Metabolic Insights into Genetic Diseases Flashcards
how do u detect genetic disorders? (4)
- Newborn screening (heal prick)
- Screening of blood for abnormal levels of specific metabolites (biochemical screen)
- Genetic screening of family members to identify known genetic mutations known to cause specific disorders
- Identification of specific symptoms can also be sometimes related to particular defects
von Gierkes diesase (type 1 GCN)
- what type of disease (autosomal dom etc)?
- caused by gene defects in: (3)
- the gene defects cause a deficieny in?
von Gierkes diesase (type 1 GCN)
- autosomal recessive diorder
- caused by gene defects in: G6PC (makes glucose-6-phosphatase) and genes tha code for transporters of G6P (need to know exact genes?)
- the gene defects cause a deficiency in glucose-6-phosphatase (means that you cant do pyruvate –> glucose-6-P –> glucose)
i) unable to produce glucose to be sent via blood - cant leave the liver as stuck as G6P
ii) prevents gluconeogenesis
von Gierkes diesase (type 1 GCN)
symptoms? (3)
treatment? (3)
von Gierkes diesase (type 1 GCN)
symptoms: hypoglycaemia, lactic acidosis (use ketones for nutrition - acidic. also produce lactic acid); enlarged liver
treatment: regular food intake (keep blood glucose sugar levels -but cant go above as glycogen stores are probs already full ! ), prevent accumulation of glycogen
Hers diesase
- what type of disease (autosomal dom etc)?
- caused by gene defects in: (3)
- the gene defects cause a deficieny in?
Hers disease
- autosomal recessive
- caused by gene defects in: PYGL gene
- the gene defects cause a deficieny in: glycogen phosphorylase in the liver (breaks down glycogen –> glucose) BUT -> can still do GNG as can occur from different sources like glycerol
Hers diesase (type 6 GCN)
symptoms? (3)
diagnosis? (3)
treatment? (3)
Hers diesase (type 6 GCN)
symptoms: enlarged liver; mild hypoglycaemia; growth retardation; hyperlipidaemia
diagnosis: elevated lactate (rely more on Cori cycle for glucose); transminase enzymes in blood; liver biopsy shows reduce PYGL activity
treatment: regulation of diet to high glucose foods t avoid hypoglcaemia
McArdles Disease
- caused by gene defects in:
- the gene defects cause a deficieny in:
- symptoms: (2)
- diagnosis? (2)
McArdles Disease:
- autosomal recessive
- caused by gene defects in: PYGL gene muscle (not liver) ( The PYGM gene provides instructions for making an enzyme called myophosphorylase. This enzyme is found only in muscle cells, where it breaks down glycogen into a simpler sugar called glucose-1-phosphate.)
- symptoms: muscle damage (rhomboylsis), inability to perform constant exercise - get second wind (can tolerate excerise after 8-10 mins)
- diagnosis: increased lvls of myoglobin and creatine in blood - dark urine. biopsy.
Galactosaemia Type 1
- what type of disease (autosomal dom etc)?
- caused by gene defects in?
- the gene defects causes?
- symtpoms?
- treatment?
- autosomal recessive
- caused by gene defects in: galactose-1-phosphate-uridyl transferase
- the gene defects causes: accumulation of galactose and galactose-1-phosphate (normally: lactose –> glucose & galactose and then the enzyme switches galactose –> glucose. but in gene defect cant swtich to galactose –> glucose)
symptoms: lethargy, failure to gain weight, jaunice, liver damage, abnormal bleeding, mental retardation, sepsis
treatment: strict diet control - no lactose / galactose
hereditary fructose intolerance:
- deficiency in ?
- causes?
- symptoms?
- treatment?
- autosomal recessive
- caused by deficieny in: aldolase B (Fructose is phosphorylated by fructokinase into Fructose1P, and then into dihydroxyacetone phosphate and glyceraldehyde by aldolase B. step 4 of glycolysis)
- *causes:**
i) accumulation of F-1-P in liver & kidneys
ii) high F-1-P inhibits glucogenolysis and GNG -> hypoglycaemia
symptoms: nauseas, bloating, abdominal pain, chronic fatigue, malabosption
treatment: dietary control of fructose intake
have nice teeth tho !!
- Inherited fructose intolerance is commonly caused by fructose aldolase deficiency
- Fructose is phosphorylated by fructokinase into Fructose1P, and then into dihydroxyacetone phosphate and glyceraldehyde by aldolase B. This feeds into glycolysis at the 3 carbon stage
- In this disorder, fructose (ingested either as fructose of the disaccharide sucrose) accumulates in the liver and kidneys as fructose 1P
- Because we build up phosphorylated fructose there is less free phosphate to be readily available to phosphorylate other metabolites
- This, in turn, inhibits glycogenolysis and gluconeogenesis resulting in hypoglycaemia. This is severe and leads to hepatic and renal failure
- People with this intolerance have a distaste for sweet food
pyruvate dehydrogenase deficiency
disease type (2)
caused by defects in? or deficieceis in (2)
symptoms?
treatment?
mutation in any of the genes coding for: PDC (theres loads).
OR deficiencies in thiamine / B1 (cofactor for enzyme) & lipoic acid. (therefore cant do pyruvate –> acetyl co-A from glucose. but can do from other sources like ketones or glycerol)
- x linked or autosomal recessive mode of inheritance
- symptoms: build up of lactic acid leads to several neurological problems (mental retardation, seizures, hypotonia, brain wasting), lactic acidosis, vomiting, breathing problems, abnormal heart beat; fatal if untreated.
- treatment: ketogenic diet
PKU - phenylketonuria
deficency in? (2)
cauese?
symptoms?
treatment?
deficiency in:
i) enzyme phenylalanine hydroxylase
ii) or dihydrobipterin reductase (recycles a co-factor for this reaction)
causes: accumulation of phenylalanine & by products in brains of children
symptoms: development delay, mental retardartion, albinsm, hyperactivity, irratibility, vomiting
treatment: diet low in phenylalanine
alkaptonuria
deficiency in what?
symptoms?
treatment??
Deficiency in homogentisate-1,2-dioxygenase (HGD): results in accumulation of homogentisic acid
symptoms: joint and cardiac problems due to deposits of homogentisic acid in adulhood
Treatment: Diet restriction and lots of vitamin C (vitamin C is an important cofactor in the deficient enzyme and trying to work on the principle disease is not black and white and there may be some active enzyme)
turns urine dark / dark blue in contact with air !
maple syrup urine disease (MSUD)
caused by deficiency in?
what does this cause?
symptoms / diagnosis / treatment?
maple syrup urine disease (MSUD)
Deficiency in branched chain alpha ketoacid dehydrogenase: so cant break down branched chain amino acids: particularly valine, leucine and isoleucine
Unable to breakdown branched amino acids (ones above) so their keto acids, and abnormal breakdown products, build up and are excreted as maple syrup urine smell
symptom: keto acidosis
diagnosis: mass spec of blood to detect specific amino acids
treatment: stritct diet controol
fatty acid related syndrome:
usual stuff xox
Medium chain acyl CoA dehydrogenase deficiency: causes a defect in beta oxidation of medium chain lipids (breaking them down).
i) reduced gluconeogensis - cant use glycerol as input -> hypoglycamia
ii) reduced ketone body production (no acetlyl co-A no ketone bodies)
clinical features: hypoketotic hypoglycaemia (see above), hyperammonemia (instead of breaking down fats - break down a.a. causes release of NH3). sudden infant death possible
Treatment via regular sugar food to prevent the need for beta oxidation, so preventing build up of fats. s
familal hypercholesterolemia
deficiney in? (2)
causes?
symtpoms?
treatment?
autosomal dominant !!
- defects in SREPB2 gene: Less receptor synthesis -> Fewer receptors -> Fewer LDL’s absorbed from blood
- defects in Apo B
- defects in low density lipoprotein break down or uptake into cells (LDL receptor defects)
- causes build up in LDL -> increased risk of plaque formation and CHD
diagnosis: high LDL levels and high cholesterol
treatment: diet control, statins
