| Background:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy(CADASIL)is a rare inherited small-vessel disease caused by mutations in NOTCH3,characterized by attacks of migraine with aura,recurrent subcortical ischemic events,vascular dementia,and psychiatric disturbances.The mutation types vary in different regions,and the clinical heterogeneity is prominent of one mutation.Despite the large population,few CADASIL cases in Shandong province were reported.Objective:To investigate the clinical heterogeneity and mutation types of CADASIL patients in Shandong,improve the understanding of CADASIL,and reduce missed diagnosis and misdiagnosis.Methods:This study collected CADASIL patients from Qilu Hospital of Shandong University and Shandong Provincial hospital with confirmed mutations in NOTCH3 and non-CADASIL patients with the typical clinical manifestations of CADASIL from Qilu Hospital of Shandong University from May 2014 to May 2020,as well as cases reported in the literature referring to Shandong province.Demographic,clinical and genetic data were statistically analyzed.The application value of CADASIL screening scale was compared and analyzed by receiver operating characteristic curve(ROC curve).Results:1.General features:Among 26 CADASIL patients,12(46.15%)were male while 14(53.85%)were female.The onset age ranged from 12 to 74 years old,with the mean age of 37.62±12.92 years old.Among 23 patients with available medical records,the mean time interval from onset to definite diagnosis was 7.22±10.17 years.Eight of them were diagnosed definitely at the initial while 15 were missed or misdiagnosed.Three patients were diagnosed with multiple sclerosis and received corticosteroid therapy.In addition,thirteen patients had a family history of cerebrovascular disease and twelve patients had the risk factors of cerebrovascular disease.2.Clinical presentations:The most common symptoms were focal neurological deficits,such as aphasia;movement disorder,sensory disorder,or the combination of these symptoms(n=10,43.48%),followed by headache(n=6,26.09%)and dizziness(n=6,26.09%).One patient developed Parkinson’s syndrome after lower limbs mobility dysfunction at first.The mean onset age of patients with headache was significantly smaller than others(P=0.036),while patients with dizziness were significantly older(P=0.019).Moreover,motor and/or sensory disorders and aphasis(n=16,69.57%),cognitive impairment(n=8,34.78%),pyramidal sign(n=7.30.43%),pseudobulbar palsy(n=7,30.43%)and mental disorders(n=4,17.39%)were found at the time of diagnosis.3.Imaging examinations:Twenty patients had undergone brain magnetic resonance imaging scanning.Paraventricular and deep white matter lesions were observed in all of them,where the number of temporal pole lesions was as much as the external capsule(n=14,70.00%).Infratentorial structure was involved in 12 patients(60.00%).The Fazekas scale score of white matter lesions ranged from 2 to 6,with a median of 5.5.There was no significant difference in the score between young and middle-old age patients(P=0.315),and the same results were seen in two patients groups with or without cerebrovascular risk factors(P=0.656).Among 11 patients received susceptibility weighted imaging sequence examination,4 had deposition of paramagnets in bilateral basal ganglia,and 4 showed cerebral microbleeds in subcortical and infratentorial areas.Sixteen patients were performed magnetic resonance angiography or digital subtraction angiography,and mild to moderate vascular stenosis was revealed in 4 of them.4.Gene mutations and phenotypes:Eighteen different mutation sites of NOTCH3 gene were detected,which were most common on exon 3,exon 4 and exon 11,and mutations on exon 2,5,18,20 and 25 were relatively rare.In this study,20 patients had mutations on the hot spots of NOTCH3 gene,including exon 4(9 cases),exon 3(8 cases)and exon 11(3 cases).Six patients had mutations of the non-hot spots,including exon 20(2 cases),exon 2(1 case),exon 5(1 case),exon 18(1 case)and exon 25(2 case).None of the patients with non-hot spots showed white matter hyperintensities on temporal polar,and the difference was statistically significant(P<0.001).Nineteen patients had mutations in the EGFR domains 1-6 of NOTCH3 protein,and seven patients had mutations in EGFR domains 7-34.The latter had a significantly lower incidence of white matter hyperintensities on temporal polar(P=0.037).Four patients carried cysteine-sparing NOTCH3 missense gene mutations of exon 3,who did not have white matter lesions involving the infratentorial structure,and the difference was statistically significant(P=0.049).5.The evaluation of CADASIL screening scaleNineteen patients were tested by two kinds of CADASIL screening scales.The sensitivity of the CADASIL Scale and CADASIL Scale-J Scale was 52.63%(10/19)and 68.42%(13/19),respectively.The specificity was 100%(10/10)in the control group.Conclusions:1.CADASIL mostly first occurs at the young age,while individual patients develop at the adolescent or late age.It is relatively common to see patients with cerebrovascular risk factors or intracranial large vessel stenosis in this study.2.Focal neurological deficit is the common first symptom of CADASIL patients in Shandong Province,which can occur from young to old age.Patients whose first clinical manifestation is headache are obviously younger than others,while patients with dizziness at the onset are older.3.The most common lesions of CADASIL involve deep periventricular white matter(of cerebral hemisphere)and pons(of brainstem)on the brain MRI image.4.There are various types of NOTCH3 gene mutations in CADASIL patients in Shandong,and exon 4 mutation is the most frequent.Bilateral temporal pole involvement may be the characteristic of patients with mutations involved in hot exons or the EGFR domains 1-6.5.In this study,nearly half of CADASIL patients were missed or misdiagnosed at the first onset.Compared with CADASIL Scale,CADASIL Scale-J is more suitable for initial screening. |
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