Galactosemia pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Galactose is an important metabolite of the human body both for neonatal and adult health, playing a vital role in systemic and cognitive development .Abnormalities in any of the enzymes involved in each of the steps of the Leloir pathway can give rise to the pathological condition called galactosemia.

• Galactose is an important metabolite of the human body both for neonatal and adult health, playing a vital role in systemic and cognitive development. ^[1]

Galactose is metabolised in the body through the Leloir pathway. ^[2]

• It begins with conversion of B-D-galactose] to A-D-galactose catalysed by the enzyme galactose mutarotase
• A-D-galactose is then converted to galactose-1-phosphate by the enzyme galactokinase with utilisation of 1 molecule of ATP
• Galactose-1-phosphate combines with UDP-glucose to form UDP-galactose and the metabolically more useful glucose-1-phosphate with the help of the enzyme galactose-1-phosphate uridyl transferase.
• UDP-Galactose can undergo isomerisation in a reversible manner into UDP-glucose by the enzyme epimerase.

Abnormalities in any of the enzymes involved in each of the steps of the Leloir pathway can give rise to the pathological condition called galactosemia.

• Deficiency or reduced activity of galactose-1-phosphate uridyl transferase enzyme leads to accumulation of galactose-1-phosphate ^[3] which:
  • Sequesters phosphate essential for energy production in the human body ^[4]
  • Inhibits enzymes involved in glucose metabolism, such as pyrophosphorylase ^[5]
  • Inhibits galactosyl trasnferase thereby leading to defects in glycosylation ^[6]
• Galactokinase deficiency results in accumulation of galactose which gets converted to galactitol by a minor pathway.^[7] This molecule predisposes to cataract by causing:
  • Swelling of the lens
  • Denaturation of the proteins
  • Rupture of cell membranes ^[8]
• Epimerase deficiency results in increased UDP-galactose and suppressed UDP-glucose with the ratio changing with the galactose concentration. This can have affects on the glycoprotein and glycolipid synthesis. ^[9]
• Galactose mutarotase enzyme deficiency results in galactose not being able to enter the Leloir pathway due to specificity of the enzymes for the B-isomer. This can have serious clinical consequences.^[10]

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