SERAC1 – 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome

SERAC1 defects underlie MEGDEL syndrome (3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome), an autosomal recessive mitochondrial disorder. Affected individuals present with elevated urinary 3-methylglutaconic acid, developmental delay, hypotonia, sensorineural hearing impairment, and Leigh-like lesions on brain MRI (PMID:22683713; PMID:32684373). Over 100 patients from more than 20 unrelated families have been reported, confirming a consistent phenotype and inheritance pattern.

Biallelic SERAC1 variants include frameshift, nonsense, splice, and missense changes. Notable pathogenic alleles are c.1018del (p.Trp340GlyfsTer9) (PMID:25051967), c.202C>T (p.Arg68Ter) (PMID:23707711), and c.671A>G (p.Asp224Gly) (PMID:26445863). More than 40 unique variants have been identified across diverse populations, with segregation confirmed in multiple consanguineous pedigrees (PMID:35943861).

The clinical spectrum encompasses 3-methylglutaconic aciduria (HP:0003535), hypotonia (HP:0001252), global developmental delay (HP:0001263), sensorineural hearing impairment (HP:0000407), dystonia, hepatopathy, seizures, and failure to thrive. Magnetic resonance imaging typically reveals bilateral basal ganglia and thalamic T2 hyperintensities consistent with Leigh-like encephalopathy.

Functional studies demonstrate that SERAC1 localizes to mitochondria-associated membranes, mediating phosphatidylglycerol remodeling. Patient fibroblasts exhibit altered cardiolipin subspecies and cholesterol accumulation, which are partially normalized by lentiviral complementation with wild-type SERAC1 (PMID:22683713). Serac1 knockout mice recapitulate key biochemical and histopathological features and show mtDNA depletion that is restored by nucleoside supplementation (PMID:35235340).

Pathogenic mechanism is loss of function leading to disrupted phospholipid exchange at the ER–mitochondria interface, impaired oxidative phosphorylation, and secondary respiratory chain deficiency. The absence of SERAC1 perturbs calcium buffering and cardiolipin composition, precipitating energy failure in high-demand tissues.

Overall, the SERAC1–MEGDEL syndrome association meets Definitive ClinGen criteria based on extensive genetic and experimental concordance. Genetic testing for SERAC1 should be incorporated into diagnostic workflows for early identification, genetic counseling, and potential nucleoside-based therapeutic strategies.

References

• Nature Genetics • 2012 • Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. PMID:22683713
• Molecular Genetics and Metabolism • 2013 • Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria. PMID:23707711
• Journal of Child Neurology • 2015 • MEGDEL Syndrome in a Child From Palestine: Report of a Novel Mutation in SERAC1 Gene. PMID:25051967
• Neurogenetics • 2016 • First missense mutation outside of SERAC1 lipase domain affecting intracellular cholesterol trafficking. PMID:26445863
• Pediatric Neurology • 2020 • MEGDEL Syndrome. PMID:32684373
• Science Translational Medicine • 2022 • SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA. PMID:35235340
• International Journal of Developmental Neuroscience • 2022 • First description of the MEGDEHL syndrome in the Tunisian population via whole-exome sequencing: Novel nonsense mutation in SERAC1 gene. PMID:35943861

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