Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

Sabbadini, Guglielmo; Francia, Ada; Calandriello, L.; Biasi, C. Di; Trasimeni, G.; Gualdi, Gianfranco; Palladini, Giovanni; Manfredi, M.; Frontali, Marina

doi:10.1093/brain/118.1.207

Cited by 68 publications

(27 citation statements)

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“…The electron microscopic demonstration of GOMwithin the basal lamina of vascular smooth-muscle cells in arterioles is specific for the diagnosis of CADASIL (4,6,(18)(19)(20)(21)(22). As shown in our demonstration, GOMwas also present within the basement membrane of pericyte in the capillaries.…”

Section: Discussionsupporting

confidence: 75%

Arg133Cys Mutation of Notch3 in Two Unrelated Japanese Families with CADASIL.

et al. 2000

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Objective More than 80 unrelated, but all Caucasian, patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), originating from various communities around the world, have been molecularly identified. To clarify the occurrence of CADASILin Orientals, we investigated Japanese families presenting as CADASIL. Methods Weperformed the PCR-SSCPand sequence analyses using genomic DNA,isolated from venous blood of participants under informed consent. Patients Weidentified two unrelated Japanese families with CADASIL,including 5 affected members through 2 generations.Results Each of the affected individuals developed recurrent strokes without risk factors resulting in progressive dementia, pseudobulbar palsy, and gait disturbances which started after the fifth decade of life. Although affected individuals had no vascular risk factors, they showed various degrees of narrowing of retinal arteries. Their MRI/ CTs showed characteristics of the disease; bilateral small infarcts in the thalamus, basal ganglia, brain stem, and deep white matter in addition to the findings of leukoaraiosis. On SPECTimaging, there was severe hypoperfusion in the cortex as well as in the white matter. Ultrastructural studies revealed an abnormal deposition of granular osmiophilic materials (GOM)within the basal lamina of pericytes in muscular capillaries. On PCR-SSCPand sequence analyses, a heterozygous Argl33Cys mutation was present, in the affected individuals, in the exon 4 of Notch3 gene which is the hot spot region for CADASILmutations in Caucasian families. None of the non-affected membersnor the 50 Japanese normal controls revealed this mutation. Conclusion Thus, our results confirm that CADASIL is a geographically widespread disorder caused by a Notch3 mutation. (Internal Medicine 39: 732-737, 2000)

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Section: Discussionsupporting

confidence: 75%

Arg133Cys Mutation of Notch3 in Two Unrelated Japanese Families with CADASIL.

et al. 2000

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“…Desmond et al found migraine in 42 of 105 individuals (40%). On the other hand, none of the members of an Italian family presented symptoms 52 . There are other families in which migraine and later insidiously progressive cognitive disorders are the sole manifestations of the disease, but the final diagnosis of CADASIL in these cases is still uncertain 53 .…”

Section: Migrainementioning

confidence: 93%

CADASIL: pathogenesis, clinical and radiological findings and treatment

André

2010

Arq. Neuro-Psiquiatr.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic cause of ischemic strokes and a most important model for the study of subcortical vascular dementia. This unrelentlessly progressive disease affects many hundreds of families all over the world but is not well studied in Brazil. This manuscript reviews pathogenetic, clinical, radiological and therapeutic features of CADASIL. The causal mutations are now very well known, but the same can not be said about its intimate pathogenetic mechanisms. The variable clinical presentation should lead physicians to actively pursue the diagnosis in many settings and to more thouroughly investigate family history in first degree relatives. A rational approach to genetic testing is however needed. Treatment of CADASIL is still largely empiric. Highquality therapeutic studies involving medications and cognitive interventions are strongly needed in CADASIL. Key words: CADASIL, etiology, genetics, diagnosis, therapeutics.cADAsIL: patogênese, achados clínicos e radiológicos e tratamento resumo CADASIL é a causa genética mais freqüente de infartos cerebrais e constitui modelo importante de estudo de demências vasculares subcorticais. De natureza inexoravelmente progressiva, afeta milhares de pessoas em todo o mundo. Sua importância é pouco reconhecida entre nós, o que nos levou à presente revisão dos principais aspectos patogenéticos, clínicos, neuroradiológicos e terapêuticos da doença. As mutações causais são hoje bem conhecidas, mas os mecanismos patogenéticos íntimos ainda permanecem misteriosos. A apresentação clínica variável deve fazer com que os médicos considerem o diagnóstico em vários contextos clínicos e investiguem de forma mais extensa que o usual a história familial deparentes de primeiro grau. Além disso, uma abordagem racional é necessária para reduzir custos e aumentar a eficiência do diagnóstico genético. O tratamento atual de pacientes com CADASIL é basicamente empírico. Estudos clínicos sobre medicamentos e intervenções cognitivas de alto nível metodológico constituem uma necessidade urgente.

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“…2,3 Such arteriopathic changes have been documented in virtually all organs of patients with CADASIL, but they are more pronounced in the brain, where they can result in small circumscribed subcortical infarcts and confluent areas of diffuse white matter abnormalities. 4 As shown by a number of MRI studies, [5][6][7][8][9][10][11] conventional T2-weighted scans of the brain are very sensitive in detecting the presence of such lesions in the brain from individuals with CADASIL. However, conventional MR scanning allows only limited quantification of the degree of tissue destruction.…”

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confidence: 99%

Correlations Between Clinical Findings and Magnetization Transfer Imaging Metrics of Tissue Damage in Individuals With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Iannucci

Dichgans

Rovaris

et al. 2001

Stroke

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Background and Purpose-We obtained magnetization transfer imaging (MTI) scans from individuals with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1) to investigate the presence, extent, and nature of pathology in white and gray matter outside proton density (PD)-visible lesions; (2) to quantify the degree of tissue damage occurring in lesions seen on PD-weighted scans; and (3) to correlate MTI-derived measures of disease burden with age, physical disability, and cognitive performance. Methods-Dual-echo, T1-weighted, and MTI scans of the brain were obtained from 33 individuals with CADASIL and 12 control subjects. Magnetization transfer ratio (MTR) values from PD-visible lesions, normal-appearing white matter (NAWM), and normal-appearing gray matter (NAGM) were measured. Histograms of MTR from the whole brain and normal-appearing brain tissue were also produced. Results-All MTR values from NAWM and NAGM regions studied were significantly lower for individuals with CADASIL than for control subjects, with the exception of those obtained from the NAWM of the infratentorial structures and the NAGM of the occipital cortex. The average MTR from PD lesions in individuals with CADASIL was significantly lower than that from all the NAWM regions. Average MTR and peak location from whole-brain and normal-appearing brain tissue histograms were significantly lower for individuals with CADASIL than for control subjects. MTR values from NAWM were strongly correlated with the extent of macroscopic lesions and their average MTR. Apart from NAGM, average MTR from all other tissues studied significantly decreased with increasing age, physical disability, and cognitive impairment. Conclusions-PD

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

Cited by 68 publications

References 0 publications

Arg133Cys Mutation of Notch3 in Two Unrelated Japanese Families with CADASIL.

Arg133Cys Mutation of Notch3 in Two Unrelated Japanese Families with CADASIL.

CADASIL: pathogenesis, clinical and radiological findings and treatment

Correlations Between Clinical Findings and Magnetization Transfer Imaging Metrics of Tissue Damage in Individuals With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

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