The Pathogenesis of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL, OMIM #125310) - Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, OMIM #125310) is a rare hereditary systemic vasculopathy and an example of pleiotropism i.e. single gene effects on multiple phenotypic traits. CADASIL is the most common monogenic form of hereditary cerebral microangiopathy disorder manifesting usually in early adulthood which cause a highly stereotyped mutations within the extracellular domain of the NOTCH3 gene. NOTCH3 mutations within the receptor extracellular domain, lead to abnormal extracellular matrix accumulation of granular osmiophilic
material (GOM) in the close vicinity of vascular smooth muscle cells (VSMCs) and around small caliber arteries and arterioles, eventually leading to a progressive loss of VSMCs.
In the brain, degeneration of smooth muscle cells in small arteries results in an impaired cerebral blood flow, arteriolar stenosis and lacunar infarcts, mainly in cerebral white matter and deep gray matter. Affected individuals exhibit a variety of symptoms, and clinical presentation of CADASIL varies even among
and within families. The disease is characterized by six main symptoms: migraine with aura, subcortical ischemic events, mood disturbances, apathy, cognitive impairment and subcortical dementia.
Usually, at the age of 30–50, patients begin to suffer from recurrent transient ischaemic attacks (TIAs) or ischaemic strokes due to subcortical lacunar infarcts. These will eventually lead to a progressive cognitive decline, psychiatric disorders, and to a subcortical type of vascular dementia. Strokes are typically ischemic, while hemorrhagic events have been only sporadically described. However, cerebral microbleeds have been found in 31-69% of CADASIL patients.
CADASIL phenotype is highly variable and although the full clinical-neuroimaging picture may be suggestive of the disease, three methods are usually needed to confirm the diagnosis of CADASIL: The genetic testing; skin biopsy and MRI. However, a genetic test remains the diagnostic gold standard to confirm the diagnosis and to identify a mutation in the underlying gene NOTCH3 encoding a transmembrane receptor protein, which is caused by at least 200 mutations in the NOTCH3 gene at locus 19p13.1–13.26. NOTCH3 mutations are usually assessed by restriction enzyme analysis of specific mutations or by sequence analysis; pathological test used to identify the GOM deposition around VSMCs examined by electron microscopy (EM) in skin biopsies is extremely helpful and considered a specific diagnostic tool for CADASIL. In addition, imaging abnormalities in CADASIL evolve as the disease progresses: Typical MRI findings are T2 weighted hyperintensities in white matter and the capsula externa, Subcortical lacunar lesions (SLLs) and Cerebral microbleeds are usually seen. No specific treatment is available at present, but only symptomatic treatment is obtainable. In this review we will discuss briefly the pathogenesis of CADASIL and on the mutations of NOTCH3 gene.