Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism¶
Chapter 430 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 430
Key Clinical Points¶
- GSDs are classified by deficient enzyme, organ involvement (liver vs. muscle), and clinical phenotype.
- GSD I (Von Gierke) presents with doll-like facies, hepatomegaly, renomegaly, hypoketotic hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia.
- GSD II (Pompe) is a lysosomal acid α-glucosidase deficiency; infantile form causes fatal cardiomyopathy within 2 years; late-onset involves progressive muscle weakness.
- GSD III (Cori/Forbes) differs from GSD I by having normal lactate and uric acid levels; features include hepatomegaly, muscle weakness, and cardiomyopathy.
- GSD V (McArdle) is a muscle phosphorylase deficiency characterized by exercise intolerance, myalgia, cramps, myoglobinuria, and the 'second wind' phenomenon.
- GSD IV (Andersen) involves branching enzyme deficiency leading to polyglucosan accumulation; can present as severe hepatic failure or adult-onset polyglucosan body disease (APBD).
- Galactosemia Type I (GALT deficiency) presents with vomiting, jaundice, and cataracts; the Duarte variant is asymptomatic.
- Hereditary fructose intolerance (Aldolase B deficiency) causes postprandial hypoglycemia, vomiting, and an aversion to sweets.
- Management includes avoiding fasting, frequent feedings, uncooked cornstarch supplementation, ERT for GSD II, and liver transplant for severe hepatic cases.
- Complications include hepatocellular adenoma (HCA), cardiomyopathy, renal failure, and pulmonary hypertension.
1. DEFINITION & OVERVIEW¶
• Glycogen Structure: Tree-like molecule of glucose residues. ◦ Joined by α-1,4 linkages (straight chains). ◦ Branched at intervals of 4–10 residues by α-1,6 linkages. • Definition: Inherited defects in glycogen metabolism are referred to as glycogen storage diseases (GSDs), also referred to as glycogenoses. • Classification Criteria: Based on primary organ involvement (liver or muscle) and clinical manifestations. • Prevalence: 1 in 10,000 to 1 in 25,000 live births. ◦ Mostly autosomal recessive; some X-linked or autosomal dominant. • Clinical Scope: Includes GSD I, II, III, IV, VI, IX (liver) and V, VII, X, XI, XII, XIII, XV (muscle), as well as galactose and fructose metabolism disorders.
2. EPIDEMIOLOGY¶
• General Prevalence: 1 in 10,000 to 1 in 25,000 live births. • Inheritance Patterns: Mostly autosomal recessive; some X-linked or autosomal dominant. • Population-Specific Clusters: ◦ GSD IV (APBD): Higher prevalence in individuals of Ashkenazi Jewish ancestry. ◦ GSD VI: Higher prevalence in the Mennonite community. ◦ GSD VII: Prevalence in individuals of Ashkenazi Jewish ancestry. ◦ Clinical variant galactosemia: Common in African Americans and native South Africans. ◦ GSD X: Higher incidence in African Americans.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
3.1 Liver Glycogen Storage Diseases¶
• GSD Type I (Von Gierke): Glucose-6-phosphatase or translocase deficiency. ◦ Type Ia: Glucose-6-phosphatase enzyme defective; leads to hypoketotic hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. ◦ Type Ib: Translocase (G6P transport into ER) defective; additional findings of neutropenia and inflammatory bowel disease. • GSD Type III (Cori/Forbes): Debranching enzyme deficiency. ◦ GSD IIIa: Liver, cardiac, and skeletal muscle involvement (~85%). ◦ GSD IIIb: Primarily liver involvement (~15%). • GSD Type IV (Andersen): Branching enzyme deficiency → accumulation of polyglucosan. ◦ Hepatic form: Rapid progression to liver failure; some cases progress to extrahepatic involvement (myopathy, cardiomyopathy). ◦ Adult Polyglucosan Body Disease (APBD): Progressive lower limb weakness and spasticity. • GSD Type VI (Hers): Liver phosphorylase deficiency; often associated with liver fibrosis and hyperlipidemia. • GSD Type IX: Phosphorylase kinase (PhK) deficiency. ◦ α2: X-linked (PHKA2); common in males. ◦ γ2: Often more severe clinical phenotype. ◦ β: Includes liver and muscle; catch-up growth is common. • GSD 0a: Glycogen synthase 2 (GYS2) deficiency; rare, no hepatomegaly, ketotic hypoglycemia. • Fanconi-Bickel Syndrome: GLUT-2 transporter deficiency; affects liver, pancreas, intestine, and kidney; presents with rickets and renal issues.
