Metabolic disorders Flashcards
What are the 2 main sites of haem synthesis
erythroblasts due to bone marrow forming RBC
hepatocytes as liver detoxifies
Which two structures join to form haem
succinyl coa
glycine
What is the p450 class of enzymes involved in
detoxification in the liver
In the liver, which two structures form ALA
S-Coa and glycine
What inhibits the formation of S-ALA
elevated levels of haem and haemin
What substances can upregulate the synthesis of S-ALA enzyme
steroids, barbiturates, testosterone, alcohol
What is the inheritance of porphyria’s
autosomal dominant
What are porphyria’s
deficiencies of enzymes in the haem biosynthesis pathways
accumulation of haem precursors which are toxic at high concentrations
triggered by drugs, chemicals and food that require more p450s fo digest
Why is drinking blood a treatment of porphyria’s
more haem = less ALA = less toxic intermediates
What factors cause symptoms of porphyria’s to vary
the enzyme affected
severity of deficiency
whether haem synthesis is affected in liver
What happens to ALA levels in porphyria’s
ALA increases as ALA synthase is blocked
Why does porphyria’s cause neurological symptoms
ALA has similar structure to GABA
ALA autoxidation generates reactive oxygen species which can damage membranes, proteins and DNA
How do porphyria’s cause hyper/madness symptoms
less haem = less hepatic tryptophan pyrrolase enzyme (TP) which is a haem dependent = increased serotonin
How do porphyria’s result in photosensitivity
accumulation of light absorbing pathways intermediates , react with molecular oxygen to form reactive oxygen species which damage the skin causing blisters and scars
What is acute intermittent porphyria
PBGD gene mutation - autosomal dominant
neurovisceral, gastroenterological, CNS symptoms
episodes caused by drugs, barbiturates and sulphonamides that trigger p450 release and increase haem synthesis
more common in women due to menstrual cycle producing hormones to be detoxified in liver
What are the treatments of AIP
glucose infusion to decrease porphyrins and repress haem biosynthesis
inject haemin to inhibit ALA synthase shunting intermediates
What is adrenal hyperplasia and what is it caused by
how can it be treated
enlarged adrenal gland
defect in 21-hydroxylase causing lack of cortisol (increases adrenal gland due to ACTH inhibition not applied) and lack of aldosterone (limited sodium reabsorption in kidneys causing dehydration)
causes intermediates prior to block up being diverted to make testosterone = external genitalia in women and early onset male puberty
treated by steroid replacement
What happens when there is a deficiency of 5 alpha reductase in foetal development
external genitalia of men fail to develop correctly and appear female at birth
due to lack of DHT which is normally expressed in the 3rd trimester when testes descend and penis grows, a stronger androgen than testosterone
What is a lysosome?
Membrane bound organelles found in most animal cells
Act as disposal system
Contain hydrolytic enzyme
PH between 4.5-5- optimal for enzymes
How do O-glycosidic bonds form ?
-glycosidic bonds form by reaction of
nucleotide sugar with hydroxyl group of an nucleotide sugar with hydroxyl group of an
amino acid (Thr, Ser or hydroxylysine) in the Golgi
How do N-glycosidic bonds form?
More complex process which involves a lipid carrier to form an activated oligosaccharides which is transferred en bloc to Asn residues
What are roles of glycoproteins?
Antibodies, fibrinogen, cell recognition
What is the role of glycolipids?
Cell recognition and stabilise membranes
What are gangliosides?
Specific groups of glycolipids found in neural tissue
Composed of ceramide (lipid backbone) with oligosaccharides (including sailic acid) linked to form head group
What is Gaucher’s disease?
Most common lysosomal storage disease
Defect in the glucosylceramidase enzyme which
cleaves glucose residue from the ceramide lipid
backbone.
Characterised by bruising, fatigue,
hepatomegaly and enlarged spleen.
Lack of the enzyme leads to accumulation of
the glucoceramide within cells, particularly
white blood cells causing accumulation in
spleen and liver in particular, can have an
impact on nervous tissue.
Autosomally recessive -1 in 50,000 born with Autosomally recessive -1 in 50,000 born with
the condition the condition
Around 1 in 100 carriers of the defect (higher Around 1 in 100 carriers of the defect (higher
in certain populations Ashkenazi Jews 1 in 10)
What are the three subtypes of Gaucher’s disease?
Type 1 Nonneuropathic
TyPE 2 Aute infantile neuropathic
Type 3 (chronic neuropathic)
Describe type 1 of Gaucher’s disease
Type 1 - nonneurpathic- most common- own in Ashkenazi Jes where it is 100 times more common than general populations - there is residual enzyme activity- least severe with brain not affected by
Symptoms: enlarged liver, spleen, due to processing of blood cells causing accumulation- also related to anaemia (fatigue) slightly reduced life expectancy
Describe type 2 of Gaucher’s disease
Type 2- (acute infantile neuropathic) SyMPTOMS- apparent at 6 moths seizures, mental retardation, death by age 3- no residual enzyme activity present in lysosome - most common mutation in Lys444pro
Describe type 3 of gauchers syndrome
most common mutation is LYs444Pro but delayed by some protective polymorphisms- found in Swedish communit
What is the treatment for Gaucher’s disease? Type 1,2 and 3?
Type 1 and 3 is enzyme replacement therapy
Type 2 no treatment
Describe Tay Sachs disease
Tay-Sachs disease
• Less common
• Defects in B-hexaosaminidase enzymes which leads to accumulation of the gM2 ganglioside
• Autosomally recessive incidence 1 in 320,000 - higher in some ethnicities- more than 100 different mutations
• Diagnosis by enzymes
What are the three subtypes of Tay sachs disease describe them?
- Infantile TSD- most common normal development but after six month relentless deterioration of mental and physical abilities. Child becomes blind, deaf, paralytic until finally death by age of 5. A common mutation is an our base pair insertion on exon 11. - framehsift so no residual activity
- Juvenile TSD- extremely rare children die between 5 and 15 years
- Late onset TSD- symptoms begins in 20s and early 30s usually non-atlas Progressive neurological deterioration psychotic episodes, physical difficulties. Wheelchair bound
variability due to compound heterozygosity
What is the treatment for Tay sachs?
There is no cure or treatment ERT is difficult due to blood brain barrier which is hard to get through
How can disease be prevented?
Prenatal diagnosis
Preimplantation genetic diagnosis
Mate selection
Describe hunters disease?
Hunters disease
* Defects in iduromate suphatase enzymes leads to an accumulation of glycosaminoglycans- affects turnover
* Very rare linkeD X condition- affects mainly males
* Diffifucalt to diagnose early on, symptoms at 1 year old as the GAG begin to accumulate leading to specific physical features including distended abdomen, large head and tongue
* Over time joint become stiff and brain development is affected leading to mental retardation
* Severe and mild forms- even mild forms lead to death in 30S
* Severe forms related to neurodegeneration/ respiratory problems with death usually before adulthood
* Treatment for the less severe from has involved enzyme replacement therapy
