SDHD – Mitochondrial disease

Autosomal recessive biallelic variants in SDHD underlie isolated mitochondrial complex II deficiency (MONDO:0044970), manifesting as early-onset progressive encephalomyopathy and, in some cases, hypertrophic cardiomyopathy. Two unrelated probands have been reported: one compound heterozygote for c.205G>A (p.Glu69Lys) and c.479G>T (p.Ter160Leu) with impaired complex II assembly demonstrated by native PAGE and complementation assays ([PMID:24367056]), and a neonate homozygous for c.275A>G (p.Asp92Gly) exhibiting severe prenatal cardiomyopathy and confirmed pathogenicity via yeast oxidative growth assays ([PMID:26008905]).

Genetic evidence supports autosomal recessive inheritance with two probands carrying LoF and missense variants that segregate with disease; segregation studies confirm that heterozygous carriers are asymptomatic. Functional studies including yeast models and patient‐derived cell assays consistently demonstrate loss of SDHD protein expression, disrupted complex II assembly, and markedly reduced enzyme activity, concordant with biochemical phenotypes. No conflicting evidence has been reported to date.

Key Take-home: SDHD-associated complex II deficiency should be considered in patients with early-onset encephalomyopathy and cardiomyopathy, and genetic testing of all SDH subunits is warranted for accurate diagnosis and counselling.

References

• Journal of medical genetics | 2014 | Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency. PMID:24367056
• Human genetics | 2015 | A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency. PMID:26008905

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