3.2 Muscle Glycogen Storage Diseases¶
• GSD Type II (Pompe): Lysosomal acid α-glucosidase deficiency. ◦ Accumulation of glycogen in lysosomes. ◦ Infantile-onset: Fatal within 2 years; cardiomyopathy, macroglossia. ◦ Late-onset: Muscle weakness starting in first year; respiratory involvement. • GSD Type V (McArdle): Muscle phosphorylase deficiency; 'second wind' phenomenon. • GSD Type VII (Tarui): Phosphofructokinase-M subunit deficiency; 'out of wind' phenomenon; associated with hemolysis and hyperuricemia. • Other Muscle GSDs: ◦ GSD IX α1: Phosphorylase kinase (muscle) deficiency. ◦ GSD X: Phosphoglycerate mutase 2 deficiency. ◦ GSD XI: Lactate dehydrogenase A deficiency. ◦ GSD XII: Aldolase A deficiency; associated with hemolytic anemia. ◦ GSD XIII: β-enolase deficiency. ◦ GSD XV: Glycogenin-1 deficiency (Polyglucosan body myopathy). • LMBR1 Deficiency: Lysosomal-associated membrane protein 2; severe cardiomyopathy and myopathy.
• Galactosemia Type I: GALT deficiency → vomiting, jaundice, sepsis, cataracts. ◦ Clinical variant: Less severe; homozygous p.Ser135Leu variants. ◦ Duarte variant: Asymptomatic. • Galactokinase (GALK) Deficiency: Cataracts and pseudotumor cerebri. • Uridine diphosphate galactose-4-epimerase (GALE) Deficiency: Similar to Type I; additional hypotonia and hearing loss. • Galactose mutarotase (GALM) Deficiency: Cataracts; mild.
3.4 Fructose Metabolism Disorders¶
• Hereditary Fructose Intolerance: Aldolase B deficiency → vomiting, jaundice, hepatomegaly, aversion to sweets, and postprandial hypoglycemia.
4. CLINICAL FEATURES¶
4.1 GSD Type I (Von Gierke)¶
• Presentation: Hepatomegaly, renomegaly, doll-like facies, and short stature. ◦ Metabolic: Hypoketotic hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. ◦ Other: Hepatic steatosis; prolonged bleeding time.
4.2 GSD Type II (Pompe)¶
• Infantile-onset: Hypotonia, muscle weakness, cardiomyopathy, macroglossia; fatal within 2 years. ◦ Late-onset: Muscle weakness starting in first year; respiratory involvement (diaphragm).
4.3 GSD Type III (Cori/Forbes)¶
• Childhood: Fasting hypoglycemia, hepatomegaly, muscle weakness, cardiomyopathy. ◦ Adulthood: Liver fibrosis/cirrhosis; proximal and distal muscle atrophy; peripheral neuropathy.
4.4 GSD Type IV (Andersen)¶
• Hepatic Form: Failure to thrive, hepatomegaly, progressive liver failure. ◦ Neuromuscular Form: Myopathy, cardiomyopathy. ◦ APBD: Progressive lower limb weakness and spasticity.
4.5 GSD Type V (McArdle)¶
• Symptoms: Exercise intolerance, myalgia, cramps, myoglobinuria. ◦ Key Sign: 'Second wind' phenomenon during exercise.
