Autosomal Dominant MPAN: Mosaicism Expands the Clinical Spectrum to Atypical Late‐Onset Phenotypes

Background Mitochondrial membrane protein‐associated neurodegeneration (MPAN) is caused by mutations in the C19orf12 gene. MPAN typically appears in the first two decades of life and presents with progressive dystonia‐parkinsonism, lower motor neuron signs, optic atrophy, and abnormal iron deposits predominantly in the basal ganglia. MPAN, initially considered as a strictly autosomal recessive disease (AR), turned out to be also dominantly inherited (AD). Objectives Our aim was to better characterize the clinical, molecular, and functional spectra associated with such dominant pathogenic heterozygous C19orf12 variants. Methods We collected clinical, imaging, and molecular information of eight individuals from four AD‐MPAN families and obtained brain neuropathology results for one. Functional studies, focused on energy and iron metabolism, were conducted on fibroblasts from AD‐MPAN patients, AR‐MPAN patients, and controls. Results We identified four heterozygous C19orf12 variants in eight AD‐MPAN patients. Two of them carrying the familial variant in mosaic displayed an atypical late‐onset phenotype. Fibroblasts from AD‐MPAN showed more severe alterations of iron storage metabolism and autophagy compared to AR‐MPAN cells. Conclusion Our data add strong evidence of the realness of AD‐MPAN with identification of novel monoallelic C19orf12 variants, including at the mosaic state. This has implications in diagnosis procedures. We also expand the phenotypic spectrum of MPAN to late onset atypical presentations. Finally, we demonstrate for the first time more drastic abnormalities of iron metabolism and autophagy in AD‐MPAN than in AR‐MPAN. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.