Abstract
Mutations in the NOTCH3 gene are responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an adult onset hereditary angiopathy leading to ischemic stroke, vascular dementia and psychiatric disorders. All mutation of NOTCH3 described so far are striking stereotyped leading to the gain or loss of cystiene residue in a given epidermal growth factor (EGF), like repeat. We report an Arabic family affected with CADASIL mutation, G1790 C, in Exon 11 of the NOTCH3 gene. This is the first novel mutation reported in Arabic CADASIL patients. This finding confirms that mutations in NOTCH3 are associated with the pathogenesis of CADASIL across different ethnic background.
Highlights
CADASIL is an autosomal dominant vascular disorder clinically characterized by a variety of symptoms including migraine with aura, mood disorder, vascular dementia, ischemic stroke and premature death.[1,2,3] The vascular lesions underlying CADASIL are a non-arteriosclerotic, non-amyloid arteriopathy affecting small cerebral arteries with accumulating of granular and osmiophilic materials within the smooth muscles cell basement membrane.[4,5] This initial thickening and expansion of the extracellular matrix can be found to a lesser extent in extra cerebral arteries such as skin arterioles.[5]Mutation in the NOTCH3 gene is usually linked to CADASIL.[6]
All mutations are located within the epidermal growth factor (EGF) repeats in the extra cellular domain of the NOTCH3 gene and a strong clustering of the mutation were observed in Exon 3 and 4.8,9 there are more than 150 mutation have been identified. (The human gene mutation database www.hgmd.org), CADASIL is far more common than previously perceived and it may often be misdiagnosed because it can present under various guises.[10]
We described for a first time, a native Arabian family with CADASIL which harbor a novel mutation in NOTCH3 genes
Summary
CADASIL is an autosomal dominant vascular disorder clinically characterized by a variety of symptoms including migraine with aura, mood disorder, vascular dementia, ischemic stroke and premature death.[1,2,3] The vascular lesions underlying CADASIL are a non-arteriosclerotic, non-amyloid arteriopathy affecting small cerebral arteries with accumulating of granular and osmiophilic materials within the smooth muscles cell basement membrane.[4,5] This initial thickening and expansion of the extracellular matrix can be found to a lesser extent in extra cerebral arteries such as skin arterioles.[5]. The proband is a male seen at age of 37 years with 2 years history of recurrent throbbing headache with visual aura, and four months history repeated attacks of numbness in left side. These attacks suggestive of TIA, he is smoker, otherwise, no systemic disorder. His mother died at age 52 after 7 years history of repeated strokes and dementia (Figure 1). One younger sister suffered from migraine started at age 32 years and her neurological exam was normal. MRI brain of the index a case and his brother, sister and mother showed multiple deep white matter lesions (Figure 2) in temporal and periventricular regions (A-D) and in basal ganglia, thalami and pons (E&F)
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