Abstract
Purpose of Review
The groundwork for mitochondrial medicine was laid 30 years ago with identification of the first disease-causing mitochondrial DNA (mtDNA) mutations in 1988. Three decades later, mutations in nearly 300 genes involving every possible mode of inheritance within both nuclear and mitochondrial genomes are now recognized to collectively comprise the largest class of inherited metabolic disease, affecting at least 1 in 4300 individuals across all ages. Significant progress has been made in recent years to improve understanding of mitochondrial biology and disease pathophysiology.
Recent Findings
Markedly improved understanding of the highly diverse molecular etiologies of multisystemic phenotypes in primary mitochondrial disease has resulted from massively parallel genomic sequencing technologies and improved bioinformatic resources that enable identification in individual patients of their disease’s precise genetic etiology. Key informatics resources of particular utility to the mitochondrial disease genomics community have been developed, including: (1) Mitocarta 2.0 repository of 1200+ verified mitochondria-localized proteins, (2) MITOMAP Web resource of curated mtDNA genome variants, and (3) Mitochondrial Disease Sequence Data Resource (MSeqDR) that centralizes Web curation and annotation of mitochondrial disease genes and variants in both genomes, ontology-defined phenotypes, and access to many analytic tools to support dual genomic data mining and interpretation. Gene and mutation-based disease categorization has proven particularly useful to identify the full clinical spectrum of disease that may affect a given individual.
Summary
Extensive genomic advances, both in technologic platforms and bioinformatics resources, have facilitated dramatic improvement in the accurate recognition and understanding of primary mitochondrial disease.
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References
Papers of particular interest, published recently, have been highlighted as: • Of importance
Dimauro S. A history of mitochondrial diseases. J Inherit Metab Dis. 2011;34:261–76.
Reid RA, Moyle J, Mitchell P. Synthesis of adenosine triphosphate by a protonmotive force in rat liver mitochondria. Nature. 1966;212:257–8.
• Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science. 1988;242:1427–30. First report of a human mitochondrial DNA disease.
Wallace DC, Zheng XX, Lott MT, Shoffner JM, Hodge JA, Kelley RI, et al. Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell. 1988;55:601–10.
Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988;331:717–9.
• McCormick E, Place E, Falk MJ. Molecular genetic testing for mitochondrial disease: from one generation to the next. Neurotherapeutics: J Am Soc Exp NeuroTherapeutics. 2013;10:251–61. Detailed review of evolution of molecular genetic testing for mitochondrial disease.
Frazier, A. E., Thorburn, D. R., and Compton, A. G. (2017) Mitochondrial energy generation disorders: genes, mechanisms and clues to pathology. J Biol Chem, jbc.R117.809194. https://doi.org/10.1074/jbc.R117.809194
Wortmann SB, Koolen DA, Smeitink JA, van den Heuvel L, Rodenburg RJ. Whole exome sequencing of suspected mitochondrial patients in clinical practice. J Inherit Metab Dis. 2015;38:437–43.
• Wallace DC, Chalkia D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harbor Perspect Biol. 2013;5:a021220. Comprehensive review of mitochondrial DNA genome complexities and relevance to human disease.
Falk MJ. Neurodevelopmental manifestations of mitochondrial disease. Journal of developmental and behavioral pediatrics : JDBP. 2010;31:610–21.
Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008;134:112–23.
Calvo SE, Clauser KR, Mootha VK. MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 2016;44:D1251–7.
Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, et al. Mitochondrial diseases. Nat Rev Dis Primers. 2016;2:16080.
Chinnery PF. Mitochondrial disease in adults: what’s old and what’s new? EMBO molecular medicine. 2015;7:1503–12.
Mitochondrial Medicine Society’s Committee on, D, Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, et al. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab. 2008;94:16–37.
Kremer LS, Bader DM, Mertes C, Kopajtich R, Pichler G, Iuso A, et al. Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat Commun. 2017;8:15824.
Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med : Off J Am Coll Med Genet. 2015;17:689–701.
Cameron JM, Levandovskiy V, Mackay N, Tein I, Robinson BH. Deficiency of pyruvate dehydrogenase caused by novel and known mutations in the E1alpha subunit. Am J Med Genet. Part A. 2004;131:59–66.
Willemsen M, Rodenburg RJ, Teszas A, van den Heuvel L, Kosztolanyi G, Morava E. Females with PDHA1 gene mutations: a diagnostic challenge. Mitochondrion. 2006;6:155–9.
