Early-onset vascular leukoencephalopathy caused by bi-allelic NOTCH3 variants

2022 ◽  
Author(s):  
Menno Stellingwerff ◽  
Corinne Nulton ◽  
Guy Helman ◽  
Stefan Roosendaal ◽  
William Benko ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Small Vessel Disease ◽  
Cerebral White Matter ◽  
Allelic Loss ◽  
Early Age ◽  
Loss Of Function ◽  
Mri Findings ◽  
Temporal Lobes ◽  
Recurrent Strokes ◽  
Clinical Records

Objective Heterozygous NOTCH3 variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with patients typically presenting in adulthood. We describe three patients presenting at an early age with a vascular leukoencephalopathy. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. Methods Clinical records and available MRI and CT scans of three patients from two unrelated families were retrospectively reviewed. Results The patients presented at 9-14 months of age with developmental delay, seizures, or both. The disease course was characterized by cognitive impairment and variably recurrent strokes, migraine attacks, and seizures. MRI findings pointed at a small vessel disease, with extensive cerebral white matter abnormalities, atrophy, lacunes in the basal ganglia, microbleeds and microcalcifications. The anterior temporal lobes were spared. Bi-allelic cysteine-sparing NOTCH3 variants in exons 1, 32 and 33 were found. Interpretation This study indicates that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.

scholarly journals CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) presenting as psychosis

2018 ◽  
Vol 31 (3) ◽  
pp. e100017 ◽  
Author(s):  
Dheerendra Kumar Mishra ◽  
Aman Kishore ◽  
Vijay Niranjan
Keyword(s):  
Autosomal Dominant ◽  
Small Vessel Disease ◽  
Significant Proportion ◽  
Psychotic Symptoms ◽  
Behavioural Disturbance ◽  
Monogenic Form ◽  
Recurrent Strokes ◽  
Spectrum Disorders ◽  
Psychotic Features ◽  
Subcortical Infarct

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is the most common monogenic form of cerebral small-vessel disease characterised by recurrent strokes. Behavioural disturbance also presents in a significant proportion of subjects as neurotic spectrum disorders and psychotic features are rarely reported. In this case report, we highlight a 32-year-old man with CADASIL syndrome, who had overt psychotic symptoms with neurological signs later on.

scholarly journals Ischemic Stroke in a Patient with Stable CADASIL during COVID-19: A Case Report

2021 ◽  
Vol 11 (12) ◽  
pp. 1615
Author(s):  
Alessandro Cruciani ◽  
Fabio Pilato ◽  
Mariagrazia Rossi ◽  
Francesco Motolese ◽  
Vincenzo Di Lazzaro ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Endothelial Dysfunction ◽  
Autosomal Dominant ◽  
Small Vessel Disease ◽  
Stroke Recurrence ◽  
Vessel Disease ◽  
Increased Risk ◽  
Recurrent Strokes ◽  
Neurological Conditions ◽  
Guillain Barré

Background: SARS-CoV-2 infection has been associated with different neurological conditions such as Guillain-Barré, encephalitis and stroke. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small-vessel disease characterized by recurrent ischemic stroke, cognitive decline, migraine and mood disturbances. One of the mechanisms involved in CADASIL pathogenesis is endothelial dysfunction, which causes an increased risk of recurrent strokes. Since COVID-19 infection is also associated with coagulopathy and endothelial dysfunction, the risk of ischemic stroke might be even higher in this population. We describe the case of a CADASIL patient who developed an acute ischemic stroke after SARS-CoV-2 infection. In patients with diseases causing endothelial dysregulation, such as CADASIL, the hypercoagulability related to COVID-19 may contribute to the risk of stroke recurrence.

CADASIL imitating multiple sclerosis: the importance of MRI markers

2002 ◽  
Vol 8 (5) ◽  
pp. 430-432 ◽  
Author(s):  
S O'Riordan ◽  
A M Nor ◽  
M Hutchinson
Keyword(s):  
Magnetic Resonance Imaging ◽  
Multiple Sclerosis ◽  
Magnetic Resonance ◽  
Autosomal Dominant ◽  
Index Case ◽  
Resonance Imaging ◽  
Mri Findings ◽  
Temporal Lobes ◽  
Diagnostic Confusion ◽  
Magnetic Resonance Imaging Mri

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can mimic multiple sclerosis (MS), leading to diagnostic confusion. We report a family with CADASIL in which the index case and the daughter of the index case were initially erroneously diagnosed with MS. Relatively specific magnetic resonance imaging (MRI) markers of CADASIL include involvement of the anterior temporal lobes and external capsules and, as illustrated in this report, these MRI findings may aid in the differentiation of the two conditions.

scholarly journals A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Bernice Lo ◽  
Sara Tomei ◽  
Valentina Mattei ◽  
Samuel N. Young ◽  
...  
Keyword(s):  
Potential Role ◽  
Autosomal Dominant ◽  
Inflammatory Diseases ◽  
Diabetic Patients ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Healthy Sibling ◽  
Dominant Disease ◽  
Terminal Effector

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

scholarly journals Correction: Bi-allelic loss of function variants in SLC30A5 as cause of perinatal lethal cardiomyopathy

2021 ◽  
Author(s):  
Johann Kaspar Lieberwirth ◽  
Pascal Joset ◽  
Anja Heinze ◽  
Julia Hentschel ◽  
Anja Stein ◽  
...  
Keyword(s):  
Allelic Loss ◽  
Loss Of Function

scholarly journals ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants

Neurogenetics ◽  
2021 ◽  
Author(s):  
Katja Kloth ◽  
Bernarda Lozic ◽  
Julia Tagoe ◽  
Mariëtte J. V. Hoffer ◽  
Amelie Van der Ven ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Neuronal Development ◽  
Autosomal Dominant ◽  
Tissue Expression ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Ankyrin G ◽  
Phenotypic Spectrum ◽  
And Function ◽  
Neurodevelopmental Phenotype

AbstractANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.

scholarly journals Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder

2021 ◽  
Author(s):  
Holger Hengel ◽  
Shabab B. Hannan ◽  
Sarah Dyack ◽  
Sara B. MacKay ◽  
Ulrich Schatz ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Allelic Loss ◽  
Loss Of Function

scholarly journals Contribution of “Omic” Studies to the Understanding of Cadasil. A Systematic Review

2021 ◽  
Vol 22 (14) ◽  
pp. 7357
Author(s):  
Elena Muiño ◽  
Israel Fernández-Cadenas ◽  
Adrià Arboix
Keyword(s):  
Growth Factor ◽  
Protein Misfolding ◽  
Drug Targets ◽  
Transforming Growth Factor ◽  
Small Vessel Disease ◽  
Transforming Growth Factor Β ◽  
Small Vessel ◽  
Vessel Disease ◽  
Extracellular Matrix Components ◽  
Recurrent Strokes

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.

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