Monogenic Metabolic Disorders

Question 1

What is metabolism?

Answer 1

a collection of chemical reactions that take place in cells in order to convert food into energy required to live

Question 2

What is an inherited metabolic disorder?

Answer 2

a genetic condition where the body cannot properly process certain substances due to defective enzymes as a result of an inherited defective gene

Question 3

Give examples of normal metabolism disrupted in a metabolic disease

Answer 3

• breakdown of carbohydrate, fat or protein to release energy
• breakdown or conversion of chemicals into other substances
• transformation of excess nitrogen into waste products

Question 4

When does an autosomal recessive disorder occur?

Answer 4

when a child inherits two copies of a mutated gene, one from each parent

Question 5

When does an autosomal dominant disorder occur?

Answer 5

when a child inherits a mutated gene from one parent

Question 6

What are the 6 disorders that affect carbohydrate metabolism?

Answer 6

• fructose metabolism disorders
• galactosemia
• glycogen storage disease
• pyruvate metabolism disorders
• pentose phosphate pathway abnormalities
• G6PD deficiency

Question 7

What are the 5 disorders that affect amino acid metabolism?

Answer 7

• homocystinuria
• tyrosinemia
• phenylketonuria (PKU)
• urea cycle disorders
• maple syrup urine disease

Question 8

What are the 4 disorders that affect lipid metabolism?

Answer 8

• Gaucher’s disease (type I, II and III)
• Tay-Sachs disease
• Neimann-Pick disease
• Fabry’s disease

Question 9

Where does fructose metabolism mainly occur?

Answer 9

liver, kidney, small intestine and adipose tissue

Question 10

What is essential fructosuria?

Answer 10

autosomal recessive disorder due to lack of fructokinase (harmless)

Question 11

What is hereditary fructose intolerance?

Answer 11

autosomal recessive disorder due to lack of fructaldolase B and can cause severe hypoglycaemia (lethal)

Question 12

What disorder affects the gluconeogenic pathway?

Answer 12

hepatic fructose 1,6-bisphosphatase deficiency

Question 13

What is hepatic fructose 1,6-bisphosphatase deficiency?

Answer 13

autosomal recessive disorder that can cause hypoglycaemia and lactic acidosis

Question 14

What are the 3 steps of fructose metabolism?

Answer 14

1. fructose enters the liver and is converted into fructose-1-phosphate by fructokinase
2. aldolase B breaks fructose-1-phosphate dihydroxyacetone phosphate (DHAP) and glyceraldehyde
3. these intermediates enter glycolysis or gluconeogenesis pathways, providing energy or serving as building blocks for other metabolic processes

Question 15

How is fructose metabolism different to glucose metabolism?

Answer 15

it bypasses key regulatory steps, which can lead to rapid fat production if consumed in excess

Question 16

What does galactokinase deficiency do?

Answer 16

prevents the body from digesting galactose, a sugar found in milk and some fruits and vegetables (galactosemia type II)

Question 17

What does galactose-1-phosphate uridyltransferase deficiency do?

Answer 17

• cause classic galactosemia
• prevent the conversion of galactose into glucose

Question 18

What of glycogen storage disorders do?

Answer 18

disrupt the normal synthesis or breakdown of glycogen; they most seriously affect the liver and muscle

Question 19

What does the liver use glycogen for?

Answer 19

glucose homeostasis

Question 20

How do glycogen storage disorders affect the liver?

Answer 20

defective enzymes prevent glycogen from being properly processed which can cause hepatomegaly (enlarged liver) and subsequent hypoglycaemia

Question 21

What do muscles use glycogen for?

Answer 21

ATP generation for muscle contraction

Question 22

What can excess glycogen in muscles due to glycogen storage disorders cause?

Answer 22

muscle cramp and fatigue

Question 23

What is Pompe’s disease caused by, what can it lead to and what its most common treatment?

Answer 23

• caused by alpha-1,4-glucosidase deficiency (branching enzyme)
• can lead to weak muscles
• most used treatment is enzyme replacement therapy via Myozyme

Question 24

What are the 2 pyruvate metabolism disorders and what do they affect?

Answer 24

• 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)

Question 25

What are the 5 fates of pyruvate?

Answer 25

- aerobic respiration - fermentation - conversion to alanine - gluconeogenesis - alcoholic fermentation

Question 26

What are the 3 pentose phosphate pathway abnormalities and what are they caused by?

Answer 26

- essential pentosuria causes excess levels of the sugar L-xylulose in the urine due to NADP-linked deficiency; autosomal recessive (benign) - ribose-5-phosphate isomerase deficiency caused by a mutated RPIA gene; autosomal recessive - transaldolase deficiency caused by a mutated TALDO1 gene; autosomal recessive

Question 27

What does G6PD do?

Answer 27

help RBCs to function normally

Question 28

What is G6PD deficiency?

Answer 28

an X-linked disorder that can lead to haemolytic anaemia

Question 29

What is haemolytic anaemia?

Answer 29

blood disorder that occurs when RBCs break down faster than the body can replace them

Question 30

Where is G6PD deficiency common?

Answer 30

in males of African, Mediterranean and Southeast Asian heritage (i.e. high-risk areas for malaria)

Question 31

What are the ways to treat G6PD deficiency?

