Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) NOTCH3 gene

CADASIL disease (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), also known as familial vascular leukoencephalopathy, is a low prevalence autosomal dominant inherited pathology, characterized by the obstruction of small arteries in the brain. It affects the central nervous system, producing transient ischemic episodes, cerebral infarctions, vascular dementia, migraine with aura and psychiatric disorders. Many people with CADASIL also develop leukoencephalopathy, which can be seen with magnetic resonance imaging (MRI).

The age of onset of the signs and symptoms of CADASIL, as well as their severity, varies widely among affected people. This disease is not associated with the usual risk factors for apoplexy and heart attacks, as are high blood pressure and high cholesterol, although some of the affected individuals may also have these problems.

CADASIL disease is due to mutations in the NOTCH3 gene, located on the short arm of chromosome 19 (19p13.12). The NOTCH3 gene consists of a total of 33 exons that encode a 2.321 amino acid receptor with a single transmembrane domain. This gene belongs to the NOTCH family of genes, composed of four members that play an important role during development, expressing themselves in different types of tissues. The products of NOTCH genes are transmembrane receptors linked to signaling and intercellular communication processes. Specifically, the NOTCH3 gene encodes a transmembrane receptor with an extracellular domain that contains 34 tandem repeats of a factor similar to epidermal growth factors (EGF: Epidermal Grow Factor).

More than 270 mutations in the NOTCH3 gene responsible for CADASIL have been described. Almost all of these mutations change a single amino acid in the Notch3 receptor. The amino acid involved in most mutations is cysteine. The addition or removal of a cysteine ​​molecule in a particular area of ​​the Notch3 receptor, known as the EGF type domain, presumably affects the function of the Notch3 receptor in vascular smooth muscle cells. The interruption of the functioning of Notch3 can cause apoptosis or death of these cells. It is believed that damage to vascular smooth muscle cells is responsible for recurrent cerebrovascular accidents and other signs and symptoms of CADASIL.

This disease is inherited with an autosomal dominant pattern, which means that one copy of the altered NOTCH3 gene in each cell is sufficient to express the disease. In most cases, an affected person inherits the mutation of an affected parent. Some rare cases may be due to new mutations in the NOTCH3 gene. These latter cases occur in people with no history of the disease in their family. 

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), by means of the complete PCR amplification of the exons of the NOTCH3 gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).