A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency

Abstract

Succinate dehydrogenase (SDH) is a crucial metabolic enzyme complex that is involved in ATP production, playing roles in both the tricarboxylic cycle and the mitochondrial respiratory chain (complex II). Isolated complex II deficiency is one of the rarest oxidative phosphorylation disorders with mutations described in three structural subunits and one of the assembly factors; just one case is attributed to recessively inherited SDHD mutations. We report the pathological, biochemical, histochemical and molecular genetic investigations of a male neonate who had left ventricular hypertrophy detected on antenatal scan and died on day one of life. Subsequent postmortem examination confirmed hypertrophic cardiomyopathy with left ventricular non-compaction. Biochemical analysis of his skeletal muscle biopsy revealed evidence of a severe isolated complex II deficiency and candidate gene sequencing revealed a novel homozygous c.275A>G, p.(Asp92Gly) SDHD mutation which was shown to be recessively inherited through segregation studies. The affected amino acid has been reported as a Dutch founder mutation p.(Asp92Tyr) in families with hereditary head and neck paraganglioma. By introducing both mutations into Saccharomyces cerevisiae, we were able to confirm that the p.(Asp92Gly) mutation causes a more severe oxidative growth phenotype than the p.(Asp92Tyr) mutant, and provides functional evidence to support the pathogenicity of the patient’s SDHD mutation. This is only the second case of mitochondrial complex II deficiency due to inherited SDHD mutations and highlights the importance of sequencing all SDH genes in patients with biochemical and histochemical evidence of isolated mitochondrial complex II deficiency.

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

“…In FA, abnormal muscle OXPHOS capacity is related to mitochondrial iron overload; decreased OXPHOS capacity in FA has been demonstrated by skeletal muscle biopsy (39) as well as 31 P-MRS (40). Mutations in nonclassical mitochondrial disease genes, including SDH subunit genes have been also associated with reduced OXPHOS capacity in muscle (41,42), although the clinical association is less clear. For this reason, in the present study we performed sensitivity analyses on the effects of excluding individuals with SDH mutations and individuals with novel gene variants of uncertain significance with respect to mitochondrial disease on our main analysis.…”

“…FA is a mitochondrial disease in which ATP production is reduced due to GAA triplet-repeat expansions in frataxin, a mitochondrial protein involved in the formation of iron-sulfur clusters necessary for respiratory chain complex function (45). Finally, individuals were studied who had genetic deficiency of isoforms of SDH, which serves as respiratory chain complex II (42,46).…”

Metabolic Alterations in Inherited Cardiomyopathies

“…Moreover, although the models in these studies recapitulate DCM features, further effort is required to understand whether the described mechanisms, resulting from genetic modifications in genes unrelated to the disease, occur also in DCM patients. On the other hand, despite the lack of direct evidences of metabolic alterations in models carrying specific DCM mutations, several mitochondrial diseases, such as Barth syndrome [49][50][51][52], OXPHOS disorders [53][54][55][56], and Leigh syndrome [57,58], are associated with the occurrence of DCM, suggesting a role of mitochondrial alterations in the pathogenesis of DCM.…”

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…Although CII deficiencies (OMIM # 252011) are rare, they still demonstrate the typical clinical heterogeneity associated with mitochondrial diseases. Many CII disorders present in childhood as retinopathies [66] or as encephalopathies [67,68], namely Leigh Syndrome [69], with accompanying cardiomyopathy [70]. Conversely, adult onset CII disorders have also been reported [71].…”