Clinical spectrum of CADASIL: a study of 7 families

doi:10.1016/S0140-6736(95)91557-5

The Lancet

Volume 346, Issue 8980, 7 October 1995, Pages 934-939

https://doi.org/10.1016/S0140-6736(95)91557-5 Get rights and content

Abstract

Summary

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain recently mapped to chromosome 19. We studied 148 subjects belonging to seven families by magnetic resonance imaging and genetic linkage analysis. 45 family members (23 males and 22 females) were clinically affected. Frequent signs were recurrent subcortical ischaemic events (84%), progressive or stepwise subcortical dementia with pseudobulbar palsy (31%), migraine with aura (22%), and mood disorders with severe depressive episodes (20%). All symptomatic subjects had prominent signal abnormalities on MRI with hyperintense lesions on T2-weighted images in the subcortical white-matter and basal ganglia which were also present in 19 asymptomatic subjects. The age at onset of symptoms was mean 45 (SD [10·6]) years, with attacks of migraine with aura occurring earlier in life (38·1 [8·03] years) than ischaemic events (49·3 [10·7] years). The mean age at death was 64·5 (10·6) years. On the basis of MRI data, the penetrance of the disease appears complete between 30 and 40 years of age. Genetic analysis showed strong linkage to the CADASIL locus for all seven families, suggesting genetic homogeneity.

CADASIL is a hereditary cause of stroke, migraine with aura, mood disorders and dementia. The diagnosis should be considered not only in patients with recurrent small subcortical infarcts leading to dementia, but also in patients with transient ischaemic attacks, migraine with aura or severe mood disturbances, whenever MRI reveals prominent signal abnormalities in the subcortical white-matter and basal ganglia. Clinical and MRI investigations of family members are then crucial for the diagnosis which can be confirmed by genetic linkage analysis. The disease is probably largely undiagnosed.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited progressive cerebral microangiopathy with considerable phenotypic variability. The purpose of this study was to describe the generalizability of a recently proposed grading system of CADASIL across multiple centers in the United States.
Electronic medical records (EMR) of an initial neurological assessment of adult patients with confirmed CADASIL were reviewed across 5 tertiary referral medical centers with expertise in CADASIL. Demographic, vascular risk factors, and neuroimaging data were abstracted from EMR. Patients were categorized into groups according to the proposed CADASIL grading system: Grade 0 (asymptomatic), Grade 1 (migraine only), Grade 2 (stroke, TIA, or MCI), Grade 3 (gait assistance or dementia), and Grade 4 (bedbound or end-stage). Inter-rater reliability (IRR) of grading was tested in a subset of cases.
We identified 138 patients with a mean age of 50.9 ± 13.1 years, and 57.2% were female. The IRR was acceptable over 33 cases (κ=0.855, SD 0.078, p<0.001) with 81.8% being concordant. There were 15 patients (10.9%) with Grade 0, 50 (36.2%) with Grade 1, 61 (44.2%) with Grade 2, 12 (8.7%) with Grade 3, and none with Grade 4. Patients with a lower severity grade (grade 0 vs 3) tended to be younger (49.5 vs. 61.9 years) and had a lower prevalence of hypertension (50% vs. 20%, p = 0.027) and diabetes mellitus (0% vs. 25%, p = 0.018). A higher severity grade was associated with an increased number of vascular risk factors (p = 0.02) and independently associated with hypertension and diabetes (p<0.05). Comparing Grade 0 vs. 3, cortical thickness tended to be greater (2.06 vs. 1.87 mm; p = 0.06) and white matter hyperintensity volume tended to be lower (54.7 vs. 72.5 ml; p = 0.73), but the differences did not reach significance.
The CADASIL severity grading system is a pragmatic, reliable system for characterizing CADASIL phenotype that does not require testing beyond that done in standard clinical practice. Higher severity grades tended to have a higher vascular risk factor burden. This system offers a simple method of categorizing CADASIL patients which may help to describe populations in observational and interventional studies.
Persistent aura and status migrainosus in CADASIL syndrome: A case report
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy characterized by a genetic predisposition to small arteries of the brain. It is produced by a mutation in the NOTCH3 gene and concerns adults. The symptomatology is diversified including migraines with or without aura, subcortical ischemic events, and cognitive impairment. The diagnosis of CADASIL is suspected by neuroimaging and confirmed by genetic testing. Treatment of the disease remains preventive. We report a case of CADASIL manifesting as status migrainosus with persistent aura.
Acute confusional migraine in CADASIL: A case report and literature review
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Acute confusional state associated with migraine in adults is an infrequent entity. Around 30–60% of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients get affected by migraine attacks—the majority with aura—often as the first symptom of the disease. Acute confusional state during migraine has been rarely described in CADASIL patients and a complete neuropsychological assessment during the acute phase has never been conducted so far.
We here describe the clinical and neuropsychological features of two distinct episodes of ACM in a 54-year-old female with CADASIL. EEG recording during acute confusional migraine and after attack resolution and neuroimaging has been reported.
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Citation Excerpt :
These manifestations are related to focal subcortical ischemic lesions and may regress in early stages of the disease. Their repetition can lead, especially after the age of 60 years, to the development of significant cognitive and motor disability that can lead to dementia associated with motor deficits, and gait and balance difficulties [1,22,29]. From the onset up to the terminal stage of the disease, both cognitive and psychiatric manifestations are frequently reported [20].
CADASIL is the most common familial cerebral small vessel disease (cSVD). Stereotyped mutations of the NOTCH3 gene are responsible for this archetypal ischemic cSVD that can lead, at the very end stage, to severe dementia. Variable cognitive alterations, mood, or behavior disturbances are frequently observed during the course of the disease. In this review, these clinical manifestations, their occurrence, severity and duration are analyzed in relation to the disease progression. Also, the potential relationships with cerebral lesions and treatment options are discussed.
A Chinese CADASIL family with p.R578C mutation at exon 11 of the NOTCH3 gene
2021, Clinical Neurology and Neurosurgery
To analyze one clinical case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL), and to perform analysis of the related gene mutation for the proband and her family.
Analysis of clinical data from the patient diagnosed with CADASIL, including clinical manifestations, blood test results and brain imaging results, followed by high-throughput sequencing of blood samples. Pathogenicity assessment of the gene mutation, and first generation verification were performed on some family members according to genetic variation interpretation standards and guidelines of the American College of Medical Genetics and Genomics (ACMG).
Onset of the proband occurred younger than 50-years-old with recurrent migraine attacks and positive family history of migraine and stroke, but without risk factors for cerebrovascular diseases. The craniocerebral magnetic resonance imaging (MRI) results showed diffusive white matter lesions and thus clinically met criteria for CADASIL diagnosis. NOTCH3 gene analysis showed a p.R578C mutation (1732 C > T) at the11th exon on chromosome 19 of the proband and some family members.
NOTCH3 mutation is related to CADASIL. In this study, we observed a rather rare familial NOTCH3 mutation in China. This report further support the mutation site is pathogenic.

