Glycogenoses and Glycogen Storage Diseases, General Aspects

NeuroLearn NeuroHelp Muscle @

General   Summary of glycogenosis     Classificaiton of glycogenoses by enzyme deficiency

Summary: Glycogenoses are resulted from abnormal metabolism of glycogen or the lack of a particular lysosomal enzyme to degrade glycogen or catabolism of glucose. Most but not all subtypes are associated with excessive glycogen storage. Glycogen storage diseases (GSD) should be reserved to the subtypes with substantial glycogen storage. Clinical manifestations of skeletal muscle inclue weakness with hypotonia, exercise intolerance or muscle cramps with or without myoglobinuria. The liver and the heart are also affected in many subtypes. The muscle biopsy can show striking glycogen storage or minimal changes. The clinicopathologic features are type specific. When glycogen storage is present in the muscle, the most common pathologic findings is subsarcoplasmic and cytoplasmic vacuoles that contain PAS(+) material.

·        Diagram of glycogen metabolism.

General features: Head  

·        There are 11 types of glycogenosis as classified by their enzymatic deficiency. Nine of them affect the muscle. Type I (Von Gierke disease) and VI (Hers disease) do not affect the muscle.

·        Many of them have several subtypes with differenc clinical features. The more severe form of type I (von Gierke), type II (Pompe’s disease), type IV (Andersen’s disease), and type VI (Tarui’s disease) glycogenoses are not compatible with prolonged survival. The less severe forms of these diseases are compatible with long-term survival.

·        Some enzymes that are involved in glycogen metabolism exist in a single isoform (e.g. acid maltase) and its deficiency is likely to involve many different tissues. Some enzymes exist as several tissue-speficif isoforms (e.g., phosphroylase) and the tissue being affected as a result of the deficiency of a particular isoform is tissue specific. Different isoforms may also be present in mature and immature msuscle.

·        Clinical presentation can be weakness and hypotonia (GSD type II and III), exercise intolerance or muscle cramps with or without myoglobinuria (GSD type V, VII, VIII, IX, X, XI) or minimal musclar symptoms but with significant systemic symptoms (GSD type V).

·        Depending on the subtype, the amount of glycogen can vary from dramatic to modest. The form of storage material may occur in form of PAS(+)-diastase sensitive, PAS(+)-diastase resistant, and polyglucosan bodies.

·        The morphologic changes are related to the time of biopsy. Muscle biopsy that are obtained after sternous exercise often reveal necrotic fibers and regenerating fibers.

Summary of characteristics of glycogenoses: Head  

Type

Enzyme

Gene location

Clinical features

Tissue/system affected

Pathology

 

 

 

 

 

 

Characterized by weakness & hypotonia

 

 

 

 

 

II (infantile form is also known as Pompe’s disease)

 

a-1,4-glucosidase (acid maltase): this is a lysosomal enzyme

17(q21-23)

Severe form: Always fatal in the first few years of live. Muscle weakness and hypotonia resembles infantile spinal muscular atrophy (SMA), cardiomegaly and hepatomegaly, characteristic EKG.

Mild form: Resembles limb-girdle dystrophy

Muscle, heart, nervous system, leukocytes, liver, kidney

Vacuolization, PAS(+) material in fibers.

III (Cori’s-Forbes’ disease)

 

Amylo-1,6-glucosidase (debranching enzyme)

1p21.  Autosomal recessive.

Mild weakness and infantile hypotonia. Hypoglycemia and ketosis. Compatible with long- term survival.

Muscle, heart, liver, leukocytes.

Vacuolization, PAS(+) material in fibers.

 

 

 

 

 

 

Exercise intolerance, fatigue, cramps, myoglobinuria (EIFCM)

 

 

 

 

 

V (McArdle’s disease)

 

Glycogen phosphorylase, M- isoform

11q13

EIFCM. Other than the fatal infantile form, it is compatible with long-term survival.

Entirely limited to muscle.

 

Minimal or no abnormal storage of glycogen.

Many necrotic and regenerating fibers.

VII (Tarui’s disease)

 

Phosphofructokinase- M isoform

1(cenàq32)

EIFCM

Muscle, mild hemolytic anemia.

