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Neuropathologic Characterisation of Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) With

Laura Gomez-Isaza1, Javier Redding-Ochoa1,2, Maria Luongo1

  • 1Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Neuropathology and Applied Neurobiology
|April 16, 2026
PubMed

Insights

Mitochondrial membrane protein associated neurodegeneration (MPAN) is a rare brain disorder. Autopsy revealed iron buildup and widespread protein aggregates, including alpha-synuclein and tau pathology, in a patient with a C19orf12 gene variant.

Area of Science:

  • Neurology
  • Neurogenetics
  • Neurobiology

Background:

  • Mitochondrial membrane protein associated neurodegeneration (MPAN) is a rare subtype of neurodegeneration with brain iron accumulation (NBIA).
  • MPAN is genetically defined by pathogenic variants in the C19orf12 gene.
  • Understanding the neuropathological features of MPAN is crucial for diagnosis and treatment.

Purpose of the Study:

  • To report the detailed neuropathological findings in an autopsy case of MPAN.
  • To correlate the genetic findings (C19orf12 variant) with the observed brain pathology.
  • To elucidate the spectrum of proteinopathies associated with MPAN.

Main Methods:

  • Autopsy-based neuropathological examination.
  • Histopathological analysis including iron staining.
  • Immunohistochemistry for alpha-synuclein and tau proteins.

Main Results:

  • The case presented with a homozygous C19orf12 missense variant.
  • Neuropathology showed iron deposition in the globus pallidus.
  • Widespread neuroaxonal spheroids and extensive alpha-synuclein pathology were observed in multiple brain regions.
  • Focal tau pathology was identified in the hippocampus and entorhinal cortex.

Conclusions:

  • This case highlights the diverse neuropathological manifestations of MPAN, extending beyond iron accumulation.
  • The presence of both alpha-synuclein and tau pathology in MPAN warrants further investigation.
  • C19orf12 variants are confirmed to cause significant neurodegenerative changes with complex protein aggregation patterns.
Keywords:
C19orf12Lewy bodyMPANNBIAneuroaxonal dystrophy

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