Giles RE, Blanc H, Cann HM, Wallace DC. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A. 1980;77:6715–9.
Egger J, Wilson J. Mitochondrial inheritance in a mitochondrially mediated disease. N Engl J Med. 1983;309:142–6.
Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, et al. Sequence and organization of the human mitochondrial genome. Nature. 1981;290:457–65.
Rahman S, Poulton J, Marchington D, Suomalainen A. Decrease of 3243 A-->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am J Hum Genet. 2001;68:238–40.
Brown MD, Torroni A, Reckord CL, Wallace DC. Phylogenetic analysis of Leber’s hereditary optic neuropathy mitochondrial DNA’s indicates multiple independent occurrences of the common mutations. Hum Mutat. 1995;6:311–25.
Hudson G, Carelli V, Spruijt L, Gerards M, Mowbray C, Achilli A, et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet. 2007;81:228–33.
Torroni A, Campos Y, Rengo C, Sellitto D, Achilli A, Magri C, et al. Mitochondrial DNA haplogroups do not play a role in the variable phenotypic presentation of the A3243G mutation. Am J Hum Genet. 2003;72:1005–12.
Wei W, Gomez-Duran A, Hudson G, Chinnery PF. Background sequence characteristics influence the occurrence and severity of disease-causing mtDNA mutations. PLoS Genet. 2017;13:e1007126.
Wang J, Schmitt ES, Landsverk ML, Zhang VW, Li FY, Graham BH, et al. An integrated approach for classifying mitochondrial DNA variants: one clinical diagnostic laboratory’s experience. Genet Med: Off J Am Coll Med Genet. 2012;14:620–6.
Kogelnik AM, Lott MT, Brown MD, Navathe SB, Wallace DC. MITOMAP: a human mitochondrial genome database. Nucleic Acids Res. 1996;24:177–9.
Ruiz-Pesini E, Lott MT, Procaccio V, Poole JC, Brandon MC, Mishmar D, et al. An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res. 2007;35:D823–8.
Lott MT, Leipzig JN, Derbeneva O, Xie HM, Chalkia D, Sarmady M, et al. mtDNA variation and analysis using Mitomap and Mitomaster. Curr Protoc Bioinformatics. 2013;44, 1 23:21–6.
• Falk MJ, Shen L, Gonzalez M, Leipzig J, Lott MT, Stassen AP, et al. Mitochondrial Disease Sequence Data Resource (MSeqDR): a global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities. Mol Genet Metab. 2015;114:388–96. Detailed overview of Mitochondrial Disease Sequence Data Resource (MSeqDR), an informatics resource for mitochondrial disease genetics and phenotypes.
Shen L, Diroma MA, Gonzalez M, Navarro-Gomez D, Leipzig J, Lott MT, et al. MSeqDR: a centralized knowledge repository and bioinformatics web resource to facilitate genomic investigations in mitochondrial disease. Hum Mutat. 2016;37:540–8.
Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel Guitton C. et al. Patient Care standards for primary mitchondrial disease: a consensus statement from the mitochondrial medicine society. Genet Med. 2017;19. https://doi.org/10.1038/gim.2017.107.
Falk MJ, Shen L, Gai X. From case studies to community knowledge base: MSeqDR provides a platform for the curation and genomic analysis of mitochondrial diseases. Cold Spring Harbor molecular case studies. 2016;2:a001065.
Bannwarth S, Procaccio V, Lebre AS, Jardel C, Chaussenot A, Hoarau C, et al. Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders. J Med Genet. 2013;50:704–14.
Shen L, Attimonelli M, Bai R, Lott MT, Wallace DC, Falk MJ,Ga X. MseqDR mvTool: A mitochondrial DNA web and API resource for comprehensive variant annotation, universal nomenclature collation, and reference genome conversion. Hum. Mutat. 2018. https://doi.org/10.1002/humu.2342.
Kaufmann P, Engelstad K, Wei Y, Kulikova R, Oskoui M, Sproule DM, et al. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology. 2011;77:1965–71.
El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab. 2015;116:4–12.
Sue CM, Bruno C, Andreu AL, Cargan A, Mendell JR, Tsao CY, et al. Infantile encephalopathy associated with the MELAS A3243G mutation. J Pediatr. 1999;134:696–700.
Koga Y, Akita Y, Takane N, Sato Y, Kato H. Heterogeneous presentation in A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene. Arch Dis Child. 2000;82:407–11.
