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

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.

Keywords

NOTCH3 - leukoencephalopathy - small vessel disease

Authors' Disclosures

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, Illumina, 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.

Publication History

Received: 08 November 2021

Accepted: 12 January 2020

Accepted Manuscript online:
13 January 2022

Article published online:
23 February 2022

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