Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited adult-onset leukodystrophy, characterized by migraine headaches, recurrent transient ischemic attacks (TIA), cognitive impairment, and psychiatric dysfunction. The pathophysiology of this condition is related to abnormalities in blood flow of small vessels, especially those of the brain. CADASIL is an adult-onset disease, with the first signs typically presenting in the fourth decade of life. Symptoms initially start off with migraine with aura, transient ischemic attacks or strokes, and/or mood disorders, such as depression. The recurrence of multiple strokes leads to cognitive defects, progressive memory loss, dementia, and hemiparesis. Affected patients may also rarely present with epileptic seizures.
The standard test for diagnosis of CADASIL uses electron micrographic analysis of skin biopsies, which reveal electron-dense granules in the media of arterioles. MRI studies show lesions around the basal ganglia, periventricular white matter and the pons. Interestingly, these lesions can be seen in individuals even before the first symptoms appear. However, definitive diagnosis requires genetic identification of mutations in the NOTCH3 gene. There is no specific treatment for the condition. Since patients are very likely to be affected with cerebrovascular complications, the use of anti-platelet agents is recommended as a preventive measure. Other risk factors for stroke, such as smoking, and the use of contraceptive pills, should also be avoided. Patients are advised to manage the disease by adopting a healthy lifestyle. CADASIL is a disease with a slow progression. By the seventh decade of their life, most patients suffer from severe cognitive impairment and dementia, and may become completely dependent.
The NOTCH3 gene is the only gene known to be implicated in the pathogenesis of CADSIL. The NOTCH genes are known to encode for membrane bound proteins that interact with ligands and play a key role in neural development in drosophila. The exact function of the human homologues of this gene is not known. However, it is likely that the gene is involved in influencing the transcription of certain genes implicated in the function and survival of vascular smooth muscle cells. Mutations in this gene may, therefore, cause these cells to die, resulting in a destruction of the arterial walls, and loss of blood supply. In addition, the abnormal NOTCH3 protein tends to aggregate in the cranial blood vessels.