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Fernández AC, Estrella J, Oglesbee D, Larson AA, Van Hove JLK. The clinical utility in hospital-wide use of growth differentiation factor 15 as a biomarker for mitochondrial DNA-related disorders. J Inherit Metab Dis. 2024 Nov 24. doi: 10.1002/jimd.12821. Epub ahead of print. PMID: 39582258.

Primary mitochondrial disorders (PMD) are chronic, multisystemic disorders involving dysfunction of the mitochondria caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Due to the clinical and genetic diversity of PMD, recognition of these disorders in a clinical setting is often difficult.

In this study, researchers explored the clinical utility of growth differentiation factor 15 (GDF15) as a biomarker for PMD. First, the team reviewed medical records from 418 cases where GDF15 levels were obtained by clinicians at a tertiary care hospital. Next, they classified each case as PMD due to mtDNA-related defects (mtDNA deletions, mtDNA depletion, tRNA variants), PMD due to structural defects or other nuclear causes, and non-mitochondrial disease. Patients with liver disease or systemic critical illness were excluded. Finally, GDF15 was assayed in a clinical laboratory.

Results show that in a real-life clinical setting—after excluding abnormal liver function and critical illness—GDF15 had good clinical utility of increasing the odds at predicting mtDNA-related primary mitochondrial disorders by 14-fold. An elevated GDF15 had 40.8% odds of identifying an mtDNA-related mitochondrial disorder versus 2.7% if not elevated. However, GDF15 did not show good clinical utility as a biomarker for structural or other nuclear-encoded primary mitochondrial disorders.

Grady LO, Zoltick ES, Zouk H, He W, Perez E, Clarke L, Gold J, Strong A, Sahai I, Yeo J, Green RC, Karaa A, Gold NB. Long-Term Health Outcomes of Individuals With Pseudodeficiency Alleles in IDUA May Inform Newborn Screening Practices for Mucopolysaccharidosis Type I. Am J Med Genet A. 2024 Nov 19:e63940. doi: 10.1002/ajmg.a.63940. Epub ahead of print. PMID: 39559959.

Starosta RT, Larson AA, Meeks NJL, Gracie S, Friederich MW, Gaughan SM, Baker PR 2nd, Knupp KG, Michel CR, Reisdorph R, Hock DH, Stroud DA, Wood T, Van Hove JLK. An integrated multi-omics approach allowed ultra-rapid diagnosis of a deep intronic pathogenic variant in PDHX and precision treatment in a neonate critically ill with lactic acidosis. Mitochondrion. 2024 Oct 15;79:101973. doi: 10.1016/j.mito.2024.101973. Epub ahead of print. PMID: 39413893.

Pyruvate dehydrogenase complex (PDH) deficiency is a mitochondrial disease that limits the breakdown of carbohydrates for energy production, leading to high levels of lactic acid, which can be life-threatening. Diagnosing mitochondrial diseases like PDH is often complex, with limited options for additional tests after a negative rapid whole-genome sequencing result.

In this study, researchers used a proteomics-based approach for ultra-rapid diagnosis of PDH deficiency. The study included a neonatal patient presenting with severe lactic acidosis on the second day of life and a negative initial ultra-rapid genome sequencing report. With multi-omics techniques, the team identified PDHX from absence of peptides in the cells, leading to the discovery of a pathogenic variant in the PDHX gene. Subsequent testing in the following months confirmed a diagnosis of PDH deficiency, and the patient was successfully treated for lactic acidosis with dichloroacetate.

Results highlight the power of rapid proteomics in guiding genomic analysis. Authors also note that these results identify dichloroacetate as a promising potential therapy for lactic acidosis in PDH deficiency.
 

Hidalgo-Gutierrez A, Shintaku J, Ramon J, Barriocanal-Casado E, Pesini A, Saneto RP, Garrabou G, Milisenda JC, Matas-Garcia A, Gort L, Ugarteburu O, Gu Y, Koganti L, Wang T, Tadesse S, Meneri M, Sciacco M, Wang S, Tanji K, Horwitz MS, Dorschner MO, Mansukhani M, Comi GP, Ronchi D, Marti R, Ribes A, Tort F, Hirano M. Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease. Ann Neurol. 2024 Sep 4. doi: 10.1002/ana.27071. Epub ahead of print. PMID: 39230499.

Mitochondrial DNA depletion/deletions syndrome (MDDS) is a group of disorders in which copies of the DNA within mitochondria (specialized cell structures that produce energy) are severely reduced in number. MDDS results in impaired energy production required for proper functioning of the body tissues and organs, affecting the brain, liver, digestive system, nerves, and skeletal muscles.

In this study, researchers identified a new and potentially treatable cause of MDDS. The team performed whole exome sequencing to investigate pathogenic variants in four patients who presented with MDDS symptoms, but did not have a known genetic cause.

Results revealed pathogenic variants in the GUK1 gene in all four patients and that the GUK1 protein has a long mitochondrial isoform and a short cytosolic isoform. The team also identified effective in vitro therapeutic strategies to restore mitochondrial DNA levels, highlighting potential treatments for this disorder. Authors note that GUK1 deficiency is the first example of impaired nucleotide monophosphate kinase causing MDDS.

Nakai R, Varnum S, Field RL, Shi H, Giwa R, Jia W, Krysa SJ, Cohen EF, Borcherding N, Saneto RP, Tsai RC, Suganuma M, Ohta H, Yokota T, Brestoff JR. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome. Nat Metab. 2024 Sep 2. doi: 10.1038/s42255-024-01125-5. Online ahead of print.

Van Hove JLK, Friederich MW, Hock DH, Stroud DA, Caruana NJ, Christians U, Schniedewind B, Michel CR, Reisdorph R, Lopez Gonzalez EDJ, Brenner C, Donovan TE, Lee JC, Chatfield KC, Larson AA, Baker PR 2nd, McCandless SE, Moore Burk MF. ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis. Mitochondrion. 2024 Sep;78:101905. doi: 10.1016/j.mito.2024.101905. Epub 2024 May 24.

Komulainen-Ebrahim J, Kangas SM, López-Martín E, Feyma T, Scaglia F, Martínez-Delgado B, Kuismin O, Suo-Palosaari M, Carr L, Hinttala R, Kurian MA, Uusimaa J. Hyperkinetic Movement Disorder Caused by the Recurrent c.892C>T NACC1 Variant. Mov Disord Clin Pract. 2024 Jun;11(6):708-715. doi: 10.1002/mdc3.14051. Epub 2024 May 2.

Kelly C, Junker A, Englestad K, Hirano M, Trumpff C, Picard M. Perceived association of mood and symptom severity in adults with mitochondrial diseases. medRxiv. 2024 Feb 4:2024.02.02.24302076. doi: 10.1101/2024.02.02.24302076.

Verma A, Lehman AN, Gokcan H, Cropcho L, Black D, Dobrowolski SF, Vockley J, Bedoyan JK. Amino acid ratio combinations as biomarkers for discriminating patients with pyruvate dehydrogenase complex deficiency from other inborn errors of metabolism. Mol Genet Genomic Med. 2023 Sep 8:e2283. doi: 10.1002/mgg3.2283. Epub ahead of print. PMID: 37688338.

Solis EM, Good LB, Vázquez RG, Patnaik S, Hernandez-Reynoso AG, Ma Q, Angulo G, Dobariya A, Cogan SF, Pancrazio JJ, Pascual JM, Jakkamsetti V. Isolation of the murine Glut1 deficient thalamocortical circuit: wavelet characterization and reverse glucose dependence of low and gamma frequency oscillations. bioRxiv. 2023 Aug 20:2023.06.05.543611. doi: 10.1101/2023.06.05.543611. Preprint.

Karaa A, Bertini E, Carelli V, Cohen BH, Enns GM, Falk MJ, Goldstein A, Gorman GS, Haas R, Hirano M, Klopstock T, Koenig MK, Kornblum C, Lamperti C, Lehman A, Longo N, Molnar MJ, Parikh S, Phan H, Pitceathly RDS, Saneto R, Scaglia F, Servidei S, Tarnopolsky M, Toscano A, Van Hove JLK, Vissing J, Vockley J, Finman JS, Brown DA, Shiffer JA, Mancuso M; MMPOWER-3 Trial Investigators. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. Neurology. 2023 Jul 18;101(3):e238-e252. doi: 10.1212/WNL.0000000000207402. Epub 2023 Jun 2.

Lareau CA, Dubois SM, Buquicchio FA, Hsieh YH, Garg K, Kautz P, Nitsch L, Praktiknjo SD, Maschmeyer P, Verboon JM, Gutierrez JC, Yin Y, Fiskin E, Luo W, Mimitou EP, Muus C, Malhotra R, Parikh S, Fleming MD, Oevermann L, Schulte J, Eckert C, Kundaje A, Smibert P, Vardhana SA, Satpathy AT, Regev A, Sankaran VG, Agarwal S, Ludwig LS. Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells. Nat Genet. 2023 Jul;55(7):1198-1209. doi: 10.1038/s41588-023-01433-8. Epub 2023 Jun 29. PMID: 37386249

Mitochondrial diseases are multisystemic, genetic disorders involving dysfunction of the mitochondria (specialized cell structures that produce energy), which affects cellular metabolism. Diverse mitochondrial DNA (mtDNA) mutations are associated with diverse phenotypes (observable characteristics), suggesting that metabolic vulnerabilities may be specific to organ and cell types.

In this study, researchers developed a multi-omics approach to investigate the properties of mitochondrial genetics. In single cells derived from six patients with mitochondrial diseases, the team quantified deletions in mtDNA alongside cell state features.

Results reveal the dynamics of pathogenic (disease-causing) mtDNA heteroplasmy (multiple variants within a cell) in individual blood and immune cells. Authors note that these findings demonstrate the power of single-cell multi-omics to reveal fundamental properties of mitochondrial genetics.

Thompson JLP, Karaa A, Pham H, Yeske P, Krischer J, Xiao Y, Long Y, Kramer A, Dimmock D, Holbert A, Gorski C, Engelstad KM, Buchsbaum R, Rosales XQ, Hirano M. The evolution of the mitochondrial disease diagnostic odyssey. Orphanet J Rare Dis. 2023 Jun 22;18(1):157. doi: 10.1186/s13023-023-02754-x.

Duque Lasio LM, Leshinski AC, Ducich NH, Flore LA, Lehman A, Shur N, Jayakar PB, Hainline BE, Basinger AA, Wilson WG, Diaz GA, Erbe RW, Koeberl DD, Vockley J, Bedoyan JK. Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin. Mol Genet Metab. 2023 Jun;139(2):107605. doi: 10.1016/j.ymgme.2023.107605. Epub 2023 May 9. PMID: 37207470; PMCID: PMC10330474.

Vogel GF, Mozer-Glassberg Y, Landau YE, Schlieben LD, Prokisch H, Feichtinger RG, Mayr JA, Brennenstuhl H, Schröter J, Pechlaner A, Alkuraya FS, Baker JJ, Barcia G, Baric I, Braverman N, Burnyte B, Christodoulou J, Ciara E, Coman D, Das AM, Darin N, Della Marina A, Distelmaier F, Eklund EA, Ersoy M, Fang W, Gaignard P, Ganetzky RD, Gonzales E, Howard C, Hughes J, Konstantopoulou V, Kose M, Kerr M, Khan A, Lenz D, McFarland R, Margolis MG, Morrison K, Müller T, Murayama K, Nicastro E, Pennisi A, Peters H, Piekutowska-Abramczuk D, Rötig A, Santer R, Scaglia F, Schiff M, Shagrani M, Sharrard M, Soler-Alfonso C, Staufner C, Storey I, Stormon M, Taylor RW, Thorburn DR, Teles EL, Wang JS, Weghuber D, Wortmann S. Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants. Genet Med. 2023 Jun;25(6):100314. doi: 10.1016/j.gim.2022.09.015. Epub 2022 Oct 29.

Hirano M, Pitceathly RDS. Progressive external ophthalmoplegia. Handb Clin Neurol. 2023;194:9-21. doi: 10.1016/B978-0-12-821751-1.00018-X.

Ju Wang JD, Chen M, Zhang C, Parker J, Saneto R, Ramirez JM. Sleep and Breathing Disturbances in Children With Leigh Syndrