Retrospective analysis of 17 patients with mitochondrial membrane protein-associated neurodegeneration diagnosed in Russia

Parkinsonism Relat Disord. 2021 Mar:84:98-104. doi: 10.1016/j.parkreldis.2021.02.002. Epub 2021 Feb 9.

Abstract

Introduction: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare neurological syndrome caused by pathogenic variants in the C19orf12 and is characterized by iron deposition in the basal ganglia and substantia nigra. Only a limited number of cohort studies were published to date and the prevalence of MPAN remains uncertain.

Methods: Recruited subjects with MPAN in Russia were diagnosed by whole-exome sequencing or Sanger sequencing of the C19orf12 gene. Data of over 14000 whole exome sequencing analyses was used to calculate the estimated disease frequency. RNA analysis was performed by RT-PCR. QSVanalyzer software was used to quantify the allelic disbalance.

Results: We describe the clinical and molecular characterizations of 17 patients with MPAN. DNA analysis detected three previously undescribed pathogenic/likely pathogenic variants in the C19orf12 gene. The estimated disease frequency was calculated to be 1:619150. We describe unusual clinical observations in several cases. One patient showed severe neurogenic muscle weakness along with a lack of marked spasticity or optic nerve atrophy. In another mild clinical case with the NM_001031726.3:c.204_214del (p.(Gly69Argfs*10)) variant in a heterozygous state, a marked allelic disbalance was observed on the RNA level with reduced expression level of the wild-type allele. Thus, this case became the first one of a possible regulatory variant causing MPAN.

Conclusion: We reported a detailed clinical and molecular characterization of the third-largest MPAN cohort. We expanded the mutational and clinical spectrum of MPAN. Moreover, we calculated the estimated MPAN frequency in the Russian population for the first time.

Keywords: MPAN; MRI; NBIA; Pathogenic variants; Russian cohort.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Exome Sequencing
  • Female
  • Globus Pallidus / diagnostic imaging
  • Globus Pallidus / pathology*
  • Humans
  • Iron Metabolism Disorders* / epidemiology
  • Iron Metabolism Disorders* / genetics
  • Iron Metabolism Disorders* / pathology
  • Iron Metabolism Disorders* / physiopathology
  • Magnetic Resonance Imaging
  • Membrane Proteins*
  • Mitochondrial Membranes*
  • Mitochondrial Proteins*
  • Neuroaxonal Dystrophies* / epidemiology
  • Neuroaxonal Dystrophies* / genetics
  • Neuroaxonal Dystrophies* / pathology
  • Neuroaxonal Dystrophies* / physiopathology
  • Retrospective Studies
  • Russia / epidemiology
  • Substantia Nigra / diagnostic imaging
  • Substantia Nigra / pathology*

Substances

  • Membrane Proteins
  • Mitochondrial Proteins

Supplementary concepts

  • Neurodegeneration with brain iron accumulation (NBIA)