Brain MRI/MRA Findings after Hydroxyurea Treatment in Children with Sickle Cell Anemia
Kerri NottageRussell E. WareMatthew SmeltzerJola DowdyWinfred C. WangJane S. HankinsKathleen J. HeltonBanu Aygün
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Keywords:
Transcranial Doppler
Stroke
Magnetic resonance angiography
CADASIL
CADASIL
Vascular dementia
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CADASIL
Stroke
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Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene.In Finland, the majority of CADASIL patients carry the pathogenic founder variant c.397C>T, (p.Arg133Cys), but the spectrum of other NOTCH3 variants has not been investigated previously.The aim of the study was to investigate the spectrum and prevalence of NOTCH3 variants Finnish CADASIL patients and to examine the clinical features associated with them. Materials and Methods: The spectrum of NOTCH3 variants and the clinical features associated with them were retrospectively examined in 294 Finnish CADASIL patients tested during January 1996 to October 2021 in the Medical Genetics laboratory of Department of Genomics of Turku University Hospital, where practically all samples of patients with suspected CADASIL in Finland are investigated.Results: The most common NOTCH3 variants in the study cohort were c.397C>T, (p.Arg133Cys) (68%) and c.3206A>G p.(Tyr1069Cys) (18%), but other less common NOTCH3 variants were detected in as many as 14% of the patients.Eight of the detected NOTCH3 variants were novel: c.520T>A,p.(Cys174Ser),c.836A>G,p.(Gln279Arg), c.1369T>G,p.(Cys457Gly), c.1338C>G,p.(Cys446Trp), c.1564T>G,p.(Cys522Gly), c.2848T>G,p.(Cys950Gly), c.6102dup,p.(Gly2035Argfs*60), and c.2410+6C>G.Other NOTCH3 variants than p.Arg133Cys and p.Tyr1069Cys were more often associated with more severe clinical features.Conclusion: This study revealed the genetic and clinical spectrum of CADASIL in the Finnish population.Sequencing of the whole NOTCH3 gene performing a gene-panel or exome sequencing is recommended when suspecting CADASIL.
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Background and purpose: small vessel disease (SVD) is a major cause of vascular dementia. CADASIL is a monogenic variant of SVD caused by mutations in NOTCH3. Mutation carriers almost invariably develop cognitive deficits. The current study determines the characteristics of cognitive abnormalities seen in CADASIL.
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Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease in adults. Many CADASIL cases were reported after NOTCH3 was identified as the causative gene of CADASIL. However, there is still no specific and effective therapies for CADASIL. In this review, we summarize recent research progress on disease models, symptomatic treatments and potential therapies for CADASIL, thereby providing a reference for follow-up CADASIL treatment research.伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy，CADASIL)是成人最常见的遗传性脑小血管病。自CADASIL的致病基因NOTCH3被鉴定以来，大量CADASIL病例被报道，但迄今仍缺乏有效的治疗药物。本文针对CADASIL的疾病模型和致病机制、对症药物治疗及潜在治疗方案研究进展进行综述，以期为后续CADASIL发病机制和治疗研究提供参考。.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small vessel diseases caused by a mutation in the NOTCH3 gene. The clinical manifestations of CADASIL range from single or multiple lacunar infarcts, transient ischemic attacks, dementia, migraine with aura to psychiatric disorders. The features of brain MRI of CADASIL include multiple lacunar infarcts and diffuse leukoencephalopathy, which frequently involves external capsules and anterior temporal regions. Almost all patients with CADASIL harbor cysteine-involving mutations in NOTCH3. In Taiwan, two thirds of CADASIL patients carry NOTCH3 p.R544C mutations, and only approximately 56% of patients with CADASIL have leukoencephalopathy with anterior temporal regions involvement.
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Brain infarction due to cerebral small vessel disease (SVD) accounts for up to 25% of all ischemic strokes. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) are among the monogenic hereditary cerebral SVDs. Herein, we reported a case of sporadic CADASIL-like disease and provided information about CADASIL and CARASIL, two of the most common of inheredited SVDs that are usually overlooked
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Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom-designed gene panel. We selected 55 leukoencephalopathy-related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small-vessel disease, but doctor’s knowledge in this sphere is still insufficient. We aimed to introduce the recommendations of the European Academy of Neurology to Russian clinicians because it can help them to discover CADASIL in time and to manage patients with this form of monogenic cerebral small-vessel disease. We present the own case report.
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CADASIL (zerebrale, autosomal-dominante Arteriopathie mit subkortikalen Infarkten und Leukenzephalopathie) ist eine hereditäre, autosomal-dominant vererbte Erkrankung, die durch Infarkte, Demenz und Leukenzephalopathie geprägt ist, jedoch auch sporadisch auftritt. Auf genetischer Basis konnten verschiedene Mutationen im Notch3-Gen auf Chromosom 19q12 identifiziert werden (Chabriat H et al. Lancet Neurol 2009; 8: 643–653). Die genaue Inzidenz ist nicht bekannt, in einer Studie in Westschottland betrug die ermittelte Inzidenz ca. 1,98–4,14 / 100 000 / Jahr (Razvi SS et al. J Neurol Neurosurg Psychiatry 2005; 76: 739–741).
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