Galactose Metabolism

Galactose Metabolism

• A 2-week-old boy is brought to the emergency department after progressive lethargy over the course of the previous week. His parents report extended episodes of vomiting after feeding ever since birth though this has not previously been extensively investigated. Physical exam shows the development of bilateral cataracts so based on clinical suspicion a metabolic panel is conducted in order to evaluate for disorders of galactose metabolism.

Introduction

Galactose metabolism refers to the biochemical pathways by which the simple sugar galactose is converted into energy and other molecules that are essential for cellular function. Galactose is a monosaccharide that is found in milk and other dairy products, as well as in some fruits, vegetables, and grains.

Galactose is an important source of energy for the body, and is metabolized through a series of enzymatic reactions that occur primarily in the liver. The first step in galactose metabolism involves the conversion of galactose to galactose-1-phosphate, which is catalyzed by the enzyme galactokinase. Galactose-1-phosphate is then converted to glucose-1-phosphate through a series of enzymatic reactions that involve the enzymes galactose-1-phosphate uridylyltransferase and UDP-glucose 4-epimerase.

Overview

• Source
  • lactose in dairy products
    • disaccharide composed of glucose and galactose
    • hydrolyzed by lactase in brush border of small intestine
• Metabolic pathway
  • trapped in cell by galactokinase
  • converted into glucose-1-phosphate through UDP mediated epimerization
  • glucose-1-phosphate can then be used
    • directly in glycogenesis
    • converted to glucose-6-phosphate and used in glycolysis
• released as free glucose in hepatocytes

Pathophysiology

• Galactokinase deficiency
  • presentation 
    • galactosemia/galactosuria
    • cataracts in childhood
    • excess galactose is converted to galactitol
    • catalyzed by aldose reductase
    • galactitol is osmotically active
  • treatment
    • galactose free diet
• Gal-1-P uridyl transferase deficiency
  • similar to galactokinase deficiency but more severe
    • Gal-1-P acts as a phosphate sink
  • presentation
    • early cataracts
    • more severe, with vomiting/diarrhea after milk ingestion
    • liver disease
    • lethargy
    • mental retardation
    • hepatomegaly
    • hyperbilirubinemia
      • jaundice
  • treatment
    •  galactose free diet
• Lactose intolerance
  • mechanism
    • lactase deficiency
      • primary
        • hereditary
          • ↑ frequency in african americans and asians
        • age-dependent
      • secondary
        • post-gastroenteritis
  • presentation
    • bloating, cramps, osmotic diarrhea
      • symptoms due to fermentation of indigestible lactose by intestinal bacteria 
      • leads to production of H₂, CH₄, organic acids
        • H₂ used in diagnosis
        • detected on breath following oral lactose load
  • treatment
    • eliminate dairy from diet
• take lactase pills when consuming dairy

Types

Galactose metabolism can be broadly divided into three main types of pathways:

1. Leloir pathway: The Leloir pathway is the primary pathway for galactose metabolism in humans. It involves the conversion of galactose to glucose-1-phosphate, which can then be used in glycolysis or other metabolic pathways. The Leloir pathway is catalyzed by a series of enzymes, including galactokinase, galactose-1-phosphate uridylyltransferase, and UDP-glucose 4-epimerase.
2. Alternative pathways: There are several alternative pathways for galactose metabolism that can be used when the Leloir pathway is disrupted. One alternative pathway involves the conversion of galactose to galactitol through the enzyme aldose reductase. Galactitol can then be converted to glucose by the enzyme sorbitol dehydrogenase. Another alternative pathway involves the conversion of galactose to glucose-6-phosphate through the enzyme galactose-6-phosphate isomerase.
3. Microbial pathways: Some microorganisms are capable of metabolizing galactose through different pathways than those used by humans. For example, some bacteria can use the tagatose-6-phosphate pathway, which involves the conversion of galactose to tagatose-6-phosphate, which can then be converted to glycolytic intermediates.

Disruptions in galactose metabolism can lead to a range of disorders, including galactosemia, which is caused by a deficiency in one of the enzymes involved in the Leloir pathway. Other disorders related to galactose metabolism include epimerase deficiency and galactokinase deficiency.

Complications

Disruptions in galactose metabolism can lead to several complications, especially if they are not detected and treated early. The most common complication of galactose metabolism disorders is galactosemia, a rare genetic disorder that affects the ability of the body to break down galactose.

Galactosemia can lead to a range of symptoms and complications, including:

1. Developmental delays: Infants with galactosemia may experience delays in their developmental milestones, such as crawling, walking, and talking.
2. Liver damage: Galactosemia can cause damage to the liver, leading to liver dysfunction, cirrhosis, or liver failure.
3. Cataracts: Galactosemia can cause cataracts, a clouding of the lens in the eye that can cause vision problems.
4. Sepsis: Infants with galactosemia are at higher risk of developing sepsis, a life-threatening condition that occurs when the body’s response to an infection causes damage to its tissues and organs.
5. Intellectual disability: If galactosemia is not diagnosed and treated early, it can lead to intellectual disability or learning disabilities.
6. Neurological symptoms: Some people with galactosemia may experience neurological symptoms, such as tremors, seizures, or difficulty with coordination.

Treatment for galactosemia typically involves avoiding foods that contain lactose or galactose, such as milk and dairy products. Infants with galactosemia may also require special infant formulas that do not contain lactose or galactose. Early diagnosis and treatment are crucial in preventing or minimizing the complications associated with galactosemia.

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