Glycogen storage disease

Presented by: Manisha .s. nadar Guided by: Dr. Puvitha

2nd year MD

Learning objectives:

What is glycogen ?

Structure, synthesis, role of hormones on glycogen

Types of GSD and genetic mutations In each

Symptoms and treatment

Questions and doubts

reference

What is glycogen?

In simple words:

(C6H10O5 )n . A polysaccharide.

or storage form of glucose in body. In a rapidly mobilizable form.

Abundantly stored in liver and muscle [liver glycogen can maintain blood glucose for 8-10 hrs, whereas most of the body’s glycogen is found in muscles].

Quick review of the structure:

Primary glycosidic bond is – α(1 4) linkage after 8 to 10 glucosyl residue a branch containing α(1 6) linkage.

Synthesis and breakdown of glycogen

As we know glycogen is the stored form of glucose, most commonly found in organs like liver and muscles. it is the primary source of energy in humans, the synthesis and breakdown of which involves many important enzymes. deficiency of these enzymes (caused by mutations) leads to glycogen storage disease of varying types.

Glycogenin (enzyme acting as a primer) polymerizes first few glucose molecules ( a oligosaccharide containing 4 glucose molecules called limit dextrin).

Later each glucose molecules are converted to simple forms (glucose-1-p) for the easy bonding α(1-4) and branching α(1-6) finally forming the complex structure glycogen.

Short recap of glycogen synthesis and important enzymes taking part in it.

Enzymatic activity and effects of epinephrine

Role of hormones on glycogen

Classification of GSD

Approximately a dozen forms of glycogenosis have been described in association with specific enzyme deficiencies. On the basis of pathophysiologic findings, they can be grouped into three categories.

1. Hepatic type:

Deficiency of hepatic enzymes involved in glycogen metabolism. It is associated with major clinical effects : enlargement of the liver due to storage of glycogen and hypoglycaemia due to a failure of glucose production. Eg: von gierke disease.

2. Myopathic type:

In striated muscle, glycogen is an important source of energy. Enzymes that are involved in glycolysis are deficient. It is associated muscle weakness due to impaired production of energy. Typical marking of myopathic GSD is by muscle cramps after exercise, myoglobinuria. And failure of exercise to induce an elevation in blood lactate levels because of a block in glycolysis. Eg: McArdle disease.

Classification of GSD

3. Type ii glycogenesis:

It is caused by a deficiency of lysosomal acid maltase and so is associated with deposition of glycogen in virtually every organ, but cardiomegaly is most prominent.

most affected patients die within 2 years of onset of cardiorespiratory failure. Therapy with the missing enzyme (glucosidase) can reverse cardiac muscle damage and modestly increase longevity.

GSD type 1(von gierke disease)

von Gierke disease caused by the buildup of a complex sugar called glycogen in the body's cells.

Signs and symptoms of this condition typically appear around the age of 3 or 4 months. infant may have hypoglycemia, which can lead to seizures. They can also have lactic acidosis, high blood levels of uric acid (hyperuricemia), and hyperlipidemia.

As they get older, children with GSDI have thin arms and legs and short stature. An enlarged liver may give the appearance of a protruding abdomen. The kidneys may also be enlarged. Affected individuals may also have diarrhea and deposits of cholesterol in the skin (xanthomas).

GSD type 1(von gierke)

other symptoms:

delayed puberty

osteoporosis

Gout

pulmonary hypertension

polycystic ovaries

two types of GSD :

type Ia (GSDIa) &type Ib (GSDIb).

people with GSDIb have neutropenia. neutropenia and oral problems are specific to people with GSDIb and are typically not seen in people with GSDIa.

Genetic changes

Mutations in two genes, G6PC and SLC37A4, cause GSDI. G6PC gene mutations cause GSDIa, and SLC37A4 gene mutations cause GSDIb.

Mutations in the G6PC and SLC37A4 genes prevent the effective breakdown of glucose 6-phosphate. Glucose 6-phosphate that is not broken down to glucose is converted to glycogen and fat so it can be stored within cells.

Von gierke’s disease

Chromosomal mutation of G6PC and SLC37A4 genes .

Cytogenetic Location: 11q23.3

GSD type 2 (pompe disease)

accumulation of glycogen in certain organs and tissues, especially muscles, impairs their ability to function normally.

three types of Pompe disease:

classic infantile-onset, non-classic infantile-onset, and late-onset.

classic form of infantile-onset Pompe disease: begins within a few months of birth.

