Inborn errors of carbohydrate metabolism

All classic disorders of carbohydrate metabolism result from a specific enzyme defect. Almost all of these enzyme defects are inherited in an autosomal recessive fashion. These metabolic diseases may be classified into three main groups, affecting the metabolism of glycogen, galactose, and fructose. Clinical manifestations are variable and range from occasional innocuous hypoglycemia to severe cognitive impairment and death within a few weeks of birth. Newborn screening enables the early detection of metabolic diseases and early initiation of appropriate dietary restrictions helps prevent disease manifestations.

Overview

• Glycogen storage disorders (GSDs; glycogenoses) are hereditary metabolic disorders characterized by defects in the enzymes responsible for glycogenolysis or glycolysis.
• 13 different types have been described
• All types cause abnormal accumulation of glycogen due to impaired glycogen metabolism.
• Only a few GSDs are relevant in clinical practice (see “Types of GSD” below).

Epidemiology

• Incidence: up to 1:20,000 live births ^[1]
• Age of onset: presentation during infancy or childhood
• Sex: ♂ = ♀
• Mode of inheritance: mostly autosomal recessive (types I, II, III, and V)

Pathophysiology

• Defective enzymes responsible for glycolysis or glycogenolysis → impaired glycogen metabolization → ↑ storage of either normal or abnormal glycogen
• Liver, heart, and muscle are the most common sites of glycogen storage and are, therefore, predominantly affected.

Types of GSD

The first six glycogen storage diseases can be remembered with the mnemonic “a Very Presumptuous Corgi Ambles in the Middle of the Highway.”

McArdle affects the Muscles.

Clinical features

Glycogen storage disorders can be classified as muscle and/or liver GSD according to the presenting symptoms.

• Muscle involvement
  • Seen in types II, III, IV, V
  • Two groups of skeletal muscle symptoms are seen:
    • Defects of muscle glycogenolysis and muscle glycolysis:
      • Easy fatiguability, exercise intolerance
      • Cramps
      • Rhabdomyolysis → myoglobinuria (burgundy-colored urine)
    • Defects of muscle glycogenesis (type IV) and lysosomal glycogenolysis (type II): progressive weakness of extremities and trunk (proximal myopathy)
  • Cardiac involvement
    • Seen in several types (e.g., type II, type III)
    • Hypertrophic cardiomyopathy and/or conduction defects are most common in type II.
• Liver involvement
  • Seen in types I, III, IV
  • Hypoglycemia (typically fasting hypoglycemia) and ketosis
  • Symptoms of hypoglycemia in infancy: seizures, hypotonia, poor feeding, cyanosis, irritability
  • Hepatomegaly → distended abdomen

Additional clinical manifestations

• Growth delay/growth retardation/failure to thrive: types I, II, III, IV
• Anemia: type I
• Hyperlipidemia: types I, III
• Macroglossia: type II
• Lactic acidosis: type I
• Hyperuricemia: type I

“Pompe punishes pump, liver, and muscle.”

Diagnostics ^[6]

• Initial tests
  • Muscle and/or liver biopsy (depending on the enzyme deficiency): glycogen storage appears as PAS-positive granules .
  • Enzyme assays in RBCs, leukocytes, liver tissue, muscle tissue, or fibroblasts (depending on the enzyme deficiency)
• Confirmatory test: DNA testing for the gene defects
• Additional tests
  • Muscle GSD ^[7]
    • Ischemic forearm test: an important test to evaluate if a patient has a metabolic disorder of muscle function
      • A sphygmomanometer cuff is tied around the arm and inflated to beyond systolic blood pressure. The patient is then asked to repeatedly form a fist. The cuff is then deflated and multiple blood samples are taken to measure serum lactate levels.
      • The normal response to an ischemic exercise test is an increase in the levels of lactate as a result of anaerobic metabolism of glucose.
      • In the case of GSD type III and type V,, not enough glucose is produced from glycogen. As a result, lactate levels do not rise.
    • ↑ Creatine kinase
    • Electroneuromyography: to identify proximal myopathy
    • EKG and/or echocardiography: to identify cardiac hypertrophy and conduction blocks
  • Liver GSD
    • ↑ Serum biotinidase serves as diagnostic biomarkers in type I and type III ^[8][9]
    • Liver function tests and abdominal ultrasonography: to detect liver cirrhosis and/or hepatic failure

Therapy ^[6]

• General
  • Most forms of GSD can be managed effectively with dietary therapy (e.g., uncooked corn starch, glucose preparations) with the aim of preventing hypoglycemia and/or muscle symptoms
  • Foods rich in fructose and galactose should be avoided in patients with GSD type I
• Definitive therapy
  • Enzyme replacement therapy is available for some forms of GSD
  • A liver transplant may be required in the case of liver GSD that progress to liver cirrhosis and/or result in poor metabolic control.
  • Cardiac involvement
    • Severe conduction defects: pacemaker implantation
    • Severe cardiomyopathy: heart transplantation (see “Therapy” in “Hypertrophic cardiomyopathy”)

Galactosemia refers to hereditary defects in enzymes that are responsible for the metabolism of galactose (galactose is a component of the disaccharide lactose, which is present in breast milk).

“Fruits from the Galapagos are kind” (galactokinase and fructokinase deficiencies present with mild symptoms).