MECR – Childhood-onset Dystonia with Optic Atrophy and Basal Ganglia Abnormalities

MEPAN syndrome is a rare autosomal recessive neurodegenerative disorder caused by biallelic loss-of-function variants in MECR. A single case report detailed a patient presenting with early childhood dystonia, basal ganglia signal abnormalities on MRI, and progressive bilateral optic atrophy, confirmed by slit-lamp exam, fundus photography, OCT, visual field testing, ERG, and VEP assessments (PMID:36262091). A subsequent study described two sisters from a consanguineous family with sudden, painless visual loss, partial recovery, and persistent central scotomas, expanding the optic phenotype to an LHON-like presentation (PMID:37734847).

Genetically, three probands from two unrelated families harbor homozygous MECR variants under an autosomal recessive inheritance pattern. Segregation within the sibling pair supports pathogenicity, and all affected individuals carry the same missense change, c.772C>T (p.Arg258Trp), in homozygous state. This variant affects a conserved residue in the mitochondrial enoyl-CoA reductase domain and is absent from population databases, consistent with a deleterious effect.

Functional assays in Saccharomyces cerevisiae and patient fibroblasts demonstrated significant loss of MECR protein stability and enzymatic activity. Yeast bearing the MECR-R258W mutation showed impaired oxidative growth, a 30 percent reduction in oxygen consumption rate, and an 80 percent decrease in MECR levels, indicating structural destabilization of the enzyme. Patient fibroblasts confirmed reduced MECR abundance and heightened sensitivity to H₂O₂, although OXPHOS complex assembly remained intact.

Mechanistically, MECR deficiency impairs mitochondrial fatty acid synthesis (mtFAS) and lipoic acid-dependent enzyme lipoylation, leading to retinal ganglion cell and basal ganglia neuron vulnerability. Lipoic acid supplementation partially rescued the yeast growth defect, suggesting a potential therapeutic avenue. These findings mirror mitochondrial optic neuropathies such as Leber hereditary optic neuropathy and autosomal dominant optic atrophy, highlighting common pathways of RGC loss.

Integration of genetic and functional data supports a Moderate ClinGen clinical validity classification. Three affected individuals across two families, autosomal recessive segregation, and concordant yeast and cellular modeling meet criteria for a moderate gene-disease association. Further natural history studies and additional cohorts would bolster this evidence base.

Key take-home: Biallelic MECR variants cause childhood-onset dystonia with optic atrophy and basal ganglia abnormalities; genetic testing for MECR and consideration of lipoic acid supplementation may inform diagnosis and management.

References

• Ophthalmic genetics • 2023 • Ophthalmic manifestations of MEPAN syndrome. PMID:36262091
• Journal of medical genetics • 2023 • Recessive MECR pathogenic variants cause an LHON-like optic neuropathy. PMID:37734847

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