Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants

Menno D. Stellingwerff, Corinne Nulton, Guy Helman, Stefan D. Roosendaal, William S. Benko, Amy Pizzino, Marianna Bugiani, Adeline Vanderver, Cas Simons, Marjo S. Van Der Knaap*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)115-121
Number of pages7
JournalNeuropediatrics
Volume53
Issue number2
Early online date23 Feb 2022
DOIs
Publication statusPublished - Apr 2022

Bibliographical note

Funding Information:
G.H. is supported by the Ochsner MD-PhD Scholarship. This study was in part financed by the Australian National Health and Medical Research Council (NHMRC 1068278) and the Medical Research Future Fund (ARG76368). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program. M.B. receives research funding from ZonMw (VENI grant 016.196.107). A.V. receives research funding from the NIH U01 NS106845, U54NS115052, Eli Lilly, Biogen, Illu-mina, Takeda, Homology, Passage Bio, and Ionis. M.S.v.d.K. receives research funding from NWO (Spinoza award), ZonMw (TOP 91217006 and 10140261910004 / 80– 86600–98–84001), Hersenstichting (DR-2019–00285), European Leukodystrophy Foundation (2019-P001 and 2020–017I2), Vanishing White Matter Foundation, Chloe Saxby and VWM Disease Incorporated, and VWM Families Foundation Inc. She has a patent P112686CA00, therapeutic effects of Guanabenz treatment in vanishing white matter, pending to VU University Medical Center. She is consultant for Calico.

Publisher Copyright:
© 2022 American Institute of Physics Inc.. All rights reserved.

Funding

G.H. is supported by the Ochsner MD-PhD Scholarship. This study was in part financed by the Australian National Health and Medical Research Council (NHMRC 1068278) and the Medical Research Future Fund (ARG76368). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program. M.B. receives research funding from ZonMw (VENI grant 016.196.107). A.V. receives research funding from the NIH U01 NS106845, U54NS115052, Eli Lilly, Biogen, Illu-mina, Takeda, Homology, Passage Bio, and Ionis. M.S.v.d.K. receives research funding from NWO (Spinoza award), ZonMw (TOP 91217006 and 10140261910004 / 80– 86600–98–84001), Hersenstichting (DR-2019–00285), European Leukodystrophy Foundation (2019-P001 and 2020–017I2), Vanishing White Matter Foundation, Chloe Saxby and VWM Disease Incorporated, and VWM Families Foundation Inc. She has a patent P112686CA00, therapeutic effects of Guanabenz treatment in vanishing white matter, pending to VU University Medical Center. She is consultant for Calico.

FundersFunder number
European Leukodystrophy Foundation2019-P001, 2020–017I2
Medical Research Future FundARG76368
VWM Disease Incorporated
VWM Families Foundation Inc
Vanishing White Matter Foundation
National Institutes of HealthU01 NS106845
National Institute of Neurological Disorders and StrokeU54NS115052
Eli Lilly and Company
Biogen
National Health and Medical Research Council1068278
ZonMw016.196.107
Nederlandse Organisatie voor Wetenschappelijk OnderzoekTOP 91217006, 10140261910004 / 80– 86600–98–84001, DR-2019–00285
State Government of Victoria

    Keywords

    • leukoencephalopathy
    • NOTCH3
    • small vessel disease

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