Abstract
Isolated defects in the mitochondrial respiratory chain complex II (CII; succinate-ubiquinone oxidoreductase) are extremely rare and mainly result from bi-allelic mutations in one of the nuclear encoded subunits: SDHA, SDHB and SDHD, which comprise CII and the assembly CII factor SDHAF1. We report an adolescent female who presented with global developmental delay, intellectual disability and childhood onset progressive bilateral optic atrophy. Whole exome sequencing of the patient and her unaffected parents identified the novel heterozygous de novo variant c.1984C > T [NM_004168.4] in the SDHA gene. Biochemical assessment of CII in the patient’s derived fibroblasts and lymphocytes displayed considerably decreased CII residual activity compared with normal controls, when normalized to the integral mitochondrial enzyme citrate synthase. Protein modeling of the consequent p.Arg662Cys variant [NP-004159.2] suggested that this substitution will compromise the structural integrity of the FAD-binding protein at the C-terminus that will ultimately impair the FAD binding to SDHA, thus decreasing the entire CII activity. Our study emphasizes the role of certain heterozygous SDHA mutations in a distinct clinical phenotype dominated by optic atrophy and neurological impairment. This is the second mutation that has been reported to cause this phenotype. Furthermore, it adds developmental delay and cognitive disability to the expanding spectrum of the disorder. We propose to add SDHA to next generation sequencing gene panels of optic atrophy.
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The data generated or analyzed during this study are included in this published article [and its supplementary information files].
In specific the novel heterozygous de novo variant c.1984C > T identified in our patient was submitted to ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/694327/) and is available online.
References
Alston CL, Davison JE, Meloni F, van der Westhuizen FH, He L, Hornig-Do HT, Peet AC, Gissen P, Goffrini P, Ferrero I, Wassmer E, McFarland R, Taylor RW (2012) Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. J Med Genet 49:569–577
Alston CL, Ceccatelli Berti C, Blakely EL, Oláhová M, He L, McMahon CJ, Olpin SE, Hargreaves IP, Nolli C, McFarland R, Goffrini P, O’Sullivan MJ, Taylor RW (2015) A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency. Hum Genet 134:869–879
Birch-Machin MA, Taylor RW, Cochran B, Ackrell BA, Turnbull DM (2000) Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol 48:330–335
Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, Munnich A, Rotig A (1995) Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 11:144–149
Carelli V, La Morgia C, Ross-Cisneros FN, Sadun AA (2017) Optic neuropathies: the tip of the neurodegeneration iceberg. Hum Mol Genet 26:R139–R150
Courage C, Jackson CB, Hahn D, Euro L, Nuoffer JM, Gallati S, Schaller A (2017) SDHA mutation with dominant transmission results in complex II deficiency with ocular, cardiac, and neurologic involvement. Am J Med Genet A 173:225–230
Duran J, Martinez A, Adler E (2019) Cardiovascular manifestations of mitochondrial disease. Biology (Basel) 8:34
Ghezzi D, Goffrini P, Uziel G, Horvath R, Klopstock T, Lochmüller H, D'Adamo P, Gasparini P, Strom TM, Prokisch H, Invernizzi F, Ferrero I, Zeviani M (2009) SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet 41:654–656
Jackson CB, Nuoffer JM, Hahn D, Prokisch H, Haberberger B, Gautschi M, Häberli A, Gallati S, Schaller A (2014) Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency. J Med Genet 51:170–175
Jha A, de Luna K, Balili CA, Millo C, Paraiso CA, Ling A, Gonzales MK, Viana B, Alrezk R, Adams KT, Tena I, Chen A, Neuzil J, Raygada M, Kebebew E, Taieb D, O'Dorisio MS, O'Dorisio T, Civelek AC, Stratakis CA, Mercado-Asis L, Pacak K (2019) Clinical, diagnostic, and treatment characteristics of SDHA-related metastatic pheochromocytoma and paraganglioma. Front Oncol 9:53
Levitas A, Muhammad E, Harel G, Saada A, Caspi VC, Manor E, Beck JC, Sheffield V, Parvari R (2010) Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. Eur J Hum Genet 18:1160–1165
Renkema GH, Wortmann SB, Smeets RJ et al (2015) SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors. Eur J Hum Genet 23:202–209
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424
Rutter J, Winge DR, Schiffman JD (2010) Succinate dehydrogenase - assembly, regulation and role in human disease. Mitochondrion 10:393–401
Shalata A, Edery M, Habib C, Genizi J, Mahroum M, Khalaily L, Assaf N, Segal I, Abed el Rahim H, Shapira H, Urian D, Tzur S, Douiev L, Saada A (2019) Primary coenzyme Q deficiency due to novel ADCK3 variants, studies in fibroblasts and review of literature. Neurochem Res 44:2372–2384
Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z (2005) Crystal structure of mitochondrial respiratory membrane protein complex II. Cell 121:1043–1057
Taylor RW, Birch-Machin MA, Schaefer J, Taylor L, Shakir R, Ackrell BA, Cochran B, Bindoff LA, Jackson MJ, Griffiths P, Turnbull DM (1996) Deficiency of complex II of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia. Ann Neurol 39:224–232
van der Tuin K, Mensenkamp AR, Tops CMJ, Corssmit EPM, Dinjens WN, van de Horst-Schrivers ANA, Jansen JC, de Jong MM, Kunst HPM, Kusters B, Leter EM, Morreau H, van Nesselrooij BMP, Oldenburg RA, Spruijt L, Hes FJ, Timmers HJLM (2018) Clinical aspects of SDHA-related pheochromocytoma and paraganglioma: a nationwide study. J Clin Endocrinol Metab 103(2):438–445
Yu-Wai-Man P, Griffiths PG, Hudson G, Chinnery PF (2009) Inherited mitochondrial optic neuropathies. J Med Genet 46:145–158
Acknowledgments
We thank the family for their cooperation. We thank Mrs. Cindy Cohen for professional language editing. We would like to thank Dr. Richard Rodenburg and Antonia Heck-Kappen and other technicians of the cell culture lab and muscle lab of the Translational Metabolic Laboratory at RadboudUMC Nijmegen for excellent technical assistance.
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Dr. Zehavi led the composition and evaluation of the manuscript; designed and conceptualized the study and interpreted the data.
Prof. Saada designed, analyzed and interpreted the biochemical data and evaluated the manuscript for content.
Dr. Jabaly-Habib evaluated the manuscript for content, and analyzed and interpreted the ophthalmological studies.
Dr. Dessau evaluated the manuscript for content, evaluated and analyzed the protein structural analysis.
Dr. Shaag evaluated the manuscript for content and analyzed and interpreted the genetic data.
Prof. Elpeleg evaluated the manuscript for content, including medical writing for content; and analyzed and interpreted the genetic data, in particular the exome sequencing.
Prof. Spiegel led the composition and evaluation of the manuscript; designed and conceptualized the study and interpreted the data. Prof. Spiegel is the corresponding author for the article, and accepts full responsibility for the work and the conduct of the study. He had full access to the data, and controlled the decision to publish.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Emek Medical Center ethics committee (study no. EMC-0067-09).
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Zehavi, Y., Saada, A., Jabaly-Habib, H. et al. A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment. Metab Brain Dis 36, 581–588 (2021). https://doi.org/10.1007/s11011-021-00671-1
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DOI: https://doi.org/10.1007/s11011-021-00671-1