Bi-allelic NIT1 variants cause a brain small vessel disease characterized by movement disorders, massively dilated perivascular spaces, and intracerebral hemorrhage

Julie W Rutten; Minne N Cerfontaine; Kyra L Dijkstra; Aat A Mulder; Jeroen Vreijling; Mark Kruit; Roman I Koning; Susanne T de Bot; Koen M van Nieuwenhuizen; Hans J Baelde; Henk W Berendse; Leon H Mei; George J G Ruijter; Frank Baas; Carolina R Jost; Sjoerd G van Duinen; Esther A R Nibbeling; Gido Gravesteijn; Saskia A J Lesnik Oberstein

doi:10.1016/j.gim.2024.101105

Bi-allelic NIT1 variants cause a brain small vessel disease characterized by movement disorders, massively dilated perivascular spaces, and intracerebral hemorrhage

Genet Med. 2024 Feb 27;26(6):101105. doi: 10.1016/j.gim.2024.101105. Online ahead of print.

Authors

Julie W Rutten¹, Minne N Cerfontaine², Kyra L Dijkstra³, Aat A Mulder⁴, Jeroen Vreijling², Mark Kruit⁵, Roman I Koning⁴, Susanne T de Bot⁶, Koen M van Nieuwenhuizen⁷, Hans J Baelde³, Henk W Berendse⁸, Leon H Mei⁹, George J G Ruijter¹⁰, Frank Baas², Carolina R Jost⁴, Sjoerd G van Duinen³, Esther A R Nibbeling², Gido Gravesteijn², Saskia A J Lesnik Oberstein²

Affiliations

¹ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: j.w.rutten@lumc.nl.
² Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
⁶ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
⁷ Department of Neurology, St Jansdal Hospital, Harderwijk, The Netherlands.
⁸ Department of Neurology, Amsterdam University Medical Center, location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁹ Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰ Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.

PMID: 38430071
DOI: 10.1016/j.gim.2024.101105

Abstract

Purpose: To describe a recessively inherited cerebral small vessel disease, caused by loss-of-function variants in Nitrilase1 (NIT1).

Methods: We performed exome sequencing, brain magnetic resonance imaging, neuropathology, electron microscopy, western blotting, and transcriptomic and metabolic analyses in 7 NIT1-small vessel disease patients from 5 unrelated pedigrees.

Results: The first identified patients were 3 siblings, compound heterozygous for the NIT1 c.727C>T; (p.Arg243Trp) variant and the NIT1 c.198_199del; p.(Ala68∗) variant. The 4 additional patients were single cases from 4 unrelated pedigrees and were all homozygous for the NIT1 c.727C>T; p.(Arg243Trp) variant. Patients presented in mid-adulthood with movement disorders. All patients had striking abnormalities on brain magnetic resonance imaging, with numerous and massively dilated basal ganglia perivascular spaces. Three patients had non-lobar intracerebral hemorrhage between age 45 and 60, which was fatal in 2 cases. Western blotting on patient fibroblasts showed absence of NIT1 protein, and metabolic analysis in urine confirmed loss of NIT1 enzymatic function. Brain autopsy revealed large electron-dense deposits in the vessel walls of small and medium sized cerebral arteries.

Conclusion: NIT1-small vessel disease is a novel, autosomal recessively inherited cerebral small vessel disease characterized by a triad of movement disorders, massively dilated basal ganglia perivascular spaces, and intracerebral hemorrhage.

Keywords: Autosomal recessive inheritance; Etat-criblé; Hemorrhagic stroke; NIT1; Small vessel disease.