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ArticlesClinical spectrum of CADASIL: a study of 7 families

Abstract

Lancet

Lancet

Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease

Acta Neuropathol (Berl)

Familiäre zerebrale Gefäberkrankung. Zbl Allgemain

Pathologie Bd

Hereditary multi-infarct dementia

Eur Neurol

Démence sous-corticale familiale avec leucoencéphalopathie artériopathique. Observation clinicopathologique

Rev Neurol (Paris)

Autosomal dominant syndrome with stroke-like episodes and leukoencephalopathy

Stroke

A familial disorder with subcortical ischemic strokes, dementia and leukoencephalopathy

Neurology

Slowly progressive familial dementia with recurrent strokes and white matter hypodensities on CT scan

Ital J Neurol Sci

Small arterial granular degeneration in familial Binswanger's syndrome

Acta Neuropathol

Autosomal dominant leukoencephalopathy and subcortical ischemic strokes: a clinicopathological study

Stroke

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps on chromosome 19q12

Nature Genet

Diagnostic and Statistical Manual of Mental disorders

A second generation linkage map of the human genome

Nature

Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain

Cephalalgia

Hereditary multi-infarct dementia unlinked to chromosome 19q12 in a large Scottish pedigree: evidence of probable locus heterogeneity

J Med Genet

Genetic analysis of 12 unrelated CADASIL families: demonstration of genetic homogeneity. Physical mapping of the gene. ASHG Meeting

Am J Hum Genet

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Clinical spectrum of CADASIL: a study of 7 families