Related Experiment Video
Updated: Oct 5, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C
S Tuominen1, V Juvonen, K Amberla
1Department of Neurology, Turku University Hospital and University of Turku, Finland.
Insights
Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) can present similarly in both homozygous and heterozygous individuals. This study highlights a homozygous patient with severe early-onset symptoms, demonstrating the wide clinical spectrum of this genetic brain disorder.
Area of Science:
- Neurogenetics
- Vascular Neurology
- Molecular Medicine
Background:
- CADASIL is an autosomal dominant genetic arteriopathy caused by Notch3 gene mutations, leading to brain infarcts, cognitive decline, and dementia.
- The Notch3 receptor protein is encoded by the Notch3 gene, and mutations disrupt its function, contributing to the disease pathology.
Observation:
- A homozygous patient with the C475T Notch3 mutation (R133C) presented with early-onset stroke at age 28.
- This homozygous patient exhibited severe neuropsychological deterioration and significant white matter changes on MRI, comparable to severely affected heterozygous carriers.
- Skin biopsy revealed characteristic granular osmiophilic material deposits in dermal arteries.
Findings:
- Despite early and severe symptoms, the homozygous patient's disease progression was slower than the most affected heterozygous individuals.
- Neuropsychological and MRI findings in the homozygous patient were at the severe end of the CADASIL spectrum.
- Cerebral blood flow was markedly reduced in the homozygous patient, assessed by positron emission tomography.
Implications:
- The clinical presentation of CADASIL in homozygous individuals falls within the known spectrum of the disease.
- This case supports the understanding that CADASIL, a dominant disorder, can show indistinguishable clinical features between heterozygous and homozygous patients.
- Further research into Notch3 mutations and their varying effects is crucial for understanding CADASIL pathogenesis and developing targeted therapies.
Background And Purpose:
CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation.
Methods:
The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically.
Results:
The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient's heterozygous son had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient.
Conclusions:
Our homozygous patient's phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.
Related Concept Videos
02:19Multiple Allele Traits
02:25Genetic Lingo
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
01:43Incomplete Dominance
02:21Pedigree Analysis
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy