| Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( CADASIL ) is an adult-onset genetic stroke. It involves the small vessels all over the body , without arteriosclerosis or amylosis.The most frequent manifestations of CADASIL include one or more of the following : recurrent ischaemic episodes ( transient ischaemic attacks or stroke), cognitive decline or dementia , migraine with or without aura, and psychiatric disturbance. The diffuse white matter hyperintensities ( WMH ) and subcortial lacunar leasions are detected by magnetic resonance imaging ( MRI) in the deep portion of brain. Cranial magnetic resonance imaging with T2-weighted hyperintense signals in the temporopolar white matter or the external capsule are the typical features of CADASIL. The natural history suggests a chronological clinicoradiological staging of the phenotype of CADASIL: stage I between 20 and 40 years with frequent migraine-like episodes and well delineated lesions of the white matter; stage II between 40 and 60 years with stroke-like episodes, bipolar or monopolar-like psychotic disorders, coalescent lesions of the white matter, and well delineated lesions of the basal ganglia; and stage III over 60 years with subcortical dementia, pseudobulbar palsy, diffuse leukoencephalopathy, and multiple well delineated lesions of the basal ganglia. Several studies revealed that the phenotype of CADASIL varies among unrelated families . The spectrum of disease is broad , it often indistinguishable from other neurological disorders such as multiple sclerosis, lacunar stroke with leukoaraiosis, and adult onset leukoencephalopathy. This makes the clinical diagnosis difficult and impiles it may be misdiagnosed or underestimated in the wilder population .Small vessels abnormalities is the leading cause for CADASIL. The diagnostic hallmark of the disease is the presence of deposits of granular osmisopilic material ( GOM ) in the small vessels on electromicroscopy which can be detected not only in the vessels of brain , but also in the skin , muscle tissue and other organs. Nevertheless , the nature , resource and function of GOM are still unknown. Skin biopsy is wildly used in clinic now. It is a important method for diagnosis with a specificity 100% and sensitivity about 45%～57%,that results in a false negative outcome.The disease is caused by mutations in the NOTCH3 gene, which encodes a trans-membrane receptor involved in cell signaling and cell differentiation. Almost all the mutations described up to now result in a gain or loss of one cysteine residue in one of 34 epidermal growth factor-like ( EGF-like ) repeats. However, the pathogenic mechanism of disease associated with genetic mutations is unclear .To date, more than 170 NOTCH3 mutations have been characterized in more than 400 CADASIL families . The mutational spectrum of CADASIL includes missens mutations, splice site mutaions , and small in-frame deletions . The majority of mutations are missense mutations (about 95%). Clustering of mutations around exon 2-6 (almost 90%) and especially exon 4 was reported and it was subsequently suggested that scanning should be limited to these exons for quick identification of suspected cases . However , further studies of the spectrum of NOTCH3 gene mutations in different geographyically localized population and revealed significant diverce from each other . It may be explained by the varies resource of population and suggests that the different population patients been should be considered when we decide to make the diagnostic strategies . Complete NOTCH3 gene mutation analysis is expensive and time consuming because of the large number of exons, and it is therefore unsuitable for routine diagnosis. Minor studies were reported aboard to describe the congruence between skin biopsy and NOTCH3 gene mutation analysis, they found a relatively high cohort between these two methods. Skin biopsy is a very reliable diagnostic method, and the sensitivity may be raised by the improvement of the technique , such as screening more vessels on electromicroscopy , and repeating the biopsy several times . Till now , a series of internal studies described several missense N0TCH3 gene mutations on exon 3,4,6,11,18, and did not show cluster of mutations . However, none of the studies had the diagnosis been systematically confirmed by biopsy.In the present study , Skin biopsy were used to diagnosis the suspect cases based on the clinical manifestations, typical MRI changes ,and /or a positive family history. Retrospective analysis of clinical features and N0TCH3 gene sequencing in patients with CADASIL were made to find out the characteristics of CADASIL, the spectrum of N0TCH3 gene mutations , and also the consequence of skin biopsy and gene detection . Our study may contribute to futher diagnosis of CADASIL , and understanding of the complicated relationship between genotype and phenotype in CADASIL.The study include the following two parts :Part 1 CADASIL clinical characteristicsAbstract Objective To investigate the clinical features, hereditary pattern, neuroimaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in CADASIL families and sporadic patient.Methods The retrospective studies on the clinical manifestations, neuroimaging characteristics, pathology and molecular genetics was performed in 6 probands and 23 family members from different CADASIL families and 1 sporadic patient.Results 1.The main clinical features of the proband including history of recurrent ischemic stroke, poor memory /cognition or dementia were noted; 2. The frequency of migraine may be unusual, the Chinese CADASIL can present the post circulation symptoms predominantly; 3. Neuroimaging examination showed subcortical multiinfarct lesions and leukoencephalopathy, primarily in frontal and parietal lobe. 5. Electron microscope examination of the skin: biopsy indicated thickening of basement membrane and presence of granular osmiophilic material (GOM) in the arterioles including 2 symptomatic patients with norma MRI and 1 patient without any symptom.Conclusions 1. Typical clinical features of CADASIL as follows: recurrent ischaemic attacks, cognitive decline, dementia and psychiatric disturbances ; 2. Low frequency of migraine is a rare characteristic of Chinese CADASIL patients, however the post circulation symptoms is predominant presentation ; 3. The frontal and parietal lobe are often involved in CADASIL patients, while the subcortical multiinfarct lesions and leukoencephalopathy are considered the characteristic MRI abnormalities.Part 2 N0TCH3 gene mutation detectionObjective Analysis the N0TCH3 gene mutations inbiopsy-proven patients with dominant arteriopathywith subcorticalinfarcts and leukoencephalopathy (CADASIL), in order to find out themutation spectrum in China, and give some advices for future diagnosis .Methods 1. Including 6 biopsy-proven CADASIL index cases and12 sporadic samples with GOM deposite ,were sequenced on exon 2 to 33of N0TCH3 gene to determine the specific mutation or polymorphismrespectively; 2. Family members from these CADASIL families were also sequenced to determine the specific mutation; 3. Analysis the mutation spectrum of domestic CADASIL patients, and the concequence of skin biopsy and gene detection.Results Three heterozygous missense mutations including C182R, C185Y, R544C located in the exon 4 and exon 11 were found in 2 probands. The mutation of C182R in exon 4 is a novel mutation which has not been reported previously in China , however, the mutation of C185Y in exon 4 is a novel mutation which has not been reported in other regions. 100 controls did not found such a mutation .And 5 cases of CADASIL were among the 3 families. 15 polymorphisms were found at the same time .Conclusions 1. C185Y in exon 4 is a novel mutation which has not been reported in other regions; 2. The first sporadic CADASIL patient was confirmed by R182C mutation in exon 4 , which is reported in China for the first time. |
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