TY - JOUR
T1 - Bi-allelic NIT1 variants cause a brain small vessel disease characterized by movement disorders, massively dilated perivascular spaces, and intracerebral hemorrhage
AU - Rutten, Julie W.
AU - Cerfontaine, Minne N.
AU - Dijkstra, Kyra L.
AU - Mulder, Aat A.
AU - Vreijling, Jeroen
AU - Kruit, Mark
AU - Koning, Roman I.
AU - de Bot, Susanne T.
AU - van Nieuwenhuizen, Koen M.
AU - Baelde, Hans J.
AU - Berendse, Henk W.
AU - Mei, Leon H.
AU - Ruijter, George J. G.
AU - Baas, Frank
AU - Jost, Carolina R.
AU - van Duinen, Sjoerd G.
AU - Nibbeling, Esther A. R.
AU - Gravesteijn, Gido
AU - Lesnik Oberstein, Saskia A. J.
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024/6/1
Y1 - 2024/6/1
N2 - 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.
AB - 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.
KW - Autosomal recessive inheritance
KW - Etat-criblé
KW - Hemorrhagic stroke
KW - NIT1
KW - Small vessel disease
UR - http://www.scopus.com/inward/record.url?scp=85188478868&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2024.101105
DO - 10.1016/j.gim.2024.101105
M3 - Article
C2 - 38430071
SN - 1098-3600
VL - 26
JO - Genetics in medicine
JF - Genetics in medicine
IS - 6
M1 - 101105
ER -