Recurrent generalized seizures as the prominent manifestation in a patient with CADASIL: a case report and literature review

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Abstract

Background

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arteriopathy typically caused by mutations in the NOTCH-3 gene. Few detailed descriptions of recurrent generalized seizures in CADASIL has been reported.

Case presentation

This article details a case of recurrent generalized seizures, which eventually be diagnosed as CADASIL with a heterozygous variant, c.1630 C > T (p. Arg544Cys), in exon 11 of the Notch 3 gene. Here, we discussed the possible pathogenesis underlying the epilepsy associated with CADASIL through the brain magnetic resonance imaging changes and the captured epileptiform waves in the electroencephalography during the patient’s follow-up period. Related literatures were also reviewed to discuss the etiology of the epilepsy.

Conclusions

Recurrent generalized seizures may be a presenting neurological manifestation of CADASIL in the absence of other discernible causes. Clinicians should comprehensively seek the possible etiology of patients with recurrent generalized seizures, considering the possible diagnosis of CADASIL.

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Most cited references 21

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Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.

S Alamowitch, F. Bach, M M Ruchoux … (1996)

Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.

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The phenotypic spectrum of CADASIL: clinical findings in 102 cases.

T Klockgether, G Rungger, M Dichgans … (1998)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized autosomal dominant disorder that leads to cerebrovascular manifestations in early adulthood. This study delineates the phenotypic spectrum and the natural history of the disease in 102 affected individuals from 29 families with biopsy-proven CADASIL. Recurrent ischemic episodes (transient ischemic attack [TIA] or stroke) were the most frequent presentation found in 71% of the cases (mean age at onset, 46.1 years; range, 30-66 years; SD, 9.0 years). Forty-eight percent of the cases had developed cognitive deficits. Dementia (28%) was frequently accompanied by gait disturbance (90%), urinary incontinence (86%), and pseudobulbar palsy (52%). Thirty-nine patients (38%) had a history of migraine (mean age at onset, 26.0 years; SD, 8.2 years), which was classified as migraine with aura in 87% of the cases. Psychiatric disturbances were present in 30% of the cases, with adjustment disorder (24%) being the most frequent diagnosis. Ten patients (10%) had a history of epileptic seizures. To delineate the functional consequences of ischemic deficits, we studied the extent of disability in different age groups. The full spectrum of disability was seen in all groups older than age 45. Fifty-five percent of the patients older than age 60 were unable to walk without assistance. However, 14% in this age group exhibited no disability at all. Kaplan-Meier analysis disclosed median survival times of 64 years (males) and 69 years (females). An investigation of the 18 multiplex families revealed marked intrafamilial variations.

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Genetics of ischaemic stroke.

Martin Dichgans (2007)

Ischaemic stroke is a heterogeneous multifactorial disorder. Epidemiological data provide substantial evidence for a genetic component to the disease, but the extent of predisposition is unknown. Large progress has been made in single-gene disorders associated with ischaemic stroke. The identification of NOTCH3 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) has led to new insights on lacunar stroke and small-vessel disease. Studies of sickle-cell disease have drawn attention to the importance of modifier genes and of gene-gene interactions in determining stroke risk. They have further highlighted a potential role of genetics in predicting stroke risk. Little is known about the genes associated with complex multifactorial stroke. There are probably many alleles with small effect sizes. Genetic-association studies on a wide range of candidate pathways, such as the haemostatic and inflammatory system, homocysteine metabolism, and the renin-angiotensin aldosterone system, suggest a weak but significant effect for several at-risk alleles. Genome-wide linkage studies in extended pedigrees from Iceland led to the identification of PDE4D and ALOX5AP. Specific haplotypes in these genes have been shown to confer risk for ischaemic stroke in the Icelandic population, but their role in other populations is unclear. Advances in high-throughput genotyping and biostatistics have enabled new study designs, including genome-wide association studies. Their application to ischaemic stroke requires the collaborative efforts of multiple centres. This approach will contribute to the identification of additional genes, novel pathways, and eventually novel therapeutic approaches to ischaemic stroke.

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Author and article information

Contributors

Shanshan Zhao:

ORCID: http://orcid.org/0000-0002-9785-2861

zhaoshsh826@hotmail.com

Journal

Journal ID (nlm-ta): BMC Neurol

Journal ID (iso-abbrev): BMC Neurol

Title: BMC Neurology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2377

Publication date (Electronic): 30 September 2022

Publication date PMC-release: 30 September 2022

Publication date Collection: 2022

Volume: 22

Electronic Location Identifier: 375

Affiliations

GRID grid.412636.4, ISNI 0000 0004 1757 9485, Department of Neurology, , the First Affiliated Hospital of China Medical University, ; Number 155, Nanjing Street, Heping District, Shenyang City, 110001 Liaoning Province China

Author information

Shanshan Zhao http://orcid.org/0000-0002-9785-2861

Article

Publisher ID: 2889

DOI: 10.1186/s12883-022-02889-7

PMC ID: 9526332

PubMed ID: 36180846

SO-VID: 463687f7-18e8-4032-be1d-8d7d359ac21e

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 25 March 2022

Date accepted : 14 September 2022

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ScienceOpen disciplines: Neurology

Keywords: cadasil,generalized seizures,notch3 gene,review,case report

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ScienceOpen disciplines: Neurology

Keywords: cadasil, generalized seizures, notch3 gene, review, case report

Recurrent generalized seizures as the prominent manifestation in a patient with CADASIL: a case report and literature review

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Abstract

Background

Case presentation

Conclusions

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Most cited references 21

Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.

The phenotypic spectrum of CADASIL: clinical findings in 102 cases.

Genetics of ischaemic stroke.

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