Leukoencephalopathy (Leukoencephalopathy) - Gen NOTCH3.

Disease CADASIL (Cerebral autosomal dominant arteriopathy With subcortical infarcts and leukoencephalopathy) is a dominantly inherited disease autosomal low prevalence, characterized by oclusionar small arteries in the brain, affecting the central nervous system by transient ischemic attacks, strokes, vascular dementia, migraine with aura and psychiatric disorders. Follows an autosomal dominant pattern and, unlike other diseases of genetic origin, rarely a de novo mutation occurs, being the cause, in the vast majority of cases inherited from parents.

CADASIL disease is caused by a mutation in the gene NOTCH3, located on the short arm of chromosome 19 (19p13.2-p.13.1) and constituted by a total of 33 exons encoding a receptor for 2321 amino acids with a single domain transmembrane. This gene belongs to the family of Notch genes, consisting of four members who play an important role during development, expressed in different tissue types. The products of the genes Notch transmembrane receptors are linked to signaling processes and intercellular communication. The NOTCH3 gene encodes a transmembrane receptor with an extracellular domain containing 34 tandem repeats similar to epidermal growth factor (EGF: Epidermal Grow Factor) factor.

The mutations described in the gene NOTCH3 determine gain or loss of a cysteine residue in the extracellular portion of EGF receptor. Thus, instead of there being 6 cysteines in the EGF residues, an odd number of these (5 or 7) is generated by altering the formation of disulfide bridges. This change in cysteine residues at odd pairs produces a conformational change in the extracellular segment, resulting in an abnormal cleavage which causes extracellular accumulation of abnormal protein.

Tests performed in IVAMI: in IVAMI perform the detection of mutations that cause the loss or gain of a cysteine residue in the extracellular regions of NOTCH3 gene associated with CADASIL, by PCR amplification and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).