Microbleed clustering in thalamus sign in CADASIL patients with NOTCH3 R75P mutation

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan.We conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images.Among the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign).We propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.

[1]  Liying Zhuang,et al.  Occurrence of Intracranial Hemorrhage and Associated Risk Factors in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: A Systematic Review and Meta-Analysis , 2022, Journal of clinical neurology.

[2]  Sung-Chun Tang,et al.  Comparison of clinical and neuroimaging features between NOTCH3 mutations and nongenetic spontaneous intracerebral haemorrhage , 2022, European journal of neurology.

[3]  R. van Doorn,et al.  NO TCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature , 2021, Neuropathology and applied neurobiology.

[4]  Haiyun Tang,et al.  NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients , 2021, Frontiers in Genetics.

[5]  D. Tozer,et al.  NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants , 2021, Journal of Neurology, Neurosurgery, and Psychiatry.

[6]  H. Fukuyama,et al.  A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan , 2020, Frontiers in Aging Neuroscience.

[7]  Eun-Jae Lee,et al.  Clinical and imaging features of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and cysteine-sparing NOTCH3 mutations , 2020, PloS one.

[8]  Yi-Chung Lee,et al.  Cerebral Microbleed Burdens in Specific Brain Regions Are Associated With Disease Severity of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy , 2020, Journal of the American Heart Association.

[9]  I. Mizuta,et al.  Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions , 2020, Frontiers in Aging Neuroscience.

[10]  A. Koster,et al.  Progression and Classification of Granular Osmiophilic Material (GOM) Deposits in Functionally Characterized Human NOTCH3 Transgenic Mice , 2019, Translational Stroke Research.

[11]  Yerim Kim,et al.  Novel Characteristics of Race-Specific Genetic Functions in Korean CADASIL , 2019, Medicina.

[12]  I. Mizuta,et al.  The CADASIL Scale-J, A Modified Scale to Prioritize Access to Genetic Testing for Japanese CADASIL-Suspected Patients. , 2019, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[13]  Sung-Chun Tang,et al.  Detrimental effects of intracerebral haemorrhage on patients with CADASIL harbouring NOTCH3 R544C mutation , 2018, Journal of Neurology, Neurosurgery, and Psychiatry.

[14]  Sven Haller,et al.  Cerebral Microbleeds: Imaging and Clinical Significance. , 2018, Radiology.

[15]  L. Pantoni,et al.  Location, number and factors associated with cerebral microbleeds in an Italian-British cohort of CADASIL patients , 2018, PloS one.

[16]  S. Tsuji,et al.  Mutations in MME cause an autosomal‐recessive Charcot–Marie–Tooth disease type 2 , 2016, Annals of neurology.

[17]  Wei‐Ju Lee,et al.  Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles , 2015, PloS one.

[18]  Takaaki Ito,et al.  Genotypic and phenotypic spectrum of CADASIL in Japan: the experience at a referral center in Kumamoto University from 1997 to 2014 , 2015, Journal of Neurology.

[19]  E. Zackai,et al.  Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome , 2015, American journal of medical genetics. Part A.

[20]  G. Terwindt,et al.  Interpretation of NOTCH3 mutations in the diagnosis of CADASIL , 2014, Expert review of molecular diagnostics.

[21]  Yiran Guo,et al.  Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. , 2013, American journal of human genetics.

[22]  N. Yamada,et al.  Clinical characteristics by topographical distribution of brain microbleeds, with a particular emphasis on diffuse microbleeds. , 2011, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[23]  D. Werring,et al.  The Microbleed Anatomical Rating Scale (MARS) , 2009, Neurology.

[24]  Eric E. Smith,et al.  MR Imaging Detection of Cerebral Microbleeds: Effect of Susceptibility-Weighted Imaging, Section Thickness, and Field Strength , 2008, American Journal of Neuroradiology.

[25]  P. Kirchhof,et al.  Detection of asymptomatic cerebral microbleeds: a comparative study at 1.5 and 3.0 T. , 2008, Academic radiology.

[26]  Max Wintermark,et al.  Imaging of intracranial haemorrhage , 2008, The Lancet Neurology.

[27]  Martin Dichgans,et al.  Blood pressure and haemoglobin A1c are associated with microhaemorrhage in CADASIL: a two-centre cohort study. , 2006, Brain : a journal of neurology.

[28]  J. S. Kim,et al.  Characteristics of CADASIL in Korea , 2006, Neurology.

[29]  L. Pantoni,et al.  The spectrum of Notch3 mutations in 28 Italian CADASIL families , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[30]  M. Viitanen,et al.  Detection of the founder effect in Finnish CADASIL families , 2004, European Journal of Human Genetics.

[31]  V. Mok,et al.  Cerebral microbleeds and white matter changes in patients hospitalized with lacunar infarcts , 2004, Journal of Neurology.

[32]  M. Ferrari,et al.  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages--3rd-6th decades. , 2003, Radiology.

[33]  T. Tabira,et al.  Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis , 2003, Journal of the Neurological Sciences.

[34]  Nils Peters,et al.  Cerebral Microbleeds in CADASIL: A Gradient-Echo Magnetic Resonance Imaging and Autopsy Study , 2002, Stroke.

[35]  M. Ferrari,et al.  Cerebral microbleeds in CADASIL , 2001, Neurology.

[36]  S. Greenberg,et al.  Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria , 2003, Current atherosclerosis reports.

[37]  J. Hatazawa,et al.  Assessment of lacunar hemorrhage associated with hypertensive stroke by echo-planar gradient-echo T2*-weighted MRI. , 2000, Stroke.

[38]  M. Dichgans,et al.  The phenotypic spectrum of CADASIL: Clinical findings in 102 cases , 1998, Annals of neurology.

[39]  J. Weissenbach,et al.  Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia , 1996, Nature.

[40]  J. Weissenbach,et al.  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12 , 1993, Nature Genetics.

[41]  P. Scheltens,et al.  White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer's disease. Evidence for heterogeneity. , 1992, Brain : a journal of neurology.

[42]  A. Alavi,et al.  MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. , 1987, AJR. American journal of roentgenology.

[43]  Y. Nagakane,et al.  Two Japanese CADASIL families exhibiting Notch3 mutation R75P not involving cysteine residue. , 2008, Internal medicine.