CADASIL with Atypical Clinical Symptoms, Magnetic Resonance Imaging, and Novel Mutations: Two Case Reports and a Review of the Literature

Sari, U Serpil; Kısabay, Ayşın; Tarhan, Serdar; Doğan, Nihal; Coskunoglu, Aysun; Çam, Sırrı; Yılmaz, Hikmet; Selçuki, Deniz

doi:10.1007/s12031-019-01313-z

Cited by 10 publications

(11 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Migraine with aura and subcortical vascular cognitive impairment, which are associated with pseudobulbar palsy and urinary incontinence, are also characteristic symptoms of CADASIL (Chabriat et al, 2009). However, it has recently been reported that a subset of patients with NOTCH3 gene mutations show atypical clinical symptoms of CADASIL, such as absence of temporal pole lesions (Ueda et al, 2015), elderly onset (Watanabe et al, 2012), and cerebellar atrophy (Sari et al, 2019). Furthermore, the exome aggregation consortium (ExAC) database study identified 206 EGFr cysteine-altering NOTCH3 mutations in the ExAC, with an overall prevalence of 3.4/1,000 individuals (Rutten et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Patients with CADASIL have various clinical symptoms, such as lacunar infarction, migraines, progressive cognitive decline, and psychiatric problems (Chabriat et al, 2009), and the most specific imaging feature of patients with CADASIL are bilateral white matter hyperintensities (WMHs), especially WMHs of anterior temporal pole on magnetic resonance imaging (MRI) (Chabriat et al, 1995(Chabriat et al, , 1998Coulthard et al, 2000;Auer et al, 2001;Tomimoto et al, 2006;Bersano et al, 2018). However, some patients with NOTCH3 mutations do not show the typical clinical and imaging features of CADASIL (Kim et al, 2006;Mizuno et al, 2008;Sari et al, 2019). Furthermore, it has been recently clarified that the potential prevalence of CADASIL may be higher than previously estimated (Rutten et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions

Okada

Washida

Irie

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary small vessel disease, with reported frequencies of 2-5/100,000 individuals. Recently, it has been reported that some patients with NOTCH3 gene mutations show atypical clinical symptoms of CADASIL. Assuming that CADASIL is underdiagnosed in some cases of lacunar infarction, this study was designed to examine the prevalence of NOTCH3 gene mutations in the patients at highest risk who were admitted for lacunar infarctions.Methods: From January 2011 to April 2018, 1,094 patients with lacunar infarctions were admitted to our hospital, of whom 31 patients without hypertension but with white matter disease (Fazekas scale 2 or 3) were selected and genetically analyzed for NOTCH3 gene mutations (Phase 1). Furthermore, 54 patients, who were 60 years or younger, were analyzed for NOTCH3 mutations (Phase 2). NOTCH3 exons 2-24, which encode the epidermal growth factor-like repeat domain of the NOTCH3 receptor, were analyzed for mutations by direct sequencing of genomic DNA.Results: Three patients presented NOTCH3 p.R75P mutations: two in the Phase 1 and one in the Phase 2 cohort. Among patients aged 60 years or younger and those without hypertension but with moderate-to-severe white matter lesions, the carrier frequency of p.R75P was 3.5% (3/85), which was significantly higher than that in the Japanese general population (4.7KJPN) (odds ratio [95% CI] = 58. 2 [11.6-292.5]). All three patients with NOTCH3 mutations had family histories of stroke, and the average patient age was 51.3 years. All three patients also showed white matter lesions in the external capsule but not in the temporal pole. The CADASIL and CADASIL scale-J scores of the three patients were 6, 17, 7 (mean, 10.0) and 13, 20, 10 (mean, 14.3), respectively. Conclusion:Among patients hospitalized for lacunar infarctions, the p.R75P prevalence may be higher than previously estimated. The NOTCH3 p.R75P mutation may be Okada et al.NOTCH3 Mutations Among Lacunar Infarctions underdiagnosed in patients with early-onset lacunar infarctions due to the atypical clinical and neuroimaging features of CADASIL. Early-onset, presence of family history of stroke, external capsule lesions, and absence of hypertension may help predict underlying NOTCH3 mutations despite no temporal white matter lesions.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions

Okada

Washida

Irie

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…3. The high ventricular lactate measured using MR spectroscopy was found to correlate with the degree of neurological impairment in individuals with MELAS syndrome (Mancuso et al, 2020;Sari et al, 2019).…”

Section: Differential Diagnosis Of Leukoaraiosismentioning

confidence: 95%

“…The brain imaging of MELAS patients has the following characteristics: T2‐FLAIR and DWI hyperintensity are present in the lesions, which are similar to the signals of cerebral infarction, although the affected portions are mostly hyperintensity on the ADC. Lesions are mostly distributed in the temporal, parietal, occipital cortex, and subcortical WM and their scope often do not conform to the anatomical vascular distribution. The high ventricular lactate measured using MR spectroscopy was found to correlate with the degree of neurological impairment in individuals with MELAS syndrome (Mancuso et al, 2020; Sari et al, 2019). Binswanger's disease is a subcortical arteriole sclerosing leukoencephalopathy.…”

Section: Differential Diagnosis Of Leukoaraiosismentioning

confidence: 97%

Leukoaraiosis and acute ischemic stroke

Tang

Luo

et al. 2021

Eur J of Neuroscience

View full text Add to dashboard Cite

Ischaemic stroke is characterized by high morbidity, high disability rate, high mortality and high recurrence rate, which can have a grave impact on the quality of life of the patients and consequently becomes an economic burden on their families and society. With the developments in imaging technology in recent years, patients with acute cerebral infarction are predominantly more likely to be diagnosed with leukoaraiosis (LA). LA is a common degenerative disease of the nervous system, which is related to cognitive decline, depression, abnormal gait, ischaemic stroke and atherosclerosis. The aetiology of LA is not clear and there is no gold standard for imaging assessment. Related studies have shown that LA has an adverse effect on the prognosis of cerebral infarction, but some experts have contrary beliefs. Hence, we undertook the present review of the literature on the mechanism and the effect of LA on the prognosis of patients with acute ischaemic stroke.

show abstract

“…Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is an autosomal dominant inherited vasculopathy characterized by migraine with aura, recurrent subcortical ischemic stroke, cognitive decline, and psychiatric disorders ( Chen et al, 2019 ; Dorszewska et al, 2020 ). CADASIL is caused by mutations in the NOTCH3 gene which is localized on chromosome 19p13 ( Joutel et al, 1997 ; Sari et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Mutations in NOTCH3 Gene may Promote the Clinical Presentation of Spinocerebellar Ataxia Type 37 Caused by Mutations in DAB1 Gene

Wang

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

Background: Autosomal dominant spinocerebellar ataxia type 37 (SCA37) and Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) result from DAB1 and NOTCH3 gene mutations, respectively.Methods: In addition to conventional diagnostic methods, next-generation sequencing (NGS) and Sanger sequencing were performed to define and confirm the DAB1 and NOTCH3 gene mutation for a Chinese pedigree. Bioinformatics analysis was also applied for the mutated DAB1 and NOTCH3 protein using available software tools.Results: Brain magnetic resonance imaging shows diffuse leukoencephalopathy and cerebellar atrophy in the proband. NGS and Sanger sequencing identified two novel heterozygous mutations: NM_021080:c.318T > G (p.H106Q) in the DAB1 gene and NM_000435:c.3298C > T (p.R1100C) in the NOTCH3 gene. Bioinformatics analysis suggested that the DAB1 and NOTCH3 gene mutations are disease-causing and may be responsible for the phenotypes.Conclusion: This is the first report of a pedigree with both SAC37 and CADASIL phenotypes carrying corresponding gene mutations. Mutations in the NOTCH3 gene may promote the clinical presentation of spinocerebellar ataxia type 37 caused by mutations in the DAB1 gene. In addition to general examinations, it is vital for physicians to apply molecular genetics to get an accurate diagnosis in the clinic, especially for rare diseases.

show abstract

CADASIL with Atypical Clinical Symptoms, Magnetic Resonance Imaging, and Novel Mutations: Two Case Reports and a Review of the Literature

Cited by 10 publications

References 41 publications

Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions

Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions

Leukoaraiosis and acute ischemic stroke

Mutations in NOTCH3 Gene may Promote the Clinical Presentation of Spinocerebellar Ataxia Type 37 Caused by Mutations in DAB1 Gene

Contact Info

Product

Resources

About