Symptoms are,

Myopathy

Hypotonia

Hepatomegaly

heart defects

If untreated, this form of Pompe disease leads to death from heart failure in the first year of life.

non-classic form of infantile-onset Pompe disease

usually appears by age 1.

Symptoms are,

delayed motor skills

progressive muscle weakness.

Cardiomegaly

most children with non-classic infantile-onset Pompe disease live only into early childhood.

late-onset type of Pompe disease may not become apparent until later in childhood, adolescence, or adulthood.

milder than the infantile-onset forms of this disorder and is less likely to involve the heart.

Most individuals experience progressive muscle weakness, especially in the legs and the trunk, including the muscles that control breathing. As the disorder progresses, breathing problems can lead to respiratory failure.

Genetic changes in GSD type2 (pompedisease)

Mutation in GAA gene [glucosidase a,acid]:

This gene is responsible for producing the acid a-glucosidase [acid maltase] this enzyme is active in lysosomes and breaks down glycogen to glucose

Cytogenetic Location of GAA gene : 17q25.3

Pompe’s disease

GSD type 3 (cori disease)

Beginning in infancy, individuals with any type of GSDIII

Hypoglycemia

Hyperlipidemia

elevated blood levels of liver enzymes

Hepatomegaly

slow growth

noncancerous (benign) tumors called adenomas may form in the liver.

some affected individuals develop chronic liver disease (cirrhosis) and liver failure later in life.

Cori’s disease

Mutation of AGL gene (amylo-a-1,6-glucosidase,4-a-glucontransferase) cytogenetic location: 1p21.2

The AGL gene is responsible for the production of debranching enzyme (break down the side chains). It also forms the isoform of the debranching enzyme (phosphorylases) in different tissues.

Cori’s disease/ forbe’s disease

GSD type 4 (Andersen’s disease)

The fatal perinatal neuromuscular type is the most severe form of GSD IV, with signs developing before birth.

Polyhydramnios

Affected fetuses have a condition called fetal akinesia deformation sequence

Decrease joint stiffness (arthrogryposis)

severe hypotonia & atrophy

The congenital muscular type of GSD IV is usually not evident before birth but develops in early infancy These babies often have dilated cardiomyopathy.

The progressive hepatic type is the most common form of GSD IV. failure to thrive hepatomegaly portal hypertension, ascites

Andersen’s disease

Mutation of GBE1 gene (1,4-a-glucan branching enzyme 1)

This gene provides instructions for making glycogen branching enzyme. As the branched structure of glycogen makes it more compact for storage and allows it to breakdown more easily when it is needed for fuel.

Cytogenetic location: 3p12.2

Andersen’s disease

GSD type 5 (McArdle disease)

inherited disorder caused by an inability to break down a complex sugar called glycogen in muscle cells.

People with GSDV typically experience,

fatigue, muscle pain, and cramps during the first few minutes of exercise (exercise intolerance) The discomfort is generally alleviated with rest.

About half of people with GSDV experience breakdown of muscle tissue (rhabdomyolysis)

destruction of muscle tissue releases a protein called myoglobin, which is filtered through the kidneys and released in the urine (myoglobinuria). Myoglobin causes the urine to be red or brown

myoglobinuria will develop life-threatening kidney failure.

features of this condition typically begin in a person's teens or twenties, but they can appear anytime from infancy to adulthood

McAdrle’s disease

Mutation of the PYGM gene (glycogen phosphorylase, muscle associated) provides the instructions to produce myophosphorylase (converts glycogen to glucose-1-phosphate). Mutation creates a premature stop signal.

Cytogenetic location :11q13.1

McAdrel’s disease

McAdrel’s disease: 1. subsarcolemmal vacuoles2. vascuolar myopathy

GSD type 6 (hers disease)

A lack of glycogen breakdown interferes with the normal function of the liver.

The signs and symptoms of GSDVI typically begin in infancy to early childhood. The first sign is usually an hepatomegaly. Affected individuals may also have hypoglycemia or lactic acidosis during fasting.

The signs and symptoms of GSDVI tend to improve with age; most adults with this condition do not have any related health problems.

Hers disease

Mutation of the PYGL gene (phosphorylase L) causes deficient liver glycogen phosphorylase which breaks down the glycogen to glucose-1-phosphate.

Cytogenetic Location : 14q22.1

Hers disease

GSD type 7 (tarui’s disease)

It is the result of phosphofrucokinase enzyme deficiency

Phosphofructokinase catalyzes the rate-limiting step in glycolysis. Phosphofructokinase deficiency leads to muscle pain and exercise-induced fatigue and weakness. Tarui disease resolves with rest, and, although no specific treatment exists, the condition may not progress to severe disability.

excess glycogen accumulates in affected tissues.. Enzyme deficiency decreases the rate of conversion of fructose-6-phosphate to fructose-1,6-diphosphate. Phosphofructokinase is found in muscle tissue and red blood cells.

Exercise intolerance in childhood much earlier and is more severe in Tarui disease than in McArdledisease. The second wind phenomenon is not seen in Tarui disease as it is in McArdle disease.

Neurologic symptoms believed attributable to Tarui disease include complex partial seizures, diplopia, hyporeflexia, central facial palsy, and upper extremity weakness.

Tarui’s disease

Mutation of PFKM gene causes deficiency of phosphofructokinase, muscle this gene provides a subunit of PFK which is essential for rapid breakdown of glycogen. More common in Ashkenazi jewish ancestry.

Cytogenetic Location : 12q13.11

Tarui’s disease

GSD type 0: has a GYS1(glycogen synthase1) gene. Mostly affects the cardiac and skeletal muscle. Cytogenetic Location : 19q13.33

GSD type 0 :GYS2 (glycogen synthase 2) gene provides liver glycogen synthase. Cytogenetic Location: 12p12.1

GSD type15 :Mutation of GYG1 (glycogenin1) gene. This gene is expressed in muscle and other tissues Glycogenin is a glycosyltransferase that catalyzes the formation of a short glucose polymer from uridine diphosphate glucose in an autoglucosylation reaction.Cytogenetic Location : 3q24

Treatment options and management of GSD

GSD type I:

GSD type Ib require intravenous therapy to correct hypoglycemia and intensive intravenous antibiotic treatment to control infections.

Because no specific treatment is available, symptomatic therapy is very important.

the future may bring adeno-associated virus vector–mediated gene experimental therapy, which may result in curative therapy, as is possible in patients with GSD type II.

The primary goals are good control of hypoglycemia and other metabolic disturbances, such as hyperlactatemia, hyperuricemia, and hyperlipidemia.

GSD type II

At present, effective specific treatment can be achieved using recombinant DNA alglucosidase alfa(Myozyme), which degrades lysosomal glycogen..

Alglucosidase alfa may be administered by intravenous infusion only. inpatient care is necessary in instances of respiratory insufficiency.

GSD type III:

Hydrolyzable cornstarch should be slowly administered between meals and overnight as well; this therapy is particularly important to prevent overnight hypoglycemia.

GSD types IV and VI:

No medication is necessary.

GSD types V and VII:

No specific therapy is available. Hospital treatment is necessary during renal insufficiency due to rhabdomyolysis.

Mnemonic: Von Gierke Put Coors And McDonalds in Her Taurus. (Imagine Von Gierke loading up his girlfriend's Ford Taurus with Coors and McDonalds for a picnic)

Type 1: Von Gierke

Type 2: Pompe

Type 3: Cori

Type 4: Andersen

Type 5: McArdle

Type 6: Hers

Type 7: Tarui

Glycogen storage disorders exhibit autosomal recessive inheritance.

Hyperlipidemia seen in von Gierke disease manifests as xanthomas and elevated VLDL.

Decreased free phosphate due to defective glucose-6-phosphatase causes increased AMP. AMP is degraded to uric acid causing hyperuricemia. This predisposes patients to gout.

Type VII (Tarui) presents in childhood with :

Exercise-induced muscle cramps and weakness

Ketosis

Hyperlipidemia

Mildly elevated transaminases

Hers' disease presents in early childhood with :

Hepatomegaly

Growth retardation

Mild hypoglycemia

Mild hyperlipidemia

Mild ketosis

2. B5. C18. D19. E22. C

Reference:

Robbins basic pathology; 9th edition; by: kumar, abbas, aster

http://www.humpath.com/spip.php?article8559&id_document=25137#documents_portfolio

https://ghr.nlm.nih.gov/

http://emedicine.medscape.com/article/119947

http://www.namrata.co/glycogen-metabolism-multiple-choice-questions-solved/