Management And Genetic Counseling

The broad variety of CADASIL symptoms in affected families often leads to its underdiagnosis and misdiagnosis. A truly negative family history by no means excludes this diagnosis because a patient with a de novo Notch3 mutation has been reported.[17] Consequently, patients presenting with neurological deficits, leukoaraiosis, and a positive family history will benefit from a mutation analysis of hotspot 3-4-5-11EGF-encoding exons. In

In the absence of stenosis and occlusions in CADASIL vasculature, hemodynamic troubles need to be explained in the light of typical vessel changes. The extensive destruction of VSMCs and pericytes suggests that hypo-tonicity may play a more important role in the patho-genesis of cerebral ischemia than vascular occlusion. Several studies, employing different specialized imaging techniques, have indicated a reduced baseline cerebral blood flow and a reduced cerebrovascular reactivity in CADASIL patients and in asymptomatic mutation carriers.1-20-22-1 Moreover, diffusion tensor MRI and proton

MR spectroscopy studies indicate that cerebral tissue damage is much more widespread than is evident on conventional MRI.[21'22] It correlates with previous pathological observations, showing a diffuse angiopathy as severe in WM as in the cortex[5,6] but with different consequences depending on the vascular density.[5,6] Interestingly, the dependence of endothelial permeability on the presence of pericytes was recently demonstrated.1-23-1 Pericyte alteration and destruction observed in CADASIL probably result in a decrease in permeability because VSMCs and pericytes secrete vascular endothelial growth factor (VEGF), a growth factor that is also the most potent permeability factor.[24] Therefore, leukoaraiosis could be the result of both oligemia and decreased permeability. The latter could explain why the only tissues affected are those depending on the blood-brain barrier because all the exchanges rely on a perfectly working capillary bed.

Now, the utmost question is: On the molecular and cellular levels, what sequence of events leads from Notch3 mutation to the characteristic VSMC alterations? Recent data suggest that trafficking and localizing, rather than signaling, of Notch3 are affected: cultured human embryonic kidney cell lines expressing mutant Notch3R142C showed a higher propensity to form intracellular aggre-gates.[13] On the opposite, the link between this cleavage product and the VSMC destruction is not explained.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

Get My Free Ebook

Post a comment