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.

Publikationsverlauf

Eingereicht: 08. November 2021

Angenommen: 12. Januar 2020

Accepted Manuscript online:
13. Januar 2022

Artikel online veröffentlicht:
23. Februar 2022

• References

• 1 van der Knaap MS, Breiter SN, Naidu S, Hart AA, Valk J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology 1999; 213 (01) 121-133
• 2 van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol 2017; 134 (03) 351-382
• 3 Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010; 9 (07) 689-701
• 4 Bugiani M, Kevelam SH, Bakels HS. et al. Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL). Neurology 2016; 87 (17) 1777-1786
• 5 Jenkinson EM, Rodero MP, Kasher PR. et al. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. Nat Genet 2016; 48 (10) 1185-1192
• 6 Schiffmann R. Fabry disease. Pharmacol Ther 2009; 122 (01) 65-77
• 7 El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab 2015; 116 (1-2): 4-12
• 8 Lanfranconi S, Markus HS. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke 2010; 41 (08) e513-e518
• 9 Ehebauer MT, Chirgadze DY, Hayward P, Martinez Arias A, Blundell TL. High-resolution crystal structure of the human Notch 1 ankyrin domain. Biochem J 2005; 392 (Pt 1): 13-20
• 10 Pippucci T, Maresca A, Magini P. et al. Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy. EMBO Mol Med 2015; 7 (06) 848-858
• 11 Greisenegger EK, Llufriu S, Chamorro A. et al. A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke. J Neurol 2021; 268 (03) 810-816
• 12 Parmeggiani A, Posar A, De Giorgi LB. et al. Sneddon syndrome, arylsulfatase A pseudodeficiency and impairment of cerebral white matter. Brain Dev 2000; 22 (06) 390-393
• 13 Bras J, Guerreiro R, Santo GC. Mutant ADA2 in vasculopathies. N Engl J Med 2014; 371 (05) 478-480
• 14 Chabriat H, Joutel A, Tournier-Lasserve E, Bousser MG. CADASIL: yesterday, today, tomorrow. Eur J Neurol 2020; 27 (08) 1588-1595
• 15 Baron-Menguy C, Domenga-Denier V, Ghezali L, Faraci FM, Joutel A. Increased Notch3 activity mediates pathological changes in structure of cerebral arteries. Hypertension 2017; 69 (01) 60-70
• 16 Domenga V, Fardoux P, Lacombe P. et al. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev 2004; 18 (22) 2730-2735
• 17 Belin de Chantemèle EJ, Retailleau K, Pinaud F. et al. Notch3 is a major regulator of vascular tone in cerebral and tail resistance arteries. Arterioscler Thromb Vasc Biol 2008; 28 (12) 2216-2224
• 18 Henshall TL, Keller A, He L. et al. Notch3 is necessary for blood vessel integrity in the central nervous system. Arterioscler Thromb Vasc Biol 2015; 35 (02) 409-420
• 19 Tikka S, Baumann M, Siitonen M. et al. CADASIL and CARASIL. Brain Pathol 2014; 24 (05) 525-544
• 20 Schoemaker D, Arboleda-Velasquez JF. Notch3 signaling and aggregation as targets for the treatment of CADASIL and Other NOTCH3-associated small-vessel diseases. Am J Pathol 2021; 191 (11) 1856-1870
• 21 Crow YJ, McMenamin J, Haenggeli CA. et al. Coats' plus: a progressive familial syndrome of bilateral Coats' disease, characteristic cerebral calcification, leukoencephalopathy, slow pre- and post-natal linear growth and defects of bone marrow and integument. Neuropediatrics 2004; 35 (01) 10-19
• 22 Teunissen MWA, Kamsteeg EJ, Sallevelt SCEH. et al. Biallelic variants in the COLGALT1 gene causes severe congenital porencephaly: a case report. Neurol Genet 2021; 7 (02) e564
• 23 Meuwissen ME, Halley DJ, Smit LS. et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med 2015; 17 (11) 843-853
• 24 Crow YJ, Chase DS, Lowenstein Schmidt J. et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A 2015; 167A [phone]