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Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series
G. Zhu, B. Didry-Barca, L. Seabra, GI. Rice, C. Uggenti, M. Touimy, MP. Rodero, RH. Trapero, V. Bondet, D. Duffy, P. Gautier, K. Livingstone, FJH. Sutherland, P. Lebon, M. Parisot, C. Bole-Feysot, C. Masson, N. Cagnard, P. Nitschké, G. Anderson,...
Language English Country England, Great Britain
Document type Journal Article
Grant support
786142
European Research Council - International
MC_UU_00035/11
Medical Research Council - United Kingdom
NLK
ProQuest Central
from 2002-05-01 to 2 months ago
Nursing & Allied Health Database (ProQuest)
from 2002-05-01 to 2 months ago
Health & Medicine (ProQuest)
from 2002-05-01 to 2 months ago
Psychology Database (ProQuest)
from 2002-05-01 to 2 months ago
- MeSH
- Child MeSH
- Haploinsufficiency * genetics MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Mutation genetics MeSH
- Brain Diseases genetics MeSH
- Neuroinflammatory Diseases genetics MeSH
- Child, Preschool MeSH
- Protein Tyrosine Phosphatase, Non-Receptor Type 1 * genetics MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Through the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation of type I interferon (IFN) signalling, we identified a cohort of individuals heterozygous for mutations in PTPN1, encoding the protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe the clinical phenotype and molecular and cellular pathology of this new disease. METHODS: In this case series, we identified patients and collected clinical and neuroradiological data through collaboration with paediatric neurology and clinical genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, and the UK) and Israel. Variants in PTPN1 were identified by exome and directed Sanger sequencing. The expression of IFN-stimulated genes was determined by quantitative (q) PCR or NanoString technology. Experiments to assess RNA and protein expression and to investigate type 1 IFN signalling were undertaken in patient fibroblasts, hTERT-immortalised BJ-5ta fibroblasts, and RPE-1 cells using CRISPR-Cas9 editing and standard cell biology techniques. FINDINGS: Between Dec 20, 2013, and Jan 11, 2023, we identified 12 patients from 11 families who were heterozygous for mutations in PTPN1. We found ten novel or very rare variants in PTPN1 (frequency on gnomAD version 4.1.0 of <1·25 × 10:sup>-6). Six variants were predicted as STOP mutations, two involved canonical splice-site nucleotides, and two were missense substitutions. In three patients, the variant occurred de novo, whereas in nine affected individuals, the variant was inherited from an asymptomatic parent. The clinical phenotype was characterised by the subacute onset (age range 1-8 years) of loss of motor and language skills in the absence of seizures after initially normal development, leading to spastic dystonia and bulbar involvement. Neuroimaging variably demonstrated cerebral atrophy (sometimes unilateral initially) or high T2 white matter signal. Neopterin in CSF was elevated in all ten patients who were tested, and all probands demonstrated an upregulation of IFN-stimulated genes in whole blood. Although clinical stabilisation and neuroradiological improvement was seen in both treated and untreated patients, in six of eight treated patients, high-dose corticosteroids were judged clinically to result in an improvement in neurological status. Of the four asymptomatic parents tested, IFN signalling in blood was normal (three patients) or minimally elevated (one patient). Analysis of patient blood and fibroblasts showed that tested PTPN1 variants led to reduced levels of PTPN1 mRNA and PTP1B protein, and in-vitro assays demonstrated that loss of PTP1B function was associated with impaired negative regulation of type 1 IFN signalling. INTERPRETATION: PTPN1 haploinsufficiency causes a type 1 IFN-driven autoinflammatory encephalopathy. Notably, some patients demonstrated stabilisation, and even recovery, of neurological function in the absence of treatment, whereas in others, the disease appeared to be responsive to immune suppression. Prospective studies are needed to investigate the safety and efficacy of specific immune suppression approaches in this disease population. FUNDING: The UK Medical Research Council, the European Research Council, and the Agence Nationale de la Recherche.
APHP Centre de Référence LEUKOFRANCE Service de Neuropediatrie Hopital Robert Debre Paris France
Department of Diagnostic Imaging Rambam Health Care Campus Faculty of Medicine Technion Haifa Israel
Department of General Paediatrics Armand Trousseau Hospital AP HP Sorbonne Université Paris France
Department of Neurology Great Ormond Street Hospital for Children London UK
Department of Neuroradiology Heidelberg University Hospital Heidelberg Germany
Department of Neuroscience Institute of Child Health University College London London UK
Department of Paediatric Neurology Oxford University Hospitals NHS Foundation Trust Oxford UK
Department of Radiology Great Ormond Street Hospital for Children London UK
Evelina London Children's Hospital Guy's and St Thomas' NHS Foundation Trust London UK
Faculty of Medical and Health Sciences Tel Aviv University Tel Aviv Israel
Institute for Neurogenomics Helmholtz Zentrum München Neuherberg Germany
Institute of Paediatric Neurology Schneider Children's Medical Centre of Israel Petach Tikva Israel
Medical School Université Paris Cité Paris France
MRC Human Genetics Unit Institute of Genetics and Cancer University of Edinburgh Edinburgh UK
Pediatric Neurology Institute Dana Dwek Children's Hospital
Service de Génétique Centre Hospitalier Universitaire d'Angers Angers France
Service de Neuropédiatrie Hôpital de la Timone Enfants Marseille France
Tel Aviv Sourasky Medical Center Faculty of Medicine Tel Aviv University Tel Aviv Israel
Translational Immunology Unit Institut Pasteur Université Paris Cité Paris France
Unit of Child Neuropsychiatry EpiCARE Network IRCCS Giannina Gaslini Genova Italy
Unité de Neurologie de l'Enfant et de l'Adolescent CHU Pellegrin Bordeaux France
Universite Paris Cité NeuroDiderot UMR INSERM 1141 Hopital Robert Debre Paris France
References provided by Crossref.org
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