Minimal to moderate amount of glycogen accumulation. Polyglucosan bodies.

VIII

 

Phosphorylase b kinase, a- and b-subunit

Xq12-q13, 16q12-q13

Exercise intolerance, muscle stiffness, weakness

Muscle, liver and heart

 

IX

 

Phosphoglycerate kinase, A-isoform

Xq13

EIFCM

Muscle, hemolytic anemia, central nervous system

Accumulation of glycogen granules may be light. Biopsy may be histochemically and histologically normal

X

 

Phosphoglycerate kinase, M-mutase

7

EIFCM

 

Accumulation of PAS(+) material and glycogen content on biochemical analysis.

XI

 

Lactate dehydrogenase, M-isoform

11

EIFCM

 

 

 

 

 

 

 

 

No or minimal muscle symptoms

 

 

 

 

 

IV (Andersen’s disease)

 

a-1,4-glucan:a1,4-glucan 6-glycosyl transferase (“branching enzyme”; amylo (1,4 à1,6 trans-glucosidase)

3

No muscle symptoms or mild wasting and weakness

Muscle, hepatomegaly, cirrhosis, liver failure, Heart.

Death usually occurs by four years of age because of cirrhosis.

PAS(+), PASD(-) material and polyglucosan bodies.

VI (Hers disease)

 

Glycogen phosphorylase- B, M, H (Brain, muscle and liver isoforms) [Chang S et al., Hum Mol Genet 1998 May;7(5):865-70]

 

 

X-linked form in Xp22.1–22.2; autosomal recessive form probably related to glycogen phosphorylase-H isoform on 14q21–22

 

Clinical presentation is heterogenous.

Muscle is not affected.

 

I (von Gierke disease)

 

A type: glucose-6-phosphatase (G6P) gene

Non-a type: glucose-6-phosphate translocase (G6PT) gene. [Jenecke et al., 2001

G6P is on chromosome 17; G6PT is on chromosome 11

Infantile onset, often associated with mild mental retardation. Compatible with long-term survival.

Fasting hypoglycemia, fasting lactate acidosis, hepatomegaly, growth retardation, hyperlipidemia, and hyperuricemia. Some patients are prone to severe infections because of neutropenia.

Other system problems include renal failure and osteoporosis.

Muscle not affected.  The liver, central nervous system, and other system.

 

 

 

 

 

 

 

 

Classification of glycogenoses by deficiency of functions: Head  

Disease

Enzyme

Function

 

 

 

Glycose-6-phosphate to glycogen (synthesis of glycogen)

 

 

IV (Andersen’s disease)

a-1,4-glucan:a1,4-glucan 6-glycosyl transferase

Branching enzyme

I (von Gierke’s disease)

Glucose-6-phosphatase

Glucose-6-phosphateàGlucose

 

 

 

Glycogen to fructose-6-phosphate (anabolism of glycogen)

 

 

II (Pompe’s disease)

a-1,4-glucosidase (acid maltase)

Lysomal breakdown of glycogen

III (Cori’s disease)

Amylo-1,6-glucosidase

Debranching enzyme

V (McArdle’s disease)

Glycogen phosphorylase, M- isoform

GlycogenàGlucose-1-phosphate (muscle)

VI (Hers disease)

Glycogen phosphorylase, H- isoform

GlycogenàGlucose-1-phosphate (liver)

 

 

 

Fructose-6-phosphate to lactate (glycolysis and beyond)

 

 

VII (Tarui’s disease)

Phosphofructokinase- M isoform

Fructose-6-phosphateàFructose-1,6-diphosphate

IX

Phosphoglycerate kinase, A-isoform

3-P-glycerol phosphateà 3-phosphoglycerate

X

Phosphoglycerate mutase, M-subunit

3-phosphoglycerateà2-phosphoglycerate

XI

Lactate dehydrogenase, M-isoform

PyruvateàLactate

 

 

 

Control

 

 

VIII

Phosphorylase b kinase, a- and b-subunit

Activation of phosphorylase-b into phosphorylase-a