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Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants
Menno D Stellingwerff1, Corinne Nulton2, Guy Helman3,4
1Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience, Amsterdam, The Netherlands.
Insights
Bi-allelic NOTCH3 variants can cause early-onset vascular leukoencephalopathy, a condition distinct from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This finding expands the understanding of NOTCH3-related neurological disorders.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Heterozygous NOTCH3 variants are associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), typically presenting in adulthood.
- CADASIL is a genetic small vessel disease affecting the brain.
Purpose of the Study:
- To investigate the genetic basis of early-onset vascular leukoencephalopathy in three pediatric patients.
- To determine if biallelic NOTCH3 variants contribute to a distinct form of leukoencephalopathy.
Main Methods:
- Retrospective review of clinical records and neuroimaging (MRI, CT) of three patients from two families.
- Whole genome sequencing to identify genetic variants.
Main Results:
- Patients presented between 9-14 months with developmental delay and seizures.
- Disease course included cognitive impairment, recurrent strokes, migraines, and seizures.
- Neuroimaging revealed extensive white matter abnormalities, atrophy, lacunes, microbleeds, and microcalcifications, with spared anterior temporal lobes.
- Bi-allelic cysteine-sparing NOTCH3 variants in exons 1, 32, and 33 were identified.
Conclusions:
- Bi-allelic loss-of-function NOTCH3 variants can cause a severe vascular leukoencephalopathy presenting in early childhood.
- This condition is clinically and genetically distinct from CADASIL.
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 to 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.
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