^{[1][2][3][4][5][6][7][8][9][10][11][12][13]}1. Introduction

Glycogen storage diseases (GSDs) are metabolic disorders of glycogen metabolism. In aggregate, GSDs are not considered rare diseases, but every individual type are. The overall estimated GSD incidence is 1 case per 20,000-43,000 live births ^[1], and a prevalence of 1:100,000 is considered for main types (including I, II, II, V and IX). There are 19 types which are classified by enzyme deficiency and affected tissue. Most of them are inherited in an autosomal recessive manner, except for one X-linked GSDIX and Danon subtypes. Disorders related with creation, deposits and degradation of glycogen, may primarily affect the liver (hepatic GSDs), the muscles (muscle GSDs), or in a multiorganic manner (mainly Pompe) ^[2]. The common characteristic of all types of GSDs is the alteration of some step in glycogenolysis/glycolysis pathway, as can be seen in figures 1a and 1b ^{[3][4][5][6][7][8][9][10][11][12][13]}.

Figure 1. (a) Glycolysis–gluconeogenesis pathway showing steps disrupted in every GSD. Abbreviations: Glycogen Synthase Deficiency (GSD 0); Von Gierke Disease (GSD Ia, Ib, Ic, Id); Pompe disease (GSD II); Cori-Forbes Disease (GSD III); Andersen Disease (GSD IV); McArdle Disease (GSD V); Hers Disease (GSD VI); Phosphofructokinase Deficiency (GSD VII); Muscle Phosphorylase b Kinase Deficiency (GSD VIII); Liver Phosphorylase Kinase Deficiency (GSD IX); Fanconi-Bickel Syndrome (GSD XI); Phosphoglucomutase 1 Deficiency (GSD XIV); Glycogenin Deficiency (XV). (b) “Zoomed in” detail of pyruvate formation in final glycolysis steps from Figure 1a. Abbreviations: Muscle Phosphoglycerate Mutase Deficiency (GSDX); Aldolase A Deficiency (GSDXII); Enolase 3 Deficiency (GSDXIII).

2. The Most Prevalent Diseases 

3). Glycogen storage disease type III (GSDIII, Cori-Forbes disease), with an incidence of 1:100,000 too, is characterized by variable liver, cardiac muscle, and skeletal muscle involvement. GSDIIIa is the most common subtype, present in about 85% of affected individuals

3). Glycogen storage disease type III (GSDIII, Cori-Forbes disease), with an incidence of 1:100,000 too, is characterized by variable liver, cardiac muscle, and skeletal muscle involvement. GSDIIIa is the most common subtype, present in about 85% of affected individuals

^[16]

. It manifests with liver and muscle involvement. GSDIIIb, with liver involvement only, comprises about 15% of all GSDIII. The clinical significance of GSDIII ranges from almost no symptoms to severe cardiac dysfunction, congestive heart failure, and, rarely, sudden death. Skeletal myopathy manifests as muscle weakness but is rarely evident in childhood because it progresses slowly. This acquires greater relevance in the third to fourth decades of life. The diagnosis is made by identifying biallelic pathogenic variants in glycogen debranching enzyme, amylo-alpha-1,6-glucosidase, or 4-alpha-glucanotransferase (AGL).

4). Type V glycogen storage disease (GSDV, McArdle’s disease) is a metabolic myopathy whose main characteristic is exercise intolerance. Incidence roughly reaches 1:100,000

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. Symptomatologically, patients present with rapid onset fatigue, myalgia, and muscle cramps

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. The symptomatology is more acute with exercise, and symptoms are usually isometric or sustained aerobic exercise. It is common for patients to experience greater exercise by exploiting the “second wind” phenomenon, which relieves myalgia and fatigue after resting for a few minutes. Normally GSDV symptoms appears in the first decade of life. Twenty-five percent of patients will present with weakness that mainly affects the proximal muscles. The diagnosis is made using PYGM molecular genetic tests (which encode glycogen phosphorylase, muscle form). This is the only known gene associated with GSDV.

