Clinical Analysis Of Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts And Leukoencephalopathy

ObjectiveTo report the clinical characteristics of cerebral autosomal recessive arteriopathywith subcortical infarcts and leukoencephalopathy(CARASIL)in two families,and HTRA1 gene variation was detected and analyzed.By searching the clinical data of CARASIL patients with gene diagnosis reported at home and abroad,the clinical characteristics,imaging manifestations,pathological manifestations and HTRA1 gene mutation of CARASIL were summarized,so as to improve the understanding of CARASIL,reduce misdiagnosis and missed diagnosis,and provide broader ideas for further research.MethodsThe clinical data and imaging characteristics of 4 CARASIL patients from 2 families admitted to the department of neurology of the first affiliated hospital of Zhengzhou university in 2017-2018 were retrospectively analyzed,as well as skin biopsy and HTRA1 and Notch3 gene tested.In the domestic information database of relatively complete,the range is relatively wide:Wanfang data,Vip data,CNKI and abroad PUBmed,EMbase to have a related literatures retrieval,and collecting accord with a standard CARASIL cases,a total of 26 cases,combined with our 4 cases,a total of 30 cases,sorting and analyzing all of the patient’s clinical manifestations,imaging features and pathological manifestations and genetic testing.The collected data would be processed,analyzed and summarized by using SPSS 22.0.Results1.Family 1:the proband had consanguineous parents.Under the light microscope of skin biopsy,pigmentation in the basal layer of the skin could be seen,collagen fiber hyperplasia in the dermis was accompanied by a small amount of inflammatory cell infiltration,and no definite amyloidosis was found.A homozygous mutation C to T transition at position 589(c.589C>T)was found in exon 3 of HTRA1 gene with the proband and both siblings.The heterozygous c.589C>T mutation appeared in another sister of the proband.Because the patient’s parents were deceased,genetic testing was not possible.Family 2:the proband also had consanguineous parents.The proband had a homozygous mutation of c.714C>G in HTRA1 gene.Other members of the family refused to undergo further examination.No mutations were found in NOTCH3 for two probands.2.Literature review:a total of 30 CARASIL patients from 25 families were included in this study,mainly from Japan and China,including 13(43.33%)males and 17(56.67%)females,and the mean onset age was 18.75±9.76 years old.In 23 cases(76.67%),the parents were first Cousins.25 cases(83.33%)had alopecia,with the average age was 18.16±9.14 years old.The mean onset age of lumbago was 26±6.94 years old.All the 30 patients had leukodystrophy,head MRI of 14 patients(46.67%)had microhemorrhage,and all the 29 patients showed different degrees of spinal lesions on MRI.One case was positive for Congo red staining in skin biopsy.HTRA1 gene detection:2 cases of compound heterozygous mutations and 28 cases of homozygous mutations,including missense,nonsense and transcoding mutations,and the mutation sites were distributed on exons 1,2,3,4 and 6 of HTRA1 gene.Conclusion1.Two novel mutations in the HTRA1 gene:c.589C>T and c.714C>G homozygous are pathogenic.2.The main clinical characteristics of CARASIL are recurrent cerebral apoplexy,cognitive and emotional disorders,low back pain,hair loss of young and middle-aged people,and most of the parents have a history of inbreeding.Not all CARASIL patients have all the characteristics,and some patients have some non-characteristic manifestations.3.The imaging manifestations are earlier than the appearance of clinical symptoms,and in addition to white matter lesions and multiple cerebral infarction,multiple microhemorrhages are also important imaging manifestations of CARASIL on MRI.4.HTRA1 gene test is required to confirm the disease.The variation of HTRA1 gene is mainly concentrated in exons 3 and 4.