| Title: | Bi-allelic NIT1 variants cause a brain small vessel disease characterized by movement disorders, massively dilated perivascular spaces, and intracerebral hemorrhage |
| Journal: | Genetics in Medicine |
| Published: | 27 Feb 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38430071/ |
| DOI: | https://doi.org/10.1016/j.gim.2024.101105 |
Publication 10160
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Abstract
PURPOSE: To describe a recessively inherited cerebral small vessel disease, caused by loss-of-function variants in Nitrilase1 (NIT1).</p>
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.</p>
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.</p>
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.</p>
19 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 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
1 Application
| Application ID | Title |
|---|---|
| 74162 | The full phenotypic spectrum of hereditary small vessel diseases and its modifiers |
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