5). Glycogen storage disease types VIII and IX (GSDVIII and GSDIX), results from a liver phosphorylase b kinase enzyme deficiency, which plays an important role in the decomposition of glycogen

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. One type is hepatic PhK deficiency (GSDIX), characterized by the presence of early-onset hepatomegaly. There is also growth retardation and, often, fasting ketosis and hypoglycaemia. Another variant is muscle PhK deficiency (GSDVIII), much less common and related to physical exercise intolerance, myalgia, muscular cramps, myoglobinuria, and progressive muscular weakness. The PhK enzyme comprises four subunits (α, β, γ, and δ). Pathogenic variants of PHKA1, which encodes the α subunit, cause the rare muscular deficiency of the X-linked disorder. The pathogenic variants of PHKA2, which also codes for the α subunit, are responsible for the most frequent variant, hepatic PhK deficiency (X-linked hepatic glycogenosis). Incidence for GSD IXα is about 1:100,000 individuals

^[20]. Pathogenic variants of PHKB, which encodes the β subunit, cause PhK deficiency in both the liver and muscle. Those of PHKG2, which encodes the γ subunit, cause PhK deficiency in the liver. The diagnosis is enhanced by clinical findings from assessing the activity of PhK in erythrocytes or the liver or muscle tissues (depending on the variant to be treated), and definitive confirmation from molecular genetic testing.

. Pathogenic variants of PHKB, which encodes the β subunit, cause PhK deficiency in both the liver and muscle. Those of PHKG2, which encodes the γ subunit, cause PhK deficiency in the liver. The diagnosis is enhanced by clinical findings from assessing the activity of PhK in erythrocytes or the liver or muscle tissues (depending on the variant to be treated), and definitive confirmation from molecular genetic testing.

An overall clinical summary of GSDs are in Ttable 1.

Table 1. Main gene and clinical characteristics of GSDs types. Abbreviations: G6PC1 (glucose-6-phosphatase catalytic subunit), SLC37A4 (Solute Carrier Family 37 Member 4), GAA (acid alpha-glucosidase), AGL (amylo-alpha-1,6-glucosidase), PYGM (glycogen phosphorylase, muscle form), PYGL (glycogen phosphorylase, liver form), PHKA1 (phosphorylase kinase regulatory subunit alpha 1), PHKA2 (phosphorylase kinase regulatory subunit alpha 2), PHKB (phosphorylase kinase regulatory subunit beta), PHKG2 (phosphorylase kinase regulatory subunit gamma 2), GYS1 (glycogen synthase 1), GYS2 (glycogen synthase 2), LAMP2 (lysosomal-associated membrane protein 2), GBE1 (1,4-alpha-glucan-branching enzyme), PFKM (phosphofructokinase, muscle), PGAM2 (phosphoglycerate mutase 2), SLC2A2 (solute carrier family 2 member 2), ALDOA (aldolase A), ENO3 (beta-enolase), PGM1 (phosphoglucomutase 1), GYG1 (glycogenin 1), EPM2A (Glucan Phosphatase, Laforin), NHLRC1 (NHL Repeat Containing E3 Ubiquitin Protein Ligase 1)

Table 1. Main gene and clinical characteristics of GSDs types. Abbreviations: G6PC1 (glucose-6-phosphatase catalytic subunit), SLC37A4 (Solute Carrier Family 37 Member 4), GAA (acid alpha-glucosidase), AGL (amylo-alpha-1,6-glucosidase), PYGM (glycogen phosphorylase, muscle form), PYGL (glycogen phosphorylase, liver form), PHKA1 (phosphorylase kinase regulatory subunit alpha 1), PHKA2 (phosphorylase kinase regulatory subunit alpha 2), PHKB (phosphorylase kinase regulatory subunit beta), PHKG2 (phosphorylase kinase regulatory subunit gamma 2), GYS1 (glycogen synthase 1), GYS2 (glycogen synthase 2), LAMP2 (lysosomal-associated membrane protein 2), GBE1 (1,4-alpha-glucan-branching enzyme), PFKM (phosphofructokinase, muscle), PGAM2 (phosphoglycerate mutase 2), SLC2A2 (solute carrier family 2 member 2), ALDOA (aldolase A), ENO3 (beta-enolase), PGM1 (phosphoglucomutase 1), GYG1 (glycogenin 1), EPM2A (Glucan Phosphatase, Laforin), NHLRC1 (NHL Repeat Containing E3 Ubiquitin Protein Ligase 1)