Functional characterization of a biallelic variant associated with global developmental delay, infantile epileptic spasms syndrome, and hypotonia.

The mitochondrial intermediate peptidase (MIP) catalyzes the post-import removal of an N-terminal octapeptide from a subset of nuclear-encoded mitochondrial proteins. While the mechanistic role of this processing remains unclear, biallelic variants have been linked to respiratory chain dysfunction and mitochondrial disease. Patients expressing these variants most often presented with cardiomyopathy, variable neurological defects, and early mortality. Here, we report the identification and functional characterization of a homozygous variant in a patient presenting with a comparatively milder clinical phenotype involving global developmental delay, infantile epileptic spasms syndrome, and hypotonia. Analyses of patient-derived fibroblasts revealed reduced MIP abundance and impaired processing of established MIP substrates MRPL12, NDUFV2, and ATP5F1. Expression of wild-type restored these defects, confirming the pathogenic nature of the variant. Thus, our findings expand the genetic and phenotypic spectrum of -linked disease.KEYWORDSCOXPD31, MIP, MIPEP, Mitochondrial disease, Mitochondrial intermediate peptidase, Mitochondrial proteostasis, OXPHOS assembly defect© 2026 The Authors. Published by Elsevier Inc.