Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare autosomal-dominant hereditary disease of the small arterial vessels in the brain. It is clinically associated with subcortical ischemic events, migraine-type headache, mood disturbances (including apathy), cognitive impairment and other clinical manifestations (such as intracerebral hemorrhage, territorial infarct, deafness and Parkinsonism).1 CADASIL is a single-gene disorder caused by mutations in the NOTCH3 gene, located on chromosome 19p13. NOTCH3 encodes a transmembrane receptor which plays a role in cellular differentiation and cell cycle regulation.2 In this study, we have uncovered a novel NOTCH3 mutation at the nucleotide position 499 (c.499C>T; p.P167S) in a family with CADASIL. We reported a case of a 71-year-old female showing headache and memory impairment, familial history of stroke and having a missense mutation from proline to serine at codon 167 in the exon 4 on NOTCH3 gene.

A 71-year-old female patient was admitted to the neurology outpatient clinic. She had suffered from chronic headaches and memory disturbance for 20 years. The headache was characterized as dull and pulsating in the bilateral temporal area. The absence of nausea, vomiting and visual or auditory symptoms eliminated the possibility of migraine. Her cognitive examination revealed a Korean Mini-Mental State Examination score of 26 and a Clinical Dementia Rating score of 0.5. The results from a complex neuropsychological test indicated a mild cognitive impairment. No other neurological symptoms were observed. The patient was a non-smoker with minimal alcohol consumption. Hypertension and hyperlipidemia had been well controlled in the patient for 8 years. There was a familial history of stroke; both of the patient's parents and three siblings had suffered a stroke previously (Fig. 1A).

Initial laboratory findings were normal. Magnetic resonance imaging of the brain revealed bilateral confluent high-signal changes in the periventricular, subcortical and left external capsular white matter ischemic lesions and microbleeds in the temporal and right parietal lobe (Fig. 1B and C). Targeted analysis of exon 4 in the NOTCH3 gene of five family members (two brothers and one sister, two sons) revealed that one sibling and her first son had the same mutation (c.499C>T), who had migrainous headache and stroke. His magnetic resonance imaging of the brain revealed high signal changes in the subcortical and right external capsular white matter ischemic lesion (Fig. 1D). Analysis of exon 4 in the NOTCH3 gene showed uncovered unclassified sequence variant (c.499C>T) (Fig. 1E).

We identified a missense mutation of proline to serine at codon 167 in exon 4 of the NOTCH3 gene, which resulted in the substitution of cytosine to thymine (c.499C>T) resulting migraine, stroke and vascular cognitive impairment. CADASIL is clinically associated with subcortical ischemic events, migraine-type headache, mood disturbances (including apathy), cognitive impairment and other clinical manifestations (such as intracerebral hemorrhage, territorial infarct, deafness and Parkinsonism).1 The NOTCH3 gene has 33 exons and most mutations are located within exons 2-23. In Korea, particularly Jeju Island, the most common mutations are found in exons 3, 6 and 11, such as the p.R544C mutation in exon 11.3

A diagnosis of CADASIL in the patient was extremely probable based on a score of 17 on the CADASIL scale (cognitive decline/dementia, leukoencephalopathy extended to external capsule, subcortical infarcts, family history in at least two generations, ranging from 0 to 25).4 There are some debates whether c.499C>T mutation in the NOTCH3 gene is responsible for the patient's condition. It has been known Cys-sparing mutation, P167S, is considered as a rare polymorphism rather than CADASIL-causing mutation, because; 1) P167S (rs202157633) is already reported as an east Asian-specific rare variant (five heterozygous individuals among 504 individuals, minor allele frequency=0.005, 1000 Genome phase 3.56 2) Prediction of functional effect of P167S was tolerated (sorting intolerant from tolerant) or benign (polymorphism phenotyping).7 However, some report suggested that possibility of same NOTCH3 gene mutation has different pattern with typical CADASIL.8 Although further background study is necessary for proving this theory, we suggested that this missense mutation is CADASIL rather than polymorphism in this family in the points that patient showed headache and memory impairment and other family members with same mutation presented CADASIL-like symptoms such as headache, stroke, or vascular cognitive impairment.

Our study has some limitations. We were unable to analyze those deceased family members who suffered from stroke and were therefore most likely to carry the mutation. Additionally, the living family member (son) with the c.499C>T mutation appears to be minimally affected. We will monitor this patient closely in the future for symptoms of CADASIL.

In conclusion, this study has suggested the possibility that missense variant of p.P167S in NOTCH3 gene has contributed to our knowledge of CADASIL and related genetic disorders.