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Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series
Gaofeng Zhu1, Blaise Didry-Barca2, Luis Seabra2
1MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
The Lancet. Neurology
|February 22, 2025
Summary
Mutations in PTPN1 cause a rare autoinflammatory encephalopathy driven by type I interferon (IFN) signaling. This condition affects children, leading to neurological decline, but some show improvement with or without treatment.
Area of Science:
- Genetics and Molecular Biology
- Immunology
- Neurology
Background:
- Identified patients with uncharacterized phenotypes showing upregulated type I interferon (IFN) signaling.
- Discovered heterozygous mutations in PTPN1, encoding protein-tyrosine phosphatase 1B (PTP1B).
- Aimed to characterize the clinical, molecular, and cellular aspects of this novel disease.
Purpose of the Study:
- To describe the clinical phenotype of a newly identified disease caused by PTPN1 mutations.
- To investigate the molecular and cellular pathology associated with PTPN1 variants.
- To understand the role of PTP1B in type I IFN signaling.
Main Methods:
- Case series involving 12 patients from 11 families across Europe and Israel.
- Genetic analysis including exome and Sanger sequencing to identify PTPN1 variants.
- Quantitative PCR, NanoString, and cell-based assays to assess gene expression and IFN signaling in patient cells.
Main Results:
- Identified ten novel or rare PTPN1 variants in heterozygous patients.
- Clinical phenotype characterized by subacute onset of motor and language skill loss, spastic dystonia, and bulbar involvement.
- Demonstrated PTPN1 variants led to reduced PTP1B levels and impaired negative regulation of type I IFN signaling, with elevated IFN-stimulated genes in patients.
Conclusions:
- PTPN1 haploinsufficiency results in a type I IFN-driven autoinflammatory encephalopathy.
- Some patients experienced neurological stabilization or recovery spontaneously, while others responded to immune suppression.
- Further prospective studies are required to evaluate specific immune suppression strategies.
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