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

• DOI: 10.1016/j.gim.2024.101105
• Publication Date: 2024-02-27T17:21:17Z
• Authors: 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 Nieuw...; 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. Nibbe...; Gido Gravesteijn; Saskia A.J. Lesni...
• Keywords: Etat-crible; NIT1; Hemorrhagic stroke; Autosomal recessive inheritance; Small vessel disease

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