MFF – Leigh Syndrome

Biallelic loss-of-function variants in MFF underlie an autosomal recessive, early-onset Leigh-like encephalopathy characterized by severe intellectual disability (HP:0010864), microcephaly (HP:0000252), tetraparesis (HP:0002273), optic atrophy (HP:0000648), and ophthalmoplegia (HP:0000602). Six unrelated probands have been described with homozygous or compound heterozygous MFF mutations, including the recurrent homozygous c.892C>T (p.Arg298Ter) variant ([PMID:30581454]). No dominant transmission or multi-generation segregation data have been reported. Patient-derived fibroblasts exhibit abnormal mitochondrial and peroxisomal morphology, markedly reduced MFF protein levels, and truncated products consistent with a loss-of-function mechanism ([PMID:30581454]); complementary Mff-/- mouse embryonic stem cells show mitochondrial elongation and altered bioenergetics ([PMID:32521505]). A heterozygous c.937G>A (p.Glu313Lys) variant has been associated with a mild mitochondrial phenotype resembling myasthenia gravis, suggesting dosage sensitivity of MFF without contradicting the recessive severe Leigh-like syndrome ([PMID:36314214]).

Key Take-home: Biallelic MFF loss-of-function variants should be considered in infants and children presenting with Leigh-like MRI patterns and combined mitochondrial-peroxisomal dysfunction, guiding genetic testing and family counseling.

References

• Frontiers in genetics • 2018 • Clinical and Biochemical Features in a Patient With Mitochondrial Fission Factor Gene Alteration. PMID:30581454
• Redox biology • 2020 • Role of mitochondrial fission-related genes in mitochondrial morphology and energy metabolism in mouse embryonic stem cells. PMID:32521505
• Journal of neuromuscular diseases • 2023 • A Heterozygous Mutation in MFF Associated with a Mild Mitochondrial Phenotype. PMID:36314214

Evidence Based Scoring (AI generated)