Inborn Errors of Metabolism Flashcards
What are the different forms of IEM?
Carbohydrate disorders, Fatty acid oxidation defects, Aminoacidopathies
What are examples of carbohydrate disorders?
Galactosemia, fructosemia
What are some examples of fatty acid oxidation defects?
Medium chain acyl-CoA, dehydrogenase deficiency.
What are some examples of aminoacidopathies?
Phenylketonuria, Alkaptonuria
What are oligosaccharides?
Two or more monosaccharides linked by O-glycosidic bonds
What is lactose synthase?
Heterodimer compromising the α-lactalbumin and β4galactosyltransferase -1
What is the function of prolactin?
Stimulates the expression of α-lactalbumin in the lactating mammary gland
What is α-lactalbumin?
The enzyme that produces the breast milk
What is the reversible equation between glucose, galactose and lactose?
Lactose and water —-(lactase)—-> Galactose + Glucose
Where is lactase located?
The brush border (microvilli) of the small intestine
What is lactase and what is its function?
β-D-galactosidase that catalyses the breakdown of lactose to galactose and glucose
What other deficiencies affect the carbohydrate absorption?
Surcease, isomaltase and trehalase deficiencies
What is lactase deficiency?
The failure to express the enzyme (lactase) that hydrolyses lactose into galactose and glucose in the small intestine
What are some symptoms that occur as milk is ingested for people with IEM??
Stools have a low pH
Stools contain glucose produced by bacteria action on undigested lactose
What happens to lactose in lactase-deficient individuals?
Gut bacteria ferment lactose to lactic acid, methane, and acetate
What does bacterial fermentation cause?
Abdominal cramps, bloating and nausea
What is lactose malabsorption?
Failure to digest or absorb lactose in the small intestine
Why does the lactase enzyme decrease in numbers after weaning?
The quantity of lactose taken in is less, if any dairy products are consumed the enzyme cannot break it down so gut bacteria have to do so.
What are symptoms of lactose intolerance?
Flatulence
Abdominal discomfort
Bloating
Diarrhea
What are the common symptoms of galactosemia?
Failure to thrive
Predisposition to sometimes life-threatening infections
Jaundice
Liver failure
What causes jaundice in galactosemia?
The liver is unable to break down bilirubin
How does galactose enter the liver?
Freely from the blood to the hepatocytes
Where is galactose metabolised?
In the liver
Explain the pathway galactose into glucose.
Enters liver through GLUT 2
GALK transforms galactose into galactose-1-phosphate
Galactose-1-phosphate turns into glucose-1-phosphate through GALT
PGM1 converts glucose-1-phosphate into glucose-6-phosphate
Glycolysis
Why are cells not equipped or adapted to utilise galactose for metabolism?
Most galactose is removed and metabolised through the liver, excreted through urine
How does galactose become galactose-1-phosphate?
Through galactokinase (phosphorylation, so ATP is used up)
What is the role of galactose in the body?
Required for glycosylation of glycoproteins and glycolipids in non-liver tissues
- Enhances immune system
What is the role of galactose in the respiratory system?
Salfated galactose residues
What does galactose in the respiratory system prevent?
Pneumonia, Influenza
What is the role of galactose in metabolism?
Biosynthesis of many complex carbohydrates
What are the complex carbohydrates that galactose biosynthesises?
Glycoproteins, glycolipids
What is the role of galactose in the gastrointestinal system?
To maintain bacteria flora
Why is the conversion of galactose into glucose thermodynamically not a favorable reaction?
it uses too much ATP (3 molecules)
What is the galactose pathway in the liver?
Lactose to Galactose + Glucose (lactase)
Galactose to Galactose-1-phosphate + UDP glucose (Galactokinase)
Galactose-1-phosphate to Glucose-1-phosphate + UDP galactose (Galactose-1-phosphate uridyl transferase)
UDP galactose and UDP glucose are reversible with each other (UDP Galactose-4-epimerase GALE)
Why does UDP galactose change to UDP glucose?
UDP galactose is toxic in high quantities so it transforms into UDP glucose which is useful
What is classic galactosemia caused by?
A mutation in the galactose-1-phosphate transferase (GALT)
What is type II galactosemia caused by?
A mutation in the galactokinase (GALK)
What is type III galactosemia caused by?
A mutation in UDP - GAlactose-4-epimerase (GALE)
What happens if GALT is not working properly?
Galactose is not converted into glucose so there is a build-up of galactose
What is galactose also converted into?
Galactitol and galactonate
Which enzyme converts galactose into galactilol?
Aldose reductase
Which disease occurs when galactose is converted to excessive galactitol?
Cataracts
What is the diagnostic test for PKU?
FeCl3 which detects phenylalanine in urine
What happens if phenylalanine is present in the urine?
FeCl3 changes colour to green, blue or black from orange/yellow
What enzyme converts phenylalanine into tyrosine?
PAH
Where does PAH-mediated hydroxylation occur?
Liver and renal tubules of kidney
What is BH4?
A cofactor required for PAH activity
What is DHPR? What is its function?
Cofactor required for the hydroxylation of Phenylalanine, Tyrosine, and Tryptophan.
Catalyses age recycling of tetrahydrobiopterin
What is PAH-mediated hydroxylation the rate-limiting step of?
Intermediary metabolism of L-Phe
What is PKU?
PAH deficiency, autosomal recessive.
Defects in the production of BH4 which may result in hyperphenylalanine
What are the symptoms of PKU?
Increased phenylalanine
Increased phenyl-ketones
Increased phenylamine
Deficiency of tyrosine
Fair skin, blue eyes, light blonde hair
Mousy or musty door of urine
What is the function of phenylalanine?
It is involved in the body’s production of melanin, decreased production of phenylalanine so decreased melanin
What happens if PKU goes untreated?
Microcephaly
Eczematous skin rash
Mousy or musty odor in urine
Severe mental retardation
Why can PKU cause sever mental retardation?
Greatly increased concentration of phenylalanine impairs brain development and function
What is the metabolic catabolism of phenylalanine?
Phenylalanine to Tyrosine (Phenylalanine hydroxylate)
Tyrosine to p-OH-phenylpyruvate (tyrosine aminotransferase)
p-OH-phenylpyruvate to homogenistic acid (4-OH-phenylpyruvate deoxygenase)
Homogenistic acid to maleylacetoacetate (homogenistic acid oxidase)
Maleylacetoacetate to Fumarylacetoacetate (maleylacetoacetate isomerase)
Fumarylacetoacetate to Fumarate + Acetoacetate (fumarylacetoacetate hydrolase)
In the phenylalanine metabolic cycle what causes PKU?
Inability to transform phenylalanine to tyrosine
In the phenylalanine metabolic cycle what causes Alkaptonuria?
Inability to convert homogenistic acid to maleylacetoacetate
What causes alkaptonuria?
Deficiency of the enzyme homogenistic deoxygenate
What are the signs of alkaptonuria?
Homogenistic acid and alkapton in urine
Blue-black pigmentation in connective tissues
Arthritis
Urine turns dark with standing or alkalisation
What happens in β-oxidation?
Carbon number is reduced by two each time
Where does β-oxidation take place?
Mitochondrial matrix
What are the carbon units lost during β-oxidation become?
CO2 in the muscle or generate ketone bodies in the liver
What are the symptoms of fatty acid oxidation diseases?
Asymptomatic
Hypoglycaemia
Lethargy
Coma
Sudden death
What causes hypoglycemia in patients with fatty acid oxidation diseases?
There is reduced levels of hepatic glucose, that is why β-oxidation needs to happen.
What might cause sudden death in patients with fatty acid oxidation disorders?
Prolonged fasting, acute illness
