metabolic insights from genetic diseases

Question 1

what diseases are babies screened for?

Answer 1

Phenylketonuria (PKU)
Maple syrup urine disease
Isovaleric acidaemia (IVA)
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
Glutaric aciduria type 1 (GA1)
Homocystinuria (pyridoxine unresponsive (HCU)

Question 2

what changes in proteins can cause gene defects?

Answer 2

reduced protein synthesis
altered amino acid composition
incorrect transport

Question 3

what are secondary gene defects?

Answer 3

do not affect the main pathway but generation of cofactors

Question 4

how are secondary gene defects classified?

Answer 4

by phenotype, not genotype

Question 5

how are IMDs detected in children?

Answer 5

neonatal screening –> heel prick
plasma metabolite analysis via mass spec
Screening of family members looking for specific genotypes

Question 6

how prevalent in von Gierke’s disease?

Answer 6

1 in 43,000

Question 7

what causes von Gierke’s disease and how does this lead to the condition?

Answer 7

deficiency of glucose-6-phosphatase
prevents liver from breaking down glycogen to glucose
prevents glucose synthesis through gluconeogenesis

Question 8

what are symptoms of von gierke’s?

Answer 8

hypoglycaemia
lactic acidosis
enlarged liver

Question 9

what is the treatment of von Gierke’s?

Answer 9

eating more regularly to maintain blood glucose

Question 10

what causes her’s disease and how does this lead to the condition?

Answer 10

deficiency of glycogen phosphorylase in the liver

prevents the liver from breaking down its glycogen stores - gluconeogenesis is not inhibited

Question 11

what is the treatment of her’s disease?

Answer 11

starch supplements several times a day

Question 12

what are symptoms of her’s disease?

Answer 12

enlarged liver

Question 13

what is the inheritance of mcardle’s disease?

Answer 13

autosomal recessive

Question 14

what causes mcardle’s disease and how does this lead to the condition?

Answer 14

deficiency of glycogen phosphorylase in the muscle only

cannot use muscle glycogen

Question 15

what are symptoms of mcardle’s disease?

Answer 15

fast exercise leads to rhabdomyolysis (muscle breakdown) due to lack of energy –> myoglobin is present in the blood

Question 16

how is McArdle’s diagnosed?

Answer 16

ischemic forearm test

Question 17

what is the inheritance pattern of galactosaemia type 1?

Answer 17

autosomal recessive

Question 18

what is the prevalence of galactosaemia type 1?

Answer 18

1 in 30-60,000

Question 19

what causes galactosaemia type 1 and how does this lead to the condition?

Answer 19

Deficiency in galactose-1-phosphate –> accumulation of galactose and galactose-1-phosphate in the tissue and of the latter in the blood

Question 20

what are the symptoms of galactosaemia type 1?

Answer 20

hypoglycaemia, acidosis – later develop cataract and mental retardation

Question 21

what is the treatment for galactosaemia type 1?

Answer 21

galactose free diet

Question 22

what causes fructose intolerance?

Answer 22

Fructose aldolase deficiency
(converts fructose-1-phoshate to dihydroxyacetone phosphate and glyceraldehyde) so F1P accumulates in the liver and kidneys

Question 23

why do people with fructose intolerance have hypoglycaemia?

Answer 23

F1P build up inhibits glycogenolysis and gluconeogenesis

Question 24

why does pyruvate dehydrogenase deficiency lead to build up of lactate?

Answer 24

pyruvate cannot be converted to acetyl CoA so pyruvate –> lactate

Question 25

how is pyruvate dehydrogenase deficiency treated?

Answer 25

thiamine (cofactor TPP)
lipoic acid
ketogenic diet

Question 26

what causes pyruvate dehydrogenase deficiency?

Answer 26

mutations in the any of the genes coding for PDC

Question 27

what is the inheritance of pyruvate dehydrogenase deficiency?

Answer 27

X-linked or autosomal recessive

Question 28

what are symptoms of pyruvate dehydrogenase deficiency?

Answer 28

mental retardation, seizures, hypotonia, brain wasting, lactic acidosis, vomiting, breathing problems, abnormal heartbeat

Question 29

what is the prevalence of phenylketonuria?

Answer 29

1 in 15000 births

Question 30

what causes phenylketonuria?

Answer 30

impaired conversion of phenylalanine to tyrosine bc of a defect in phenylalanine hydroxylase

Question 31

how is PKU treated?

Answer 31

phenylalanine restricted diet supplemented with tyrosine

Question 32

what causes alkaptonuria?

Answer 32

deficiency in homogentisate-1,2-dioxygenase

Question 33

what are symptoms of alkpatonuria?

Answer 33

black urine

joint and cardiac problems

Question 34

how is alkaptonuria treated?

Answer 34

diet restriction

lots of vitamin C

Question 35

what causes maple syrup urine?

Answer 35

Deficiency in branched alpha ketoacid dehydrogenase.

–> no breakdown of branched amino acids –> keto acids build up and are excreted

Question 36

what causes medium chain acyl-coA dehydrogenase deficiency?

Answer 36

cannot break down medium chain fats - cannot use beta oxidation efficiently –> body compensates by ketoacidosis
leads to fat buildup

Question 37

how is medium chain acyl-coA dehydrogenase deficiency treated?

Answer 37

eat regularly

prevent body from needing to undergo fatty acid oxidation

Question 38

what is familial hypercholesterolaemia?

Answer 38

inherited high cholesterol due to a genetic defect that reduces the amount of functional LDL receptors (mainly in the liver)

Question 39

what causes familial hypercholesterolaemia?

Answer 39

genetic defect that reduces the amount of functional LDL receptors

defects in SREBP2

Question 40

what are the treatments for familial hypercholesterolaemia?

Answer 40

statins - stop body from producing own cholesterol

bile acid binding resins - increase amount of bile - increase amount of cholesterol need: lower LDL