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Modeling Mitochondrial Disease Using Brain Organoids: A Focus on Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes
Published on: October 10, 2025
Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction
1Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy.
Neurology
|October 24, 2008
Summary
A novel Mitofusin 2 (MFN2) mutation (R104W) causes Charcot-Marie-Tooth disease (CMT2) with cognitive and visual impairments. This MFN2 mutation affects brain energy metabolism, highlighting similarities to primary mitochondrial disorders.
Area of Science:
- Neurogenetics
- Mitochondrial Biology
- Neurology
Background:
- Charcot-Marie-Tooth disease (CMT2) is a heterogeneous axonal neuropathy.
- Mutations in the Mitofusin 2 (MFN2) gene are a common cause of CMT2.
- MFN2 mutations can lead to complex phenotypes, including hereditary motor and sensory neuropathy V (HSMN V) and VI (HMSN VI).
Observation:
- A novel MFN2 missense mutation, R104W, was identified in an Italian family.
- Affected individuals presented with peripheral neuropathy, cognitive impairment, and visual disturbances.
- One patient also exhibited spastic paraparesis, indicating central nervous system involvement.
Findings:
- The R104W mutation is located in the MFN2 GTPase domain, affecting a conserved amino acid.
- Sural nerve biopsies revealed normal mitochondrial networks.
- Magnetic resonance spectroscopy (MRS) showed impaired high-energy phosphates (HEPs) in the visual cortex of affected individuals.
Implications:
- Cognitive impairment is a potential feature of MFN2-related CMT2.
- The study highlights the widespread peripheral and central nervous system involvement in MFN2 disorders.
- MFN2-related neuropathies share similarities with primary mitochondrial disorders, suggesting a common pathogenic mechanism.
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