Language

English

Publication Date

7-1-2026

Journal

JIMD Reports

DOI

10.1002/jmd2.70096

PMID

42375813

PMCID

PMC13312033

PubMedCentral® Posted Date

6-29-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Biallelic pathogenic variants in PNPT1 cause combined oxidative phosphorylation deficiency 13 (COXPD13) (MIM #614932), linking mitochondrial dysfunction to type I interferon (IFN) activation through cytosolic leakage of mitochondrial double‐stranded RNA (mt‐dsRNA). This mechanism connects mitochondrial disease to interferonopathies such as Aicardi–Goutières syndrome (AGS). We describe a 7‐month‐old female infant with compound heterozygous PNPT1 variants presenting with severe hypotonia, feeding difficulties necessitating gastrostomy, dystonia, and elevated serum lactate. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar, brainstem, and basal ganglia atrophy, with a lactate peak on MR spectroscopy (consistent with an inverted doublet). Serum immune profiling revealed a mild but elevated type I IFN signature. Given the mechanistic overlap with AGS, off‐label tofacitinib, a Janus kinase (JAK) inhibitor that blocks IFN‐driven JAK/STAT signaling, was initiated following pediatric interferonopathy dosing protocols. Tofacitinib was associated with normalization of serum type I IFN biomarkers, reduction in lactate and transaminases, improvement in dystonic movements, ventilatory stability, and improved growth/nutrition without treatment‐limiting adverse events. To our knowledge, this represents the first reported use of JAK inhibition in COXPD13. The observed clinical and biochemical stabilization supports defining COXPD13 as a “mitochondrial interferonopathy” and suggests that IFN‐signature screening may identify mitochondrial disease patients who could benefit from targeted immunomodulation.

Keywords

COXPD13, JAK inhibitor, mitochondrial interferonopathy, PNPT1, polynucleotide phosphorylase (PNPase), tofacitinib, type I interferon

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.