Answer 31

- replacement treatment - avoiding certain antibiotics, antimalarials, certain chemicals and broad beans

Question 32

What causes tyrosinemia?

Answer 32

lack of the enzyme that metabolises tyrosine

Question 33

What are treatments of tyrosinemia?

Answer 33

- restriction of tyrosine and phenylalanine in the diet - nitisinone (used to treat hereditary tyrosinemia type 1, too much tyrosine in the blood)

Question 34

What causes homocystinuria?

Answer 34

lack of cystathionine beta-synthase which is needed to metabolise homocysteine

Question 35

What are treatments of homocystinemia?

Answer 35

- vitamin B6 (pyridoxine) - vitamin B12 (cobalamin) - supplement of betaine and special diet

Question 36

What is PKU?

Answer 36

accumulation of phenylalanine in all body fluids which can lead to severe mental retardation if left untreated

Question 37

What is treatment for PKU?

Answer 37

low phenylalanine diet

Question 38

Where does the urea cycle take place and what does it do?

Answer 38

in the liver to incorporate excess nitrogen into urea and also the de novo synthesis of arginine

Question 39

What deficiencies can cause urea cycle disorders?

Answer 39

- ornithine transcarbamylase (OTC) – X-linked - carbamyl phosphate synthetase (CPS) – autosomal recessive - argininosuccinic acid synthetase (ASS) – autosomal recessive - argininosuccinic lyase (ASL) – autosomal recessive - arginase (ARG) – autosomal recessive

Question 40

What is maple syrup urine disease caused by?

Answer 40

a deficiency in branched chain alpha-keto acid dehydrogenase activity which leads to accumulation of branched chain amino acids leucine, isoleucine and valine, as well as downstream branched chain alpha-keto acids

Question 41

What are organic acidaemias?

Answer 41

a group of inherited metabolic disorders that cause a buildup of toxic organic acids in the body

Question 42

What are the 3 organic acidaemias?

Answer 42

- isovaleric acidaemia - propionyl CoA carboxylase deficiency – major cause of ketotic hyperglycinaemia syndrome; propionic acidaemia (PA) - methylmalonyl CoA apomutase deficiency – leads to neonatal metabolic ketoacidosis; methylmalonic acidemia (MMA)

Question 43

What does cellular respiration in the mitochondria involve?

Answer 43

- glycolysis – breakdown of glucose in the cytosol - conversion of pyruvate into acetyl CoA - TCA cycle – acetyl CoA is converted into energy precursors - oxidative phosphorylation – electron transport from the energy precursors leads to the phosphorylation of ADP, leading to ATP

Question 44

What do genetic defects in oxidative phosphorylation cause?

Answer 44

a group of disorders that affect the body's ability to produce energy

Question 45

What are the 2 copper disorders?

Answer 45

- Wilson disease – excessive copper due to impaired biliary copper excretion - Menkes disease – copper deficiency due to impaired function of cuproenzymes

Question 46

What are the 2 iron disorders?

Answer 46

- hereditary haemochromatosis – excessive iron due to a mutation in haemochromatosis protein (HFE) - hepcidin deficiency – body doesn't produce enough hepcidin (iron-regulating hormone)

Question 47

What are peroxisomes?

Answer 47

organelles in the cytoplasm of all eukaryotic cells that contain the reducing enzyme catalase and some oxidases

Question 48

What does catalase do?

Answer 48

break down hyrogen peroxide into oxygen and water

Question 49

What are the 2 peroxisomal disorders?

Answer 49

- Zellweger syndrome – autosomal recessive disorder of peroxisomal biogenesis due to a mutated PEX gene (causes nerve damage, hepatomegaly and abnormal facial features) - Adrenoleukodystrophy – X-linked recessive disorder of beta oxidation due to mutation of ABCD1 gene; VLCFA buildup in adrenal glands, white matter of brain, testes

Question 50

What are the 6 main lysosomal storage disorders?

Answer 50

- hurler syndrome – deficiency in enzyme catalysing the degradation of glycosaminoglycans; developmental delay; abnormal bone structure - Krabbe disease – galactocerebrosidase (GALC) deficiency; infantile globoid cell leukodystrophy; developmental delay; nerve damage - Gaucher’s disease – acid β glucosidase mutation; most common lysosomal glycolipid storage disorder; hepatomegaly; bone pain - Tay-Sachs disease – excessive accumulation of ganglioside GM2; nerve damage - Niemann-Pick disease – acid sphingomyelinase deficiency; nerve damage; hepatomegaly - Fabry disease – α galactosidase A deficiency; X-linked recessive; pain in the extremities

Question 51

What is newborn screening used for?

Answer 51

to detect rare diseases and prevent them doing irreversible damage to the development

Question 52

What are the main treatments for metabolic disorders?

Answer 52

- reduction or removal of food/drug that cannot be metabolised properly i.e. customised diet - removal of toxic products e.g. blood treatment to remove toxic by-products - replacement of enzyme or chemical that is missing or inactive e.g. enzyme replacement therapy or supplements

Question 53

Give examples of drug development efforts for metabolic disorders

Answer 53

- enzyme replacement - pharmacological chaperones (non-competitive, stabilise mutant protein and allow protein to interact normally with the natural substrate) - gene therapy (works by introducing a healthy or modified gene into a patient's cells to replace a faulty gene or increase the production of beneficial proteins)