Monogenic Metabolic Disorders
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What is metabolism?
a collection of chemical reactions that take place in cells in order to convert food into energy required to live
What is an inherited metabolic disorder?
a genetic condition where the body cannot properly process certain substances due to defective enzymes as a result of an inherited defective gene
Give examples of normal metabolism disrupted in a metabolic disease
• breakdown of carbohydrate, fat or protein to release energy • breakdown or conversion of chemicals into other substances • transformation of excess nitrogen into waste products
When does an autosomal recessive disorder occur?
when a child inherits two copies of a mutated gene, one from each parent
When does an autosomal dominant disorder occur?
when a child inherits a mutated gene from one parent
What are the 6 disorders that affect carbohydrate metabolism?
• fructose metabolism disorders • galactosemia • glycogen storage disease • pyruvate metabolism disorders • pentose phosphate pathway abnormalities • G6PD deficiency
What are the 5 disorders that affect amino acid metabolism?
• homocystinuria • tyrosinemia • phenylketonuria (PKU) • urea cycle disorders • maple syrup urine disease
What are the 4 disorders that affect lipid metabolism?
• Gaucher’s disease (type I, II and III) • Tay-Sachs disease • Neimann-Pick disease • Fabry’s disease
Where does fructose metabolism mainly occur?
liver, kidney, small intestine and adipose tissue
What is essential fructosuria?
autosomal recessive disorder due to lack of fructokinase (harmless)
What is hereditary fructose intolerance?
autosomal recessive disorder due to lack of fructaldolase B and can cause severe hypoglycaemia (lethal)
What disorder affects the gluconeogenic pathway?
hepatic fructose 1,6-bisphosphatase deficiency
What is hepatic fructose 1,6-bisphosphatase deficiency?
autosomal recessive disorder that can cause hypoglycaemia and lactic acidosis
What are the 3 steps of fructose metabolism?
• fructose enters the liver and is converted into fructose-1-phosphate by fructokinase • aldolase B breaks fructose-1-phosphate dihydroxyacetone phosphate (DHAP) and glyceraldehyde • these intermediates enter glycolysis or gluconeogenesis pathways, providing energy or serving as building blocks for other metabolic processes
How is fructose metabolism different to glucose metabolism?
it bypasses key regulatory steps, which can lead to rapid fat production if consumed in excess
What does galactokinase deficiency do?
prevents the body from digesting galactose, a sugar found in milk and some fruits and vegetables (galactosemia type II)
What does galactose-1-phosphate uridyltransferase deficiency do?
• cause classic galactosemia • prevent the conversion of galactose into glucose
What of glycogen storage disorders do?
disrupt the normal synthesis or breakdown of glycogen; they most seriously affect the liver and muscle
What does the liver use glycogen for?
glucose homeostasis
How do glycogen storage disorders affect the liver?
defective enzymes prevent glycogen from being properly processed which can cause hepatomegaly (enlarged liver) and subsequent hypoglycaemia
What do muscles use glycogen for?
ATP generation for muscle contraction
What can excess glycogen in muscles due to glycogen storage disorders cause?
muscle cramp and fatigue
What is Pompe’s disease caused by, what can it lead to and what its most common treatment?
• caused by alpha-1,4-glucosidase deficiency (branching enzyme) • can lead to weak muscles • most used treatment is enzyme replacement therapy via Myozyme
What are the 2 pyruvate metabolism disorders and what do they affect?
• pyruvate dehydrogenase (converts pyruvate to acetyl CoA for TCA cycle) deficiency affects the mitochondria and causes lactic acidosis (can be autosomal recessive or X-linked) • pyruvate carboxylase (gluconeogenesis from pyruvate and alanine) deficiency also causes lactic acidosis (autosomal recessive)