metabolic insights from genetic diseases Flashcards
what diseases are babies screened for?
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)
what changes in proteins can cause gene defects?
reduced protein synthesis
altered amino acid composition
incorrect transport
what are secondary gene defects?
do not affect the main pathway but generation of cofactors
how are secondary gene defects classified?
by phenotype, not genotype
how are IMDs detected in children?
neonatal screening –> heel prick
plasma metabolite analysis via mass spec
Screening of family members looking for specific genotypes
how prevalent in von Gierke’s disease?
1 in 43,000
what causes von Gierke’s disease and how does this lead to the condition?
deficiency of glucose-6-phosphatase
prevents liver from breaking down glycogen to glucose
prevents glucose synthesis through gluconeogenesis
what are symptoms of von gierke’s?
hypoglycaemia
lactic acidosis
enlarged liver
what is the treatment of von Gierke’s?
eating more regularly to maintain blood glucose
what causes her’s disease and how does this lead to the condition?
deficiency of glycogen phosphorylase in the liver
prevents the liver from breaking down its glycogen stores - gluconeogenesis is not inhibited
what is the treatment of her’s disease?
starch supplements several times a day
what are symptoms of her’s disease?
enlarged liver
what is the inheritance of mcardle’s disease?
autosomal recessive
what causes mcardle’s disease and how does this lead to the condition?
deficiency of glycogen phosphorylase in the muscle only
cannot use muscle glycogen
what are symptoms of mcardle’s disease?
fast exercise leads to rhabdomyolysis (muscle breakdown) due to lack of energy –> myoglobin is present in the blood
how is McArdle’s diagnosed?
ischemic forearm test
what is the inheritance pattern of galactosaemia type 1?
autosomal recessive
what is the prevalence of galactosaemia type 1?
1 in 30-60,000
what causes galactosaemia type 1 and how does this lead to the condition?
Deficiency in galactose-1-phosphate –> accumulation of galactose and galactose-1-phosphate in the tissue and of the latter in the blood
what are the symptoms of galactosaemia type 1?
hypoglycaemia, acidosis – later develop cataract and mental retardation
what is the treatment for galactosaemia type 1?
galactose free diet
what causes fructose intolerance?
Fructose aldolase deficiency
(converts fructose-1-phoshate to dihydroxyacetone phosphate and glyceraldehyde) so F1P accumulates in the liver and kidneys
why do people with fructose intolerance have hypoglycaemia?
F1P build up inhibits glycogenolysis and gluconeogenesis
why does pyruvate dehydrogenase deficiency lead to build up of lactate?
pyruvate cannot be converted to acetyl CoA so pyruvate –> lactate
how is pyruvate dehydrogenase deficiency treated?
thiamine (cofactor TPP)
lipoic acid
ketogenic diet
what causes pyruvate dehydrogenase deficiency?
mutations in the any of the genes coding for PDC
what is the inheritance of pyruvate dehydrogenase deficiency?
X-linked or autosomal recessive
what are symptoms of pyruvate dehydrogenase deficiency?
mental retardation, seizures, hypotonia, brain wasting, lactic acidosis, vomiting, breathing problems, abnormal heartbeat
what is the prevalence of phenylketonuria?
1 in 15000 births
what causes phenylketonuria?
impaired conversion of phenylalanine to tyrosine bc of a defect in phenylalanine hydroxylase
how is PKU treated?
phenylalanine restricted diet supplemented with tyrosine
what causes alkaptonuria?
deficiency in homogentisate-1,2-dioxygenase
what are symptoms of alkpatonuria?
black urine
joint and cardiac problems
how is alkaptonuria treated?
diet restriction
lots of vitamin C
what causes maple syrup urine?
Deficiency in branched alpha ketoacid dehydrogenase.
–> no breakdown of branched amino acids –> keto acids build up and are excreted
what causes medium chain acyl-coA dehydrogenase deficiency?
cannot break down medium chain fats - cannot use beta oxidation efficiently –> body compensates by ketoacidosis
leads to fat buildup
how is medium chain acyl-coA dehydrogenase deficiency treated?
eat regularly
prevent body from needing to undergo fatty acid oxidation
what is familial hypercholesterolaemia?
inherited high cholesterol due to a genetic defect that reduces the amount of functional LDL receptors (mainly in the liver)
what causes familial hypercholesterolaemia?
genetic defect that reduces the amount of functional LDL receptors
defects in SREBP2
what are the treatments for familial hypercholesterolaemia?
statins - stop body from producing own cholesterol
bile acid binding resins - increase amount of bile - increase amount of cholesterol need: lower LDL