4.6 GSD Type VI & IX¶
• Type VI (Hers): Hepatomegaly, liver fibrosis, hyperlipidemia; common in Mennonite community. ◦ Type IX: Phenotype varies by subunit (α2, γ2, β); includes hepatomegaly and muscle weakness.
5. DIFFERENTIAL DIAGNOSIS¶
5.1 Hypoglycemia Workup¶
• Differentiation: Distinguish GSD types based on metabolic markers. ◦ GSD I vs. GSD III: GSD I has high lactate/uric acid; GSD III has normal levels.
5.2 Muscle vs. Liver GSD¶
• Clinical Distinction: Muscle-specific symptoms (myalgia, myoglobinuria) vs. liver-specific symptoms (hepatomegaly, hyperlipidemia).
6. INVESTIGATIONS & DIAGNOSIS¶
6.1 Diagnostic Criteria¶
• Biochemical Markers: Glucose, lactate, uric acid, and triglycerides. ◦ High Lactate + High Uric Acid → Suggests GSD I. ◦ Normal Lactate + Normal Uric Acid + Hepatomegaly → Suggests GSD III.
6.2 Diagnostic Algorithm¶
- Clinical Assessment: Identify primary organ involvement (Liver vs. Muscle) and age of onset.
- Biochemical Screening: Measure glucose, lactate, uric acid, and triglycerides to differentiate GSD types.
- Confirmatory Testing: Genetic testing (DNA sequencing, panels, or whole exome/genome sequencing) to identify specific enzyme deficiency.
7. MANAGEMENT & TREATMENT¶
7.1 Pharmacologic Therapy¶
• Enzyme Replacement Therapy (ERT): Specifically for GSD II.
7.2 Surgical & Procedural Therapy¶
• Liver Transplant: For severe hepatic GSDs (e.g., GSD I, IV).
7.3 Dietary Management¶
- Fast Prevention: Avoid fasting periods.
- Feeding Schedule: Frequent feedings.
- Supplementation: Uncooked cornstarch supplementation.
8. PROGNOSIS & COMPLICATIONS¶
8.1 Hepatic Complications¶
• Tumors: Hepatocellular adenoma (HCA) and carcinoma (HCC). ◦ Liver Disease: Fibrosis, cirrhosis, liver failure.
8.2 Muscular Complications¶
• Cardiac: Cardiomyopathy, heart failure. ◦ Skeletal: Myopathy, muscle atrophy, respiratory failure.
8.3 Metabolic Complications¶
• Renal: Renal stones, hyperfiltration injury, renal failure. ◦ Systemic: Gout, hyperlipidemia, pulmonary hypertension.
9. SPECIAL CONSIDERATIONS¶
• Ashkenazi Jewish: Higher prevalence of GSD IV (APBD) and GSD VII. • Mennonite Community: Higher prevalence of GSD VI. • African American / Native South African: Common for Clinical variant galactosemia. • African American: Higher incidence of GSD X.
10. KEY PEARLS & CLINICAL TRAPS¶
• GSD I vs. III: Key differentiator is the presence/absence of lactic acidosis and hyperuricemia. • GSD V vs. VII: 'Second wind' (GSD V) vs. 'Out of wind' (GSD VII). • Galactose Disorders: Duarte variant is asymptomatic; Galactokinase deficiency causes cataracts. • Fructose Disorders: Hereditary fructose intolerance presents with postprandial hypoglycemia. • GSD II: Only GSD involving lysosomal accumulation; requires ERT.
Reference Tables¶
TABLE 430-1 Features of Glycogen Storage Diseases, Galactose Metabolism Disorders, and Fructose Metabolism Disorders…¶
Harrison's 22e, p.3361
| TYPE | EPONYM | DEFICIENT ENZYME | CLINICAL FEATURES | COMMENTS |
|---|---|---|---|---|
| Muscle Glycogen Storage Diseases | ||||
| Glycogen synthase 1 | Cardiomyopathy, cardiac arrythmia, muscle weakness, exercise intolerance |
|||
| II | Pompe | Lysosomal acid α-glucosidase |
Classic infantile-onset: Hypotonia, muscle weakness, cardiomyopathy, fatal within first 2 years of life Nonclassic infantile-onset: Presentation within first year of life with less severe cardiomyopathy and slower progression than the classic form Late-onset: Absence of cardiomyopathy in first year of life; kinematic/muscle weakness noted as early as first year of life, progressive skeletal muscle weakness, early involvement of proximal lower extremity muscles and respiratory muscles, especially the diaphragm |
Higher frequency being reported since advent of newborn screening; enzyme (GAA) levels are undetectable or very low in infantile-onset form and variable in late-onset form when measured in skin or muscle |
| McArdle | Muscle phosphorylase | Exercise intolerance, myalgia, cramps, myoglobinuria with strenuous exercise, increased CK levels; “second wind” phenomenon |
||
| VII | Tarui | Phosphofructokinase-M subunit |
As for type V, with additional findings of compensated hemolysis, hyperuricemia; “out of wind” phenomenon rather than “second wind” phenomenon observed in GSD V |
Rare, prevalent in individuals of Ashkenazi Jewish ancestry |
| Phosphorylase kinase (muscle) |
Exercise intolerance, myalgia, cramps, muscle weakness and atrophy, myoglobinuria with strenuous exercise |
|||
| X | Phosphoglycerate mutase 2 |
Exercise intolerance, cramps, myoglobinuria with strenuous exercise |
Rare, most patients African American | |
| Lactate dehydrogenase A | Exercise intolerance, cramps, myoglobinuria with strenuous exercise, dermatitis |
|||
| XII | Aldolase A | Muscle weakness, myoglobinuria with strenuous exercise, with additional finding of hemolytic anemia |
Rare | |
| β-enolase | Exercise intolerance, myalgia, cramps, myoglobinuria with strenuous exercise |
|||
| XV (also known as polyglucosan body myopathy 2) |
Glycogenin-1 | Often classified as two subtypes: GSD XV: Progressive cardiac arrhythmia and/ or cardiomyopathy causing heart failure and necessitating cardiac transplantation in some cases Polyglucosan body myopathy 2: Progressive myopathy with proximal and distal muscle weakness |
Rare | |
| Lysosomal-associated membrane protein 2 |
Severe progressive cardiomyopathy with WPW pattern progressing to heart failure, cardiac arrythmia, and heart failure in early childhood/adolescence; myopathy with muscle weakness, retinopathy, intellectual disability, and developmental delay |
|||
| PRKAG2 deficiency | AMP-activated gamma 2 protein kinase |
Progressive cardiac arrhythmia and cardiomyopathy progressing to heart failure in childhood to adulthood; congenital/infantile form is rapidly fatal with hypertrophic cardiomyopathy with WPW pattern; other involvement includes myalgia and seizures |
Autosomal dominant | |
| Galactose Metabolism Disorders | ||||
| Galactose-1-phosphate uridyltransferase (GALT) |
Vomiting, jaundice, sepsis, cataracts, aminoaciduria, hepatomegaly, failure to thrive |
|||
| Clinical variant galactosemia |
Less severe disease course compared to classic galactosemia; caused by homozygous p.Ser135Leu variants, most common in African Americans and native South Africans |
|||
| Duarte | Galactose-1-phosphate uridyltransferase (GALT) |
Asymptomatic | ||
| II | Galactokinase (GALK) | Cataracts and pseudotumor cerebri | Clinical continuum with very mild to severe phenotype |
|
| Uridine diphosphate galactose-4-epimerase (GALE) |
Similar to galactosemia type I; additional findings of hypotonia and hearing loss |
|||
| IV | Galactose mutarotase (GALM) |
Cataracts | Identified in Japan; considered to be mild |