A Rare Mutation Associated with Cerebral Arteriopathy with Subcortical Infarct and Leukoencephalopathy (CADASIL) (P2-5.002)

Abstract

<h3>Objective:</h3> To report a rare cause of CADASIL with a point mutation in exon 5 of NOTCH 3 gene causing a non-cysteine change and its implication. <h3>Background:</h3> CADASIL is a rare genetic non-amyloid arteriopathy primarily affecting small brain vessels. Its prevalence in population is 2 to 5/100,000, but may be underestimated and underdiagnosed. Although there is over 200 different NOTCH-3 mutations described worldwide, 95% of them are missense mutation in the exons 2–24, which leads to a gain or loss of a cysteine residue in one of 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. Non-cysteine mutations are rare and their role is not well determined. <h3>Design/Methods:</h3> Case report <h3>Results:</h3> 58-year-old man with a three-year progressive cognitive decline, history of headaches, fatigue, and generalized weakness was admitted to the neurology wards for worsening weakness and increased need for assistance in daily life. Neurological exam was significant for mild left hemiparesis. MoCA score was 19/30. Brain MRI showed one subacute and numerous chronic lacunar ischemic strokes including in the corpus callosum, also seen on previous outpatient MRIs. These changes had been attributed to demyelinating disease by the outpatient physician. An extensive workup including autoimmune was unrevealing. Classical leukoencephalopathy was not present, but hyperintensities in the temporal lobe raised concern for CADASIL. DNA sequencing revealed a non-cysteine mutation with c.754 G&gt;A transition in exon 5 of NOTCH 3 gene resulting in a substitution of Valine to Methionine (V252M). This is the second case of this mutation reported in the literature. Non-cysteine mutation may affect NOTCH-3 signaling output and possibly lead to a milder leukoencephalopathy and extensive involvement of corpus callosum with lacunar infarctions resembling demyelinating disease. <h3>Conclusions:</h3> CADASIL with a point mutation in exon 5 of NOTCH 3 gene causing a non-cysteine change may present with milder disease and not classical MRI changes. <b>Disclosure:</b> Dr. Delpirou Nouh has nothing to disclose. Dr. Mahmoud has nothing to disclose. Juliane Chainakul has nothing to disclose. Robert Hamilton has nothing to disclose. Dr. Sidorov has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Allergan. Dr. Sidorov has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BioHaven .