High prevalence of mitochondrial membrane protein-associated neurodegeneration (MPAN) in Estonia

Background: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia, neuropsychiatric abnormalities, and cognitive decline. Hartig et al. (2011) identified that biallelic pathogenic variants in C19orf12 gene cause MPAN. More than 200 affected individuals have been described to date. The prevalence of MPAN is roughly estimated at less than one in 1,000,000. This study aimed to analyze the estimated prevalence of MPAN in Estonia.

Methods: We did a retrospective analysis of all diagnosed MPAN cases. We extracted allele frequency from The Genome Aggregation Database, encompassing variant frequency information from 2,410 individuals of the Estonian Genome Bank. A Bayesian method based on the Hardy-Weinberg principle was used for prevalence calculation.

Results: We identified five individuals with childhood-onset MPAN in four families (age range 13-33 years). In all of them, brain MRI revealed iron accumulation in both the globus pallidus and substantia nigra. Four were homozygous for the most common deletion c.171_181del p.(Gly58fs) (NM_031448.6). One female carried c.172G>A p.(Gly58Arg)and c.391A>G (p.Lys131Glu) on one and c.215C>T (p.Pro72Leu) on the second allele. The allele frequency of the most common c.171_181del11 deletion is 0.002075 in the Estonian population. The estimated prevalence of MPAN 1:176,669 (95% CI: 1:76,201- 1:1,147,273) based on frequencies of pathogenic alleles in Estonian general population.

Conclusion: Individuals homozygous for the deletion c.171_181del11 were initially reported in a Polish cohort of 52 MPAN patients with an allele frequency of 0.001. It was thought to be a founder variant in the Eastern European (Polish) population. Our data suggest that this is maybe a founder variant also in the Baltic population. Careful carrier testing for at-risk relatives should be performed in all detected families.

Funding: PRG471,PSG774.