31. Metabolic Insights from Genetic Disease Flashcards
What 6 inherited diseases are newborn babies screened for (via heelprick)?
What causes inherited metabolic disorders?
Phenylketonuria (PKU), Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), maple syrup urine disease (MSUD), isovaleric acidaemia (IVA), glutaric aciduria type 1 (GA1), homocystinuria (pyridoxine unresponsive)(HPU). Can’t cure but treat effects.
Gene defects change protein activity, PRIMARY - due to reduced synthesis, incorrect transport or atered aa composition, SECONDARY - defects in cofactor regeneration. Could prod toxic metabolite.
Give an example of the following deficiencies:
a) Carbohydrate metabolism
b) AA metabolism
c) Organic acid meabolism
d) FA metabolism (mitochondrial defects)
a) glycogen storage disease
b) PKU, MSUD, GA1
c) alcaptonuria
d) MCAD
What is the main cause of the following disorders?
a) Von Gierke’s disease (Type 1 glycogen storage disease)
b) galactosemia
c) fructose intolerence
d) PKU
e) MCAD deficiency
f) familal hypercholestreolaemia
a) deficiency of glucose-6-phosphatase
b) deficiency of galactose-1-phosphate uridyltransferase
c) deficiency of fructose aldolase
d) defect in phenylalanine hydroxylase
e) thus impaired FA oxidation
f) reduced number of functional LDL receptors = high blood chol
If the following features were found from a newborn heelprick, what disorder could it be?
a) hypoglycaemia
b) cataracts
c) metabolic acidosis
d) unusual urine odour
e) neurological dysfunction
How else are these things detected?
a) glycogen storage disease (e.g. von GIerke’s)
b) galactosemia
c) organic acid defects (e.g. PDC deficiency)
d) AA and organic acid defects
e) urea cycle defects (build up of NH3 in blood)
Use mass spec to analyse chemical composition of blood, family screening for certain genotypes
Describe von Gierke’s disease and the treatment for it.
Describe Her’s disease and the treatment for it.
Deficiency of glucose-6-phosphatase (glucose-6-phosphate -> glucose in liver), liver can’t make glycogen stores accessibile to body. It also prevents glucose synthesis from glucogenic AA and lactate (Cori cycle) in liver. Thus fasting kids have hypoglycaemia, lactic acidosis and hepatomegaly (full of glycogen). Treatment = starch/dextrose several times a day (slow release BG)
Defiency of glycogen phosphorylase in liver, fasting kids have hypoglycaemia and hepatomegaly. Treatment = starch/dextrose
Describe McArdle’s disease. How is it diagnosed and managed?
What is galactose?
What is galactosaemia type 1? What does it cause and how is it treated?
Autosomal recessive, muscle glycogen phosphorylase deficiency, fast exercise = rhabdomyolysis, raised blood cretine kinase and Mb, dark urine (due to Mb). Manage exercise carefully (2nd wind - move to supplying muscles from FA and BG). Diagnose with ischemic forarm test (lack of lactate), biopsy and sequencing.
Major sugar in milk. Converted by liver -> glucose. Glucose + galactose = lactose. UDP enables the epimerisation to glucose1-phosphate
Deficiency in galactose-1-phosphate uridyl transferase. Autosomal recessive. Baby can’t use galactose, so it (and galactose-1-phosphate) accumulates in tissue and blood (galactosaemia). Kids have hypoglycaemia (galactose-1-phosphate uses up phosphate in cells so reduces other reactions that depend on it e.g. hexokinase), acidosis (keto), cateracts and mental retardation later. Treatment = galactose-free diet (if started early, no disease effect)
Describe fructose intolerance - what commonly causes it?
Describe pyruvate dehydrogenase deficiency.
Inherited, commonly caused by fructose aldolase deficiency. Fructose accumulates in liver and kidneys as fructose-1-phosphate which inhibits GNG and glycogenolysis, leading to hypoglycaemia. Severe = hepatic and renal failure. Distaste of sweet food. Treatment = reduce amount of dietary fructose
Rare, build up of lactate -> lactic acidosis. Treatment = thiamine (PDC cofactor), lipoic acid and ketogenic diet (induce body to use ketones and fats as main fuel so not as much glycolysis and lactate accumulate)
Describe PKU. What are the symptoms and treatments?
Imparied conversion of phenylalanine -> tyrosine due to defect in phenylalanine hydroxylase (or rarer = dihydrobiopterin reductase which recycles cofactor for main reaction). Causes high conc of phenylalanine which has 2 SEs: side reaction creates phenylpyruvate and phenylethylamine, and these + phenylalanine are excreted in urine (aminoaciduria).
Develops 3-6m. Symptoms: eczema, dev delay, hyperactivity, mental retardation, vomiting, reduced melanin in skin. Treatment = phenylalanine restricted diet (but still have a little b/c its essential AA) supplemented with tyrosine
Describe alkaptonuria. How is it treated?
What is maple syrup urine disease? How is it treated?
Deficiency in homogentisate-1,2-dioxygenase, black urine (alkapton - black b/c oxidises), joint and cardiac problems due to homogentisate (substrate for enzyme that’s deficient) deposits. Treatment = diet restriction (of phenylalanine and tyrosine) and lots of vit C - not perfect
Deficiency in branched-chain alpha-ketoacid dehydrogenase, can’t break down branched AAs (e.g. leucine and isoleucine) so their keto acids (and abnormal breakdown prods) build up and are excreted -> urine smells like syrup. Treatemnt: not abstinance, but controlled amounts
Describe MCAD D. What are the symptoms and how is it treated?
What is familial hypercholesterolaemia? What are the symptoms and how is it treated?
Medium-chain acyl-CoA dehydrogenase deficiency. Affects beta ox: impaired ability to use fat - can use long chains up to certain point. Buildup of medium chain fats. Increased energy demand so ketoacidosis and low BG during fasting, fat presence. Treatment: regular food - prevent need for beta ox
Genetic defect reducing number of functional LDL receptors (defect in LDL receptor or in transcription factor that controls its prod e.g SREBP2), in liver mainly. Symptoms: high blood chol, tendon xanthomas, premature coronary heart disease. Treatment: diet modification, statins (blocks HMG CoA reductase), bile acid binding resins (increases body’s demand for chol so more removed from blood)
