Mitochondrial membrane protein-associated neurodegeneration (mpan) in Denmark - prevalence, clinical features and molecular background

Background Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an ultra-rare neurodegenerative disease belonging to a group of diseases known as neurodegeneration with brain iron accumulation (NBIAs). Clinical findings include gait disturbances, spasticity, and cognitive impairment, as well as iron deposition in the basal ganglia. The disease is typically inherited in an autosomal recessive pattern and caused by pathogenic variants in the C19orf12 gene, which encodes a mitochondrial membrane protein, the function of which is not fully understood. Objective This nationwide study aimed to identify and describe MPAN patients in Denmark, focusing on the prevalence, clinical features, and pathogenic variants. Additionally, the study sought to further elucidate the genotype-phenotype spectrum of MPAN with additional cases that expand understanding of disease characteristics associated with C19orf12 variants. Methods A case-based approach was applied in the description of the clinical and genetic features of the included patients. Three patients were identified at Copenhagen University Hospital, Rigshospitalet, and one patient at Aarhus University Hospital, through a Danish national network, NeuroGENet. Clinical data was extracted from health records with patient consent. Results The prevalence of MPAN in Denmark was estimated to be 1/1,500,000. Four patients with biallelic pathogenic variants in C19orf12 were identified, including two siblings. All patients’ parents were consanguineous of Middle Eastern backgrounds. Of the two patients, homozygous for c·187 G > C, p.(Ala63Pro), one showed no signal changes on MRI of the brain, while the other did reveal discreet hypointensities, most likely representing iron. Both patients had milder phenotypes. Two patients were homozygous for c·32C > T, (p.Thr11Met) and had more severe symptoms with cognitive impairment and iron deposition on MRI. Discussion and conclusions The prevalence of C19orf12 -related diseases is considered low among the ethnic Danish population, in comparison to other published estimates. The identified patients homozygous for c·187 G > C, p.(Ala63Pro) tend to have milder phenotypes and show a lesser tendency to brain iron accumulation. Given these findings and the broad clinical spectrum of patients with pathogenic C19orf12 variants, it may be more appropriate to classify patients as being on a C19orf12 -disease-spectrum rather than belonging to the group of NBIAs.