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

Autor:	Rutten JW; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: j.w.rutten@lumc.nl., Cerfontaine MN; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Dijkstra KL; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Mulder AA; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands., Vreijling J; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Kruit M; Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands., Koning RI; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands., de Bot ST; Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands., van Nieuwenhuizen KM; Department of Neurology, St Jansdal Hospital, Harderwijk, The Netherlands., Baelde HJ; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Berendse HW; Department of Neurology, Amsterdam University Medical Center, location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Mei LH; Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands., Ruijter GJG; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands., Baas F; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Jost CR; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands., van Duinen SG; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Nibbeling EAR; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Gravesteijn G; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Lesnik Oberstein SAJ; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 Jun; Vol. 26 (6), pp. 101105. Date of Electronic Publication: 2024 Feb 27.
DOI:	10.1016/j.gim.2024.101105
Abstrakt:	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. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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