Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Mitochondrial complex II deficiency, nuclear type 1 (MONDO:0100294) is a rare autosomal recessive disorder characterized by impaired activity of succinate dehydrogenase (complex II), manifesting in early‐onset encephalopathy, cardiomyopathy, hypotonia, and lactic acidosis. SDHA (HGNC:10680) encodes the flavoprotein subunit of complex II, which catalyzes the oxidation of succinate to fumarate and funnels electrons into the respiratory chain. Biallelic pathogenic SDHA variants disrupt FAD binding or protein stability, leading to markedly reduced complex II activity and multisystem mitochondrial dysfunction.
Genetic evidence supports a strong gene–disease association. Compound heterozygous SDHA variants (c.1945_1946del (p.Leu649GlufsTer4)) were identified in two unrelated patients presenting with encephalopathy, developmental regression, cardiomyopathy, muscle weakness, and elevated lactate (PMID:37064335). A separate cohort included a patient with recessive SDHA missense variants (c.1523C>T (p.Thr508Ile)) causing leukodystrophy and cardiomyopathy (PMID:22972948). Four additional patients harbored splice‐site and missense variants (including c.565T>G (p.Cys189Gly)) leading to isolated complex II deficiency and Leigh syndrome–like features (PMID:24781757). These reports encompass at least seven unrelated probands with diverse loss‐of‐function and hypomorphic alleles, consistent with autosomal recessive inheritance.
Functional assessments corroborate pathogenicity. Patient‐derived fibroblasts and muscle biopsies demonstrate severely reduced complex II enzymatic activity and absent SDHA protein on western blot and immunohistochemistry. Yeast complementation assays confirm that missense variants impair FAD incorporation and enzyme assembly, while lentiviral complementation restores complex II function in patient cells (PMID:24781757). The concordance between genetic findings and biochemical deficits supports haploinsufficiency of SDHA as the primary mechanism.
No conflicting evidence has been reported linking SDHA variants to alternative disorders in the context of isolated complex II deficiency. Experimental and clinical data converge on a loss‐of‐function model.
In summary, SDHA is definitively implicated in mitochondrial complex II deficiency, nuclear type 1 through multiple biallelic loss‐of‐function variants across unrelated families, supported by robust functional studies. Diagnostic sequencing of SDHA should be considered in patients with early‐onset encephalopathy, cardiomyopathy, and elevated lactate. Therapeutic approaches including riboflavin and mitochondrial cofactor supplementation may offer partial benefit.
Key Take-home: Biallelic SDHA variants cause autosomal recessive complex II deficiency with consistent clinical and biochemical features, enabling targeted genetic diagnosis and management.
Gene–Disease AssociationStrongMultiple (≥7) unrelated probands across four reports; consistent autosomal recessive inheritance; concordant functional and biochemical data Genetic EvidenceStrongAt least seven probands with biallelic SDHA loss-of-function variants (frameshift, splice, missense) demonstrating AR segregation and reaching genetic evidence cap Functional EvidenceModeratePatient cells and yeast models show severely reduced complex II activity, SDHA protein loss, and rescue by complementation |