MFF – Encephalopathy due to defective mitochondrial and peroxisomal fission 2

A rare autosomal recessive encephalopathy has been linked to biallelic loss-of-function variants in MFF, encoding the mitochondrial fission factor. To date, only a single unrelated proband has been reported, a young child of Indian descent presenting with global developmental regression, spasticity and visual impairment, harboring a novel homozygous truncating variant c.355C>T (p.Arg119Ter) (PMID:32181496). No additional segregation data are available, and only three prior reports have described pathogenic MFF variants in this phenotype.

Functional studies demonstrate concordant mitochondrial fission defects: patient-derived lymphoblastoid cells exhibit abnormal mitochondrial morphology attributable to impaired fission (PMID:32181496), and Mff–/– mouse embryonic stem cells display elongated mitochondria and altered metabolic profiles, including increased oxidative phosphorylation and ATP production (PMID:32521505). These data support a loss-of-function mechanism but further clinical series and segregation analyses are required to strengthen the association.

Key take-home: MFF sequencing should be considered in early-onset encephalopathy with fission defects, though evidence remains limited for definitive clinical validity.

References

• Clinical genetics • 2020 • Encephalopathy due to defective mitochondrial and peroxisomal fission 2 caused by a novel MFF gene mutation in a young child. PMID:32181496
• Redox biology • 2020 • Role of mitochondrial fission-related genes in mitochondrial morphology and energy metabolism in mouse embryonic stem cells. PMID:32521505

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