SDHB – SDHB-related Mitochondrial Complex II Deficiency

Bi-allelic pathogenic variants in SDHB (succinate dehydrogenase subunit B) cause an autosomal-recessive mitochondrial disease characterized by isolated complex II deficiency. SDHB encodes the iron–sulfur subunit of mitochondrial complex II, which catalyzes succinate oxidation in the tricarboxylic acid cycle and feeds electrons into the respiratory chain. Loss of SDHB disrupts complex II assembly and activity, leading to severe energy failure in high-demand tissues.

Clinical Validity and Genetic Evidence

SDHB-related complex II deficiency has been reported in at least 15 unrelated probands with early-onset encephalopathy, seizures, sepsis, leukodystrophy, cardiomyopathy, and Leigh syndrome ([PMID:34839152]; [PMID:25736212]; [PMID:27604842]; [PMID:22972948]; [PMID:32124427]). All cases follow an autosomal-recessive inheritance pattern, with homozygous or compound-heterozygous SDHB variants confirmed by clinical exome or targeted sequencing. Representative variants include five missense substitutions (p.Ser198Gly, p.Arg242His, p.Leu257Val, p.Arg230His, p.Asp48Val) and one frameshift (p.Ser239fs), among others. Segregation analysis in affected families and absence of disease in heterozygous carriers support recessive transmission.

Functional and Experimental Evidence

Enzymatic assays in patient muscle and fibroblast cultures demonstrate profound loss of complex II catalytic activity. Western blot and BN-PAGE studies show diminished SDHB steady-state levels and impaired complex assembly. Yeast and Drosophila models of SDHB deficiency exhibit reduced respiratory growth, hypersensitivity to oxidative stress, and rescue of enzyme activity upon wild-type SDHB expression ([PMID:25736212]; [PMID:33162331]). These concordant functional data confirm that SDHB loss-of-function variants underlie the mitochondrial phenotype.

Mechanism and Pathogenesis

Pathogenic SDHB variants disrupt iron–sulfur cluster incorporation into the SDHB subunit, leading to its proteolytic degradation and failure of complex II assembly. Accumulated succinate contributes to metabolic signaling perturbations and may exacerbate neuronal injury. The primary mechanism is loss of SDHB function, resulting in isolated complex II deficiency and energy failure in the central nervous system, muscle, and heart.

Clinical Integration and Utility

SDHB should be included in diagnostic gene panels for early-onset mitochondrial disease and Leigh syndrome. Identification of bi-allelic SDHB variants enables definitive molecular diagnosis, informs recurrence risk counseling under autosomal-recessive inheritance, and guides supportive management. Heterozygous carriers are at risk for SDHB-related tumor syndromes and may benefit from tailored surveillance of paraganglioma/pheochromocytoma.

Key Take-home: Bi-allelic SDHB variants cause a well-validated autosomal-recessive mitochondrial disease through loss of complex II activity, with clear diagnostic and counseling implications.

References

• Clinical neurology and neurosurgery | 2022 | A novel bi-allelic variant in the SDHB gene causes a severe mitochondrial complex II deficiency: a case report. PMID:34839152
• Human molecular genetics | 2015 | Additive effect of nuclear and mitochondrial mutations in a patient with mitochondrial encephalomyopathy. PMID:25736212
• JIMD reports | 2017 | Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling. PMID:27604842
• Journal of medical genetics | 2012 | Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. PMID:22972948
• Molecular genetics and metabolism | 2020 | The genetic basis of isolated mitochondrial complex II deficiency. PMID:33162331
• Annals of human genetics | 2020 | Novel variant p.(Ala102Thr) in SDHB causes mitochondrial complex II deficiency: Case report and review of the literature. PMID:32124427

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