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

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article number101105
JournalGenetics in medicine
Volume26
Issue number6
DOIs
Publication statusPublished - 1 Jun 2024

Keywords

  • Autosomal recessive inheritance
  • Etat-criblé
  • Hemorrhagic stroke
  • NIT1
  • Small vessel disease

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