Familial deep cavitating state with a glutathione metabolism defect

John Rendu, Laetitia Van Noolen, Catherine Garrel, Julie Brocard, Isabelle Marty, Christelle Corne, Julien Fauré, Gérard Besson, John Rendu, Laetitia Van Noolen, Catherine Garrel, Julie Brocard, Isabelle Marty, Christelle Corne, Julien Fauré, Gérard Besson

Abstract

Adult genetic disorders causing brain lesions have been mostly described as white matter vanishing diseases. We present here the investigations realized in patients referred for psychiatric disorder with magnetic resonance imaging showing atypical basal ganglia lesions. Genetic explorations of this family revealed a new hereditary disease linked to glutathione metabolism.

Keywords: NIT1.

Conflict of interest statement

Nothing to report.

© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
(A) Pedigree of the family. (B and C) Sequencing for the c.457G > A and c.670dupA variants upper part shows a control sequence (C) and the lower part shows the sequence from patient II.5 (P). (D) NIT1 protein detection. Proteins were extracted from skin cutaneous control (C) or patient II.5 (P) fibroblasts and separated on SDS‐PAGE. Anti‐Nit1 antibody (Abcam®) or anti‐Tubulin antibody (loading control) was used for the western blot. (E) GC/MS detection of a dGSH derivative in the urine of patient II.4 as described.9, 10 The compound only present in the patient urine is marked by an arrow on the chromatogram (upper part) with retention time of 34.45 min. It was identified as dGSH by mass spectrometry (lower part) by the presence of two specific peaks (circle). The mass spectrum of the compound is similar to the one present in the urine of Nit1‐Knock Out mice and corresponds to a dGSH derivative (m/z 398 for the apparent molecular ion, m/z 383 for M‐15, and m/z 355) as previously described9. The same peaks were observed in urine of his brothers (II.5 and II.7) but were undetectable in the other siblings tested and the mother.
Figure 2
Figure 2
Brain MRI of the patient II.5. Axial T2‐weighted image showing deep cavitating state (3 T).

References

    1. Besson G, Hommel M. Historical aspects of lacunes and the “lacunar controversy”. Adv Neurol 1993;62:1–10.
    1. Marie P. Des foyers lacunaires de désintégration et de différents autres états cavitaires du cerveau. Rev Med 1901;281–298.
    1. Reuling R, Herring A. Cavities in the brain produced by the bacillus aerogenes capsulatus. Bull Johns Hopkins Hosp 1899;62–65.
    1. Ayrignac X, Menjot de Champfleur N, Menjot de Champfleur S, et al. Brain magnetic resonance imaging helps to differentiate atypical multiple sclerosis with cavitary lesions and vanishing white matter disease. Eur J Neurol 2016;23:995–1000.
    1. Yavuz H. A review of infantile vanishing white matter disease and a new mutation. Acta Neurol Taiwan 2017;26:167–176.
    1. Lerman‐Sagie T, Leshinsky‐Silver E, Watemberg N, et al. White matter involvement in mitochondrial diseases. Mol Genet Metab 2005;84:127–136.
    1. Wong L‐JC. Mitochondrial syndromes with leukoencephalopathies. Semin Neurol 2012;32:55–61.
    1. Zhang J, Liu M, Zhang Z, et al. Genotypic spectrum and natural history of cavitating leukoencephalopathies in childhood. Pediatr Neurol 2019;94:38–47.
    1. Peracchi A, Veiga‐da‐Cunha M, Kuhara T, et al. Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione. Proc Natl Acad Sci USA 2017;114:E3233–E3242.
    1. Jones PM, Bennett MJ. Urine organic acid analysis for inherited metabolic disease using gas chromatography‐mass spectrometry. Methods Mol Biol 2010;603:423–431.
    1. Ayrignac X, Carra‐Dalliere C, Menjot de Champfleur N, et al. Adult‐onset genetic leukoencephalopathies: a MRI pattern‐based approach in a comprehensive study of 154 patients. Brain 2015;138(Pt 2):284–292.
    1. Scelsa B, Gasperini S, Righini A, et al. Mild phenotype in Molybdenum cofactor deficiency: a new patient and review of the literature. Mol Genet Genomic Med 2019;7:e657.
    1. Claerhout H, Witters P, Régal L, et al. Isolated sulfite oxidase deficiency. J Inherit Metab Dis 2018;41:101–108.
    1. Niehaus TD, Patterson JA, Alexander DC, et al. The metabolite repair enzyme Nit1 is a dual‐targeted amidase that disposes of damaged glutathione in Arabidopsis. Biochem J 2019;476:683–697.
    1. Mittag S, Valenta T, Weiske J, et al. A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β‐catenin signalling pathway. Cell Discov 2016;2:15039.

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