Yang YL, Sun F, Zhang Y, Qian N, Yuan Y, Wang ZX, et al. Clinical and laboratory survey of 65 Chinese patients with Leigh syndrome. Chin Med J. 2006;119:373–7.
Santorelli FM, Tanji K, Shanske S, Krishna S, Schmidt RE, Greenwood RS, et al. The mitochondrial DNA A8344G mutation in Leigh syndrome revealed by analysis in paraffin-embedded sections: revisiting the past. Ann Neurol. 1998;44:962–4.
Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, et al. Phenotypic heterogeneity of the 8344A>G mtDNA “MERRF” mutation. Neurology. 2013;80:2049–54.
Ogawa E, Shimura M, Fushimi T, Tajika M, Ichimoto K, Matsunaga A, et al. Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients. J Inherit Metab Dis. 2017;40:685–93.
Thorburn, D. R., Rahman, J., and Rahman, S. (1993) Mitochondrial DNA-associated Leigh syndrome and NARP. in GeneReviews((R)) (Adam, M. P., Ardinger, H. H., Pagon, R. A., Wallace, S. E., Bean, L. J. H., Stephens, K., and Amemiya, A. eds.), Seattle (WA). pp.
Rantamaki MT, Soini HK, Finnila SM, Majamaa K, Udd B. Adult-onset ataxia and polyneuropathy caused by mitochondrial 8993T-->C mutation. Ann Neurol. 2005;58:337–40. Adult-onset ataxia and polyneuropathy caused by mitochondrial 8993T→C mutation
White SL, Collins VR, Wolfe R, Cleary MA, Shanske S, DiMauro S, et al. Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet. 1999;65:474–82.
Tatuch Y, Christodoulou J, Feigenbaum A, Clarke JT, Wherret J, Smith C, et al. Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet. 1992;50:852–8.
Uziel G, Moroni I, Lamantea E, Fratta GM, Ciceri E, Carrara F, et al. Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families. J Neurol Neurosurg Psychiatry. 1997;63:16–22.
Caporali L, Maresca A, Capristo M, Del Dotto V, Tagliavini F, Valentino ML, et al. Incomplete penetrance in mitochondrial optic neuropathies. Mitochondrion. 2017;36:130–7.
Damas J, Carneiro J, Amorim A, Pereira F. MitoBreak: the mitochondrial DNA breakpoints database. Nucleic Acids Res. 2014;42:D1261–8.
Rotig A, Cormier V, Blanche S, Bonnefont JP, Ledeist F, Romero N, et al. Pearson’s marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy. J Clin Invest. 1990;86:1601–8.
Kearns TP, Sayre GP. Retinitis pigmentosa, external ophthalmophegia, and complete heart block: unusual syndrome with histologic study in one of two cases. AMA ArchOphthalmol. 1958;60:280–9.
DiMauro, S., and Hirano, M. (1993) Mitochondrial DNA deletion syndromes. in GeneReviews((R)) (Adam, M. P., Ardinger, H. H., Pagon, R. A., Wallace, S. E., Bean, L. J. H., Stephens, K., and Amemiya, A. eds.), Seattle (WA). pp.
Longley MJ, Graziewicz MA, Bienstock RJ, Copeland WC. Consequences of mutations in human DNA polymerase gamma. Gene. 2005;354:125–31.
Nurminen A, Farnum GA, Kaguni LS. Pathogenicity in POLG syndromes: DNA polymerase gamma pathogenicity prediction server and database. BBA clinical. 2017;7:147–56.
Saneto RP, Naviaux RK. Polymerase gamma disease through the ages. Developmental disabilities research reviews. 2010;16:163–74.
Saneto RP, Lee IC, Koenig MK, Bao X, Weng SW, Naviaux RK, et al. POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders. Seizure. 2010;19:140–6.
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Marni J. Falk reports other from REATA Pharmaceuticals, grants, personal fees and other from Stealth Pharmaceuticals, other from United Mitochondrial Disease Foundation, other from GENESIS, grants and other from Raptor Pharmaceuticals, outside the submitted work. The other authors declare that they have no conflict of interest.
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McCormick, E.M., Muraresku, C.C. & Falk, M.J. Mitochondrial Genomics: A Complex Field Now Coming of Age. Curr Genet Med Rep 6, 52–61 (2018). https://doi.org/10.1007/s40142-018-0137-x
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DOI: https://doi.org/10.1007/s40142-018-0137-x