U01.01.099 Disorders of galactose metabolism

Galactose metabolism disorders are inherited conditions that affect the breakdown and processing of galactose, a sugar found in milk and dairy products. These disorders can result in the accumulation of toxic substances, leading to various symptoms. Below is a detailed overview of two primary disorders: Galactokinase Deficiency and Classic Galactosemia.

1. Galactokinase Deficiency

Overview:

Genetic basis: Hereditary deficiency of galactokinase, an enzyme responsible for converting galactose to galactose-1-phosphate.
Inheritance pattern: Autosomal recessive.
Pathophysiology: Accumulation of galactitol (a sugar alcohol) occurs if galactose is present in the diet, which leads to damage in various tissues.

Symptoms:

Galactose in the blood (galactosemia) and urine (galactosuria).
Infantile cataracts: Galactitol accumulation in the lens of the eye.
Failure to track objects or develop a social smile.
Relatively mild condition: Less severe than Classic Galactosemia.

Feature	Description
Inheritance	Autosomal recessive
Main Symptoms	Galactosemia, galactosuria, infantile cataracts
Outcome	Mild, benign condition (often asymptomatic)

Points to Remember:

Galactokinase deficiency is a milder form of galactose metabolism disorder.
The main feature is the development of cataracts in infants.
Treatment includes dietary restrictions of galactose and lactose (galactose + glucose).

2. Classic Galactosemia

Overview:

Genetic basis: Caused by a deficiency in the enzyme galactose-1-phosphate uridyltransferase.
Inheritance pattern: Autosomal recessive.
Pathophysiology: Toxic substances, including galactitol, accumulate in various tissues, including the eye lens.

Symptoms:

Symptoms develop when the infant starts feeding (lactose present in breast milk and formula).
Failure to thrive.
Jaundice and hepatomegaly.
Infantile cataracts and intellectual disability.
Increased risk of E. coli sepsis in neonates.

Feature	Description
Inheritance	Autosomal recessive
Main Symptoms	Failure to thrive, jaundice, hepatomegaly, cataracts, intellectual disability, E. coli sepsis
Toxic Accumulation	Galactose-1-phosphate, galactitol in the eye lens
Treatment	Exclusion of galactose and lactose from the diet

Points to Remember:

Classic Galactosemia is more severe and can cause long-term developmental issues if untreated.
Dietary management: Eliminate galactose and lactose to prevent toxic accumulation.
Early diagnosis and treatment are critical to avoid severe complications like intellectual disability.

3. Galactose Metabolic Pathway and Key Enzymes

Enzyme	Function	Product
Galactokinase	Converts galactose to galactose-1-phosphate	Galactose-1-P
Aldose reductase	Converts galactose to galactitol (toxic)	Galactitol
Galactose-1-phosphate uridyltransferase	Converts galactose-1-P to glucose-1-P	Glucose-1-P
UDP-galactose 4-epimerase	Converts UDP-galactose to UDP-glucose	UDP-glucose

Key Pathways:

Galactose → Galactose-1-P → UDP-galactose (via galactokinase and uridyltransferase).
Galactitol formation (from galactose via aldose reductase) can cause toxicity, especially in the eye lens, leading to cataracts.

4. Mnemonic for Galactose Metabolism Defects

FAB GUT:
- F = Fructose (Aldolase B defect, as a comparison to galactose).
- GUT = Galactose-1-Phosphate Uridyltransferase defect (Classic Galactosemia).

Conclusion

Galactokinase deficiency is generally benign, with cataracts being the primary symptom.
Classic Galactosemia is a more severe disorder requiring immediate dietary management to prevent long-term complications.

By recognizing the key differences between these two disorders, students can better understand their clinical presentations and management strategies for the USMLE Step 1.

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USMLE Step 1 Review Series

Curriculum

U01.01.099 Disorders of galactose metabolism

1. Galactokinase Deficiency

Overview:

Symptoms:

Points to Remember:

2. Classic Galactosemia

Overview:

Symptoms:

Points to Remember:

3. Galactose Metabolic Pathway and Key Enzymes

Key Pathways:

4. Mnemonic for Galactose Metabolism Defects

Conclusion

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