Autosomal Dominant MPAN: Mosaicism Expands the ClinicalSpectrum to Atypical Late-Onset Phenotypes

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Angelini et al, Movement Disorders 2023 (published online 22 august )

ABSTRACT: 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.

FIGURE: Family pedigrees and molecular results (next generation sequencing [NGS] and Sanger sequencing data on electropherograms). Pedigrees (upper panel) and identification of C19orf12 variants in probands and mosaic parents using NGS (medium panel) and Sanger sequencing (lower panels)
in the four families. NGS reads are presented following a reverse complementary alignment on human genome (Hg19), showing the wild-type nucleotide as a T (patients P4 and P5) or a C (patients P2 and P3) and the variant as an A (Interface from Alamut visual Software). For patients P2 and P4 mosaïcism was calculated as 2-fold the percentage of variant nucleotides considering at these positions in total reads a 50% proportion of each allele, as shown for patient P3. In lower panels, electropherograms of forward Sanger sequencing display C19ORF12 coding DNA (Mutation Surveyor software). Of note the barely visible mosaic variant c.271G > T in frontal cortex of patient P2 with the Sanger method (P2, see arrow).