.

In 1952, Cori and Cori demonstrated that glucose-6-phosphatase (G6Pase) deficiency was
a cause of GSD type I.

In 1978, Narisawa et al proposed that a transport defect of glucose-6-phosphate (G6P) into

the microsomal compartment may be present in some patients with GSD type I.

Thus, GSD type I is divided into GSD type Ia caused by G6Pase deficiency and GSD type Ib
resulting from deficiency of a specific translocase T1

Von Gierke disease is inherited, which means it is passed down through families.

• If both parents carry the defective gene related to this condition, each of their
children has a 25% chance of developing the disease.

GSD Ia: caused by deficiency of the catalytic subunit of glucose-6-phosphatase (G6Pase),

GSD Ib: due to deficiency of the endoplasmic reticulum (ER) glucose-6-phosphate (G6P)
translocase.
Symptoms :
 Enlarged liver and kidneys
 Low blood sugar
 High levels of lactate, fats, and uric acid in the blood
 Impaired growth and delayed puberty
 Bone thinning from osteoporosis Increased mouth ulcers and infection
 Frequent infection
 Liver tumors
 Osteoporosis
 Short height
 Underdeveloped secondary sexual characteristics (breasts)
 Ulcers of the mouth

TREATMENT:-
Initially glucose via a nasogastric tube.
 As children get older, glucose is replaced with cornstarch
taken orally
GSD II (Pompe’s Disease)
• Caused by Acid Maltase Deficiency
• GSD II is a lysosomal storage disorder, caused by the generalized
deficiency of the lysosomal enzyme, acid maltase or α-
glucosidase.
• Although the defect involves a single ubiquitous enzyme, it
manifests as three different clinical phenotypes: Infantile,
juvenile, and adult

• Glycogen storage disease, type II (GSD-II).

• Acid maltase deficiency (AMD).
• Disease Families
• Lysosomal storage disease.
• Glycogen storage disease.
• Neuromuscular disease/metabolic muscle disease.

• Note:-Acid alpha-glucosidase, also called α-1,4-glucosidase and acid maltase, is

an enzyme (EC [Link]) that helps to break down glycogen in the lysosome.
 In the infantile form, infants seem normal at birth, but
within a few months they develop muscle weakness,
trouble breathing, and an enlarged heart.
 Cardiac failure and death usually occur before age
2, despite medical treatment.

 The juvenile and adult forms of GSD II affect mainly

the skeletal muscles in the body's limbs and torso.
 Decreased muscle strength and weakness
developed
 Pompe’s Disease Signs &
Symptoms

Infantile onset < 12 months Late onset > 12 months

Daytime somnolence
Morning headache
Head lag Shortness of breath/ sleep
Respiratory
insufficiency apnea
Enlarged tongue Cardiomegaly/ Scapular winging
cardiomyopathy
Respiratory Scoliosis
insufficiency

Delayed motor Low back pain

development Gait abnormality
Organomegaly Muscle weakness
Muscle weakness

Unusual symptoms or clusters of more common symptoms

 Diagnosis
Muscle biopsy shows a severe vacuolar myopathy with
accumulation of both intralysosomal and free glycogen in both
the infantile and childhood variants
Treatment :
Enzyme replacement therapy using recombinant human α-
glucosidase, obtained in large quantities from rabbit milk has been
used successfully;

Four infants with Pompe disease were treated with spectacular

results: although one patient died of an intercurrent infection at 4
years of age, all four patients showed remarkable clinical
improvement in motor and cardiac function and parallel
improvement in muscle morphology.
GSD lll(Cori disease)
 GSD III is caused by a deficiency of glycogen debrancher enzyme
activity. The normal structure of glycogen has branches. In GSD III,
glycogen is able to be partially broken down to release some
glucose. However, the remaining glycogen that is not completely
broken down has short outer chains and collects in the liver, muscle,
and heart. The build-up of this atypical form of glycogen can cause
damage to tissues.
 It is an autosomal recessive disorder due to deficiency of GDE
(glycogen de- branching enzymes.)which causes storage of
glycogen with an abnormally compact structure, known as
phosphorylase limit dextrin

glycogen debrancher enzyme

Glycogen G1P
CORI Cycle
 CAUSE:-

 This disease principally affects the liver.

 It causes swelling of the liver, slowing of growth,

 low blood sugar levels and, sometimes, seizures.

 Muscle weakness may develop later in life, and is most

pronounced in the muscles of the forearms, hands,
lower legs and feet.

 Weakness often is accompanied by loss of muscle bulk

and exercise intolerance.
Diagnosis:- liver biopsies. Biopsy of the liver shows
inflammatory changes (swollen liver cells) with great
elevations of abnormal- structured glycogen content and
a deficiency of the debrancher enzyme (GDE).
Treatment:-protein supplements for muscle disorder
Glycogen storage disease type III has an autosomal recessive pattern
of inheritance
 GSD lV(Andersen disease)
 GSD IV is caused by a deficiency of glycogen branching enzyme.
The normal structure of glycogen is formed by branches. The absence of glycogen
branching enzyme leads to formation of glycogen with fewer branch points and
longer outer chains than normal
Extremely rare hereditary metabolic disorder produced by
absence of the enzyme amylo-1:4,1:6-transglucosidase,.
Which is an essential mediator of the synthesis of glycogen.
An abnormal form of glycogen, amylopectin, is produced and accumulates in
body tissues, particularly in the liver and heart.

Abnormally structured glycogen forms.

Glycogen branching enzyme
G1P UDPG Glycogen
Symptoms :
 Growth delay in childhood
 Enlarged liver
 Progressive cirrhosis of the liver (which may lead to liver failure)
 May affect muscles and heart in late-onset type
 Progressive cirrhosis of the liver (which may lead to liver failure)
 May affect muscles and heart in late-onset type
 Poor infant weight gain
 Lack of infant muscle tone
 Gastro intestinal Problems
Treatment:-
 No treatment apart from liver transplantation has been found to
prevent progression of the disease. Most children with this
condition die before two years of age.
Recent Cases Reported in India
2016:-Sudheer sold off his farm and home to save his child
from liver failure, but it is not
enough([Link]
Parents get to know that both their children had a condition
called Glycogen Storage Disease. This condition – if not
controlled, destroys the liver and weakens muscles.
Sudheer's 2-year-old son Akhilesh has a rare illness that has
caused liver damage. Since he turned two last month,
Akhilesh's conditon is getting worse. He needs a liver
transplant at the soonest.(16 Lakh for liver transplant)

2018:-Poor Parents' All 3 Kids Have Severe Liver Disease, Need

Urgent Help([Link]
Durga Prasad was just 2 years old and started walking on his
own when his stomach started swelling up. He was diagnosed
with glycogen storage disease, a condition where the liver
cannot control the glycogen and glucose levels causing
abnormal amounts of glycogen levels in liver causing liver
failure. Because he was too young to undergo a transplant,
the doctors asked the parents to wait.(25 lakh for treatment)
 GSD V(Mc Ardle’s Disease )

Caused by Myophosphorylase Deficiency

Under normal circumstances, muscles cells rely on oxidation of fatty acids during rest or
light activity.
Mc Ardle’s Disease is a metabolic disease affecting skeletal muscle

There are three isoforms of glycogen phosphorylase: brain/heart, liver, and

muscle, all encoded by different genes.

Note:- Myophosphorylase is one of three related enzymes called glycogen

phosphorylases that break down glycogen in cells. Myophosphorylase is
found only in muscle cells, where it breaks down glycogen into a simpler
sugar called glucose-1-phosphate
Symptoms:-
Muscle cramps during exercise Extreme fatigue after exercise Burgundy-

colored urine after exercise

 People with McArdle's disease develop severe muscle cramps and
fatigue in the first few minutes of activity.

 Some adults develop a progressive proximal weakness fixed motor

weakness.

 About one half of all patients will have experienced

myoglobinuria (dark urine) following intense exercise.
 GSD VI(Hers disease)

 GSD VI is one of the least severe forms of GSD

 Caused by a deficiency in liver glycogen phosphorylase or other
components of the associated phosphorylase cascade system.
 GSD VI is caused by a deficiency of liver phosphorylase enzyme,
which helps with the breakdown of glycogen to glucose. Due to the
inability to breakdown glycogen to glucose and the resulting
storage of extra glycogen in the live

liver phosphorylase enzyme

Glycogen G1P
Symptoms :-Hepatomegaly(enlarged liver)
 Hypoglycaemia
 Growth retardation
 Hyperlipidaemia: high level of cholesterol or triglycerides in your blood.
 No specific symptoms are associated with Hers disease (glycogen storage disease, type VI).
 Hepatomegaly may be present; however, because many causes of hepatic injury exist,
suspicion must be high.
 Growth retardation is possible.
 The liver isoform of phosphorylase is deficient.
 A mutation has been mapped to chromosome 14. A splicing site mutation has been
identified.
Diagnosis :-
 Blood sugar testing
 Cholesterol testing
 Liverfunction tests may also be seen
Treatment:Need frequent feeding to avoid hypoglycaemia.
 GSDVII (Phosphofructokinase Deficiency)

First described by Tarui

This disease is one of the metabolic muscle disorders that interferes with the
processing of food (in this case, carbohydrates) for energy production.
Although glucose may be available as a fuel in muscles, the cells cannot metabolize
it.
Symptoms :
Muscle cramps with exercise Anemia
 Symptoms
 Its similar to McArdle's glycogen storage
disease but more severe.
 Consider other causes of muscle weakness
and myoglobinuria
 GSD IX(Phosphorylase Kinase
Deficiency)
 GSD type IX is a disorder in which the body cannot break down
glycogen .People with GSD IX are deficient in an enzyme called
phosphorylase kinase (PhK). A deficiency in PhK causes glycogen to
accumulate in various tissues including liver, muscle, red blood cells,
and sometimes in the heart.
 Phosphorylase kinase (PhK) is a specific protein kinase which
activates glycogen phosphorylase to release glucose-1-phosphate
from glycogen.
Phosphorylase Kinase
Glycogen G1P
Symptoms :-
 People with GSD IX develop enlarged livers and may have low blood
sugar due to inability to breakdown glycogen
Diagnosis:-
 Blood profiling
 Biopsy of liver
Treatment:-
 It can be prevented by maintaining a high carbohydrate (starchy foods)
diet, adequate amounts of protein in the diet, and avoiding long periods
of not eating.
 GSD 0(Glycogen Synthase
Deficiency)
GSD 0 is caused by a deficiency of glycogen synthase (GS), a key-
enzyme of glycogen synthesis. Consequently, patients with GS
deficiency have decreased liver glycogen concentration, resulting
in fasting hypoglycaemia.
glycogen synthase
G1P UDPG Glycogen
Symptoms:- Before breakfast drowsiness
 Tiredness
 looking pale
 vomiting.
Secondary symptoms
 Quick to tire, muscle cramps
Diagnosis :-
 Blood tests
 Blood glucose: hypoglycaemia is likely
 Liver function tests: monitoring for hepatic failure
Treatment :-
 cornstarch to reduce overnight hypoglycemia.
GSD Type Enzyme Symptoms Diagnosis Treatment
Deficiency

Type l G6PTase Hepatomegaly Liver biopsy cornstarch taken orally

Low blood sugar
Impaired growth
Type lll Debranching Swollen abdomen Liver biopsy protein supplements for
Enzyme Tissue damage abnormal- muscle disorder
Muscle weakness structured glycogen

Type lV Branching Growth delay in abnormal- liver transplantation

Enzyme childhood structured glycogen
Enlarged liver with long outer
chain
Type Vl Liver Hepatomegaly blood sugar testing Need frequent feeding
phosphorylase hypoglycaemia Cholesterol to avoid
growth retardation testing hypoglycaemia.
hyperlipidaemia. liver function
Type lX Phosphorylase enlarged livers and Blood profiling Prevent by taking high
Kinase may have low blood Biopsy of liver carbohydrate diet
sugar
Type 0 Glycogen Tiredness Blood tests cornstarch to reduce
 References:-
 [Link]
 [Link]
_storage_disease types
 [Link]

 [Link]
110505030652-phpapp01/95/glycogen-storage-disease-gsd-4-
[Link]?cb=1304582937
 Protease assay
Substrate :
casein

•Folin & Ciocalteus Phenol, or Folin’s reagent: reacts with free tyrosine to produce a blue
colored chromophore.

•Quantified and measured using a spec-660nm

• more tyrosine released from casein, more chromophores are

generated and the stronger the activity of the protease.

•Draw standard curve .

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