SUCLG1 – Leigh syndrome

SUCLG1 is linked to Leigh syndrome in an autosomal recessive manner. A single unrelated patient presented on day 1 of life with severe lactic acidosis, elevated Krebs cycle metabolites, progressive myopathy, hepatopathy, and bilateral sensorineural hearing loss, culminating in Leigh disease. This individual harbored a homozygous c.40A>T (p.Met14Leu) variant that abolishes the initiator methionine, confirmed by succinyl-CoA ligase deficiency in fibroblasts (PMID:20453710). Genetic confirmation is limited to this proband without additional familial segregation.

Functional analyses across multiple studies demonstrate concordant biochemical defects. Western blot and enzyme assays reveal absent SUCLG1 protein and SCS activity in patient cells, with secondary depletion of SUCLA2 and mtDNA, and mitochondrial dysfunction rescued by wild-type SUCLG1 expression (PMID:20693550; PMID:27484306). The mechanistic data support a loss-of-function mechanism. Taken together, current evidence provides limited genetic but moderate functional support for SUCLG1 deficiency causing Leigh syndrome. Key take-home: SUCLG1 testing can inform diagnosis in neonates with lactic acidosis and Leigh-like presentations.

References

• Pediatric research • 2010 • Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy. PMID:20453710
• Journal of medical genetics • 2010 • The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein. PMID:20693550
• Molecular genetics and metabolism • 2016 • Expanding the phenotypic spectrum of Succinyl-CoA ligase deficiency through functional validation of a new SUCLG1 variant. PMID:27484306

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