Samenvatting van de colleges van het deel pathofysiology van het vak Medical biochemistry and pathofysiology tijdens het derder jaar van de bachelor biomedische wetenschappen aan de UvA
Many metabolic diseases can be treated if you know the reason of the disease.
In metabolic disorder one enzyme is defect in a metabolic pathway conversion
step doesn’t take place. So the substrates will be high and the products will be
low.
Diagnostic options
- Metabolite analysis in plasma, urine, tissue etc.
- Enzyme measurement in cells, tissues
- Mutation analysis in DNA
Mevalonate kinase converts mevalonate to mevalonate P. MKD (mevalonate
kinase deficiency) mevalonic aciduria and hyper IgD syndrome.
Squalene Sqs deficiency.
Very many defects in the conversion pathway of lanosterol to cholesterol. Many
are very severe and can be fatal.
Hyper IgD and periodic fever syndrome (HIDS)
- Autosomal recessive disorder
- Rare but most common in Netherlands (>100)
- Symptoms during fever
o Swollen lymph nodes
o Enlarged spleen
o Abdominal pain, vomiting, diarrhea
o Joint pains
o Skin rash
- Blood chemistry during fever episodes
o Granulocytosis and monocytosis
o Elevated ESR, CRP and SAA
o Elevated IL-1beta and TNF-alfa
- Onset <1 year (vaccinations)
- Often no clear cause
- Provoked by vaccinations, small infections, stress, trauma etc.
- Episodes last 3-7 days
- Recurrent every 3-12 weeks
- No effective treatment
- Autoinflammatory disease!
,Autoinflammatory disease
- Characterized by lifelong recurring, seemingly spontaneous episodes of
fever and inflammation (no antibodies)
- Due to dysregulation if innate immune system
- Often associated with increased/prolonged production of pro-inflammatory
cytokine IL-1beta
- Inherited
o Familiar meditrranean fever (FMF)
o TNF-receptor associated periodic fever syndrome (TRAPS)
o Cryopyrin associated periodic fever syndrome (CAPS)
o Hyper-IgD and periodic fever syndrome (HIDS)
Inflammasomes proteins present in immune system and are usually inactive. If
body senses danger signals they open up and convert procaspase 1 to caspase
1. This activates other proteins that activate the inflammatory reaction.
MA is more severe than HIDS. Have also more problems with mental retardation
and large spleen and liver. Most patients die within 5/6 years of life. Also have
the common fever symptoms of HIDS.
With MA the activity of the mevalonate kinase is way lower than with HIDS. There
are different places on the gene where mutations can take place, but the V377I
mutation is only found in HIDS and is thought to have something to do with the
less severe symptoms.
HIDS is due to temperature-sensitive mutation temporary block in isoprenoid
biosynthesis which prevents timely availability of isoprenoid end products
involved in immune regulation
Is end product feedback regulation in isoprenoid biosynthesis pathway. So if
levels of product increase it inhibits enzyme in beginning pathway.
Because MK activity is low, then HMG-CoA activity increases to try to make
enough end product. In HIDS slightly elevated, while in MA high increase.
Onset of fever MK activity blocked so end products no longer made
During fever end products start to decrease in amount so get increase in
HMG-CoA reductase
End of fever get so much mevalonate that eventually will be converted by MK
so end products made again
Which isoprenoids are limiting and contribute to inflammatory phenotype of HIDS
Geranylgeranyl-PP geranylation (RhoA GTPases)
- Is limiting in MKD-HIDS
- By adding precursor of this, you reduce HMG-CoA reductase activity. This
also causes less IL-1beta secretion.
- If this step is limited than there is way more secretion of IL-1beta
- If this step doesn’t take place there is incorrect activation of Rho GTPases
o Normally inactive in GDP form and bound to GDI. If it becomes
active with GTP and is bound to effector and GEF in membrane. This
causes signal transduction
o Rho is mostly active in membrane and not in cytosol
- In HIDS it is in high temperatures active in cytosol and not in membrane
2
, o Rho not bound to GDI and becomes active in cytosol and gives
incorrect signaling. Not bound to effector and GEF
Incorrect activation of GTPases can increase inflammasome, but also in pro-IL-
1beta but maybe also in inflammation. But is not sure
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