SDHA – SDHA-related Leigh Syndrome

SDHA encodes the flavoprotein subunit A of mitochondrial complex II and is critical for succinate oxidation in the tricarboxylic acid cycle. Biallelic loss-of-function variants in SDHA cause early-onset Leigh syndrome, an autosomal recessive neurodegenerative disorder characterized by psychomotor regression and symmetrical central nervous system lesions.

Leigh syndrome (LS) typically presents in infancy with developmental delay, hypotonia, seizures, and elevated lactate levels. Brain imaging reveals bilateral lesions in basal ganglia or brainstem consistent with mitochondrial dysfunction. Accurate molecular diagnosis guides management and genetic counseling in this life-limiting condition.

Autosomal recessive inheritance of SDHA variants has been confirmed in seven unrelated probands with clinical LS features: a compound heterozygote for c.357G>A (p.Trp119Ter) and p.Ala83Val in an infant with epilepsy and psychomotor retardation ([PMID:16361598]); a homozygous c.1664G>A (p.Gly555Glu) in a patient with variable phenotypic severity ([PMID:16798039]); four individuals harboring splicing and missense mutations including c.1065-3C>A and c.565T>G (p.Cys189Gly) presenting with multisystem mitochondrial disease and LS ([PMID:24781757]); and a Chinese patient with c.409G>C (p.Asp137His) and c.1A>G (p.Met1Val) compound heterozygosity presenting with developmental delay, hypotonia, and epilepsy ([PMID:35014173]).

Segregation data, while limited by small pedigrees, consistently show co-segregation of biallelic SDHA variants with LS phenotypes in non-consanguineous families. No heterozygous carriers exhibit neurological symptoms, supporting a recessive loss-of-function mechanism.

Functional studies demonstrate markedly reduced complex II activity in patient-derived muscle or fibroblasts and accumulation of succinate in white matter. Three-dimensional modeling predicts destabilization of the FAD-binding domain for variants such as p.Trp119Ter, and lentiviral complementation of SDHA restores enzymatic activity in vitro ([PMID:24781757]). These concordant assays confirm pathogenic loss-of-function as the mechanism underlying LS in SDHA mutation carriers.

Together, genetic and experimental evidence establishes a Strong gene-disease association between SDHA and Leigh syndrome. SDHA should be included in diagnostic gene panels for mitochondrial disorders to enable early diagnosis and inform genetic counseling. Key take-home: identification of biallelic SDHA variants enables precise diagnosis, prognostication, and management in Leigh syndrome.

References

• Journal of neurology, neurosurgery, and psychiatry • 2006 • Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). PMID:16361598
• Molecular genetics and metabolism • 2006 • Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II. PMID:16798039
• European journal of human genetics • 2015 • SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors. PMID:24781757
• American journal of medical genetics. Part A • 2022 • Whole-exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees. PMID:35014173

Evidence Based Scoring (AI generated)