PNPT1 mutations may cause Aicardi-Goutie` res-Syndrome - Kölner UniversitätsPublikationsServer

Bamborschke, Daniel, Kreutzer, Mona, Koy, Anne, Koerber, Friederike, Lucas, Nadja, Huenseler, Christoph, Herkenrath, Peter, Lee-Kirsch, Min Ae and Cirak, Sebahattin (2021). PNPT1 mutations may cause Aicardi-Goutie` res-Syndrome. Brain Dev., 43 (2). S. 320 - 325. AMSTERDAM: ELSEVIER. ISSN 1872-7131

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DOI:10.1016/j.braindev.2020.10.005

Abstract

Background: Aicardi-Goutie'res syndrome (AGS) is a clinically and genetically heterogenous autoinflammatory disorder caused by constitutive activation of the type I interferon axis. It has been associated with the genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1. The clinical diagnosis of AGS is usually made in the context of early-onset encephalopathy in combination with basal ganglia calcification or white matter abnormalities on cranial MRI and laboratory prove of interferon I activation. Case presentation: We report a patient with early-onset encephalopathy, severe neurodevelopmental regression, progressive secondary microcephaly, epilepsy, movement disorder, and white matter hyperintensities on T2 weighted MRI images. Via whole-exome sequencing, we identified a novel homozygous missense variant (c.1399C > T, p.Pro467Ser) in PNPT1 (NM_033109). Longitudinal assessment of the interferon signature showed a massively elevated interferon score and chronic type I interferon-mediated autoinflammation. Conclusion: Bi-allelic mutations in PNPT1 have been reported in early-onset encephalopathy. Insufficient nuclear RNA import into mitochondria with consecutive disruption of the respiratory chain was proposed as the main underlying pathomechanism. Recent studies have shown that PNPT1 deficiency causes an accumulation of double-stranded mtRNAs in the cytoplasm, leading to aberrant type I interferon activation, however, longitudinal assessment has been lacking. Here, we present a case of AGS with continuously elevated type I interferon signature with a novel likely-pathogenic homozygous PNTP1 variant. We highlight the clinical value of assessing the interferon signature in children with encephalopathy of unknown origin and suggest all patients presenting with a phenotype of AGS should be screened for mutations in PNPT1. (C) 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Item Type:

Journal Article

Creators:

Creators	Email	ORCID	ORCID Put Code
Bamborschke, Daniel	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Kreutzer, Mona	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Koy, Anne	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Koerber, Friederike	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Lucas, Nadja	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Huenseler, Christoph	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Herkenrath, Peter	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Lee-Kirsch, Min Ae	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Cirak, Sebahattin	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED