Menno D Stellingwerff1, Corinne Nulton2, Guy Helman3,4, Stefan D Roosendaal5, William S Benko6, Amy Pizzino7, Marianna Bugiani8, Adeline Vanderver7,9, Cas Simons3,4, Marjo S van der Knaap1,10. 1. Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience, Amsterdam, The Netherlands. 2. Department of Neurology, University of Pittsburgh Medical Center, Pennsylvania, United States. 3. Translational Bioinformatics, Murdoch Children's Research Institute, The Royal Children's Hospital, Victoria, Australia. 4. Genetics and Genomics, Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia. 5. Department of Radiology, Amsterdam University Medical Centers, Amsterdam, The Netherlands. 6. Department of Neurology, University of California Davis, Sacramento, California, United States. 7. Division of Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, Pennsylvania, United States. 8. Department of Pathology, Amsterdam UMC, location VUmc, The Netherlands. 9. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States. 10. Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.
Abstract
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. Thieme. All rights reserved.
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. Thieme. All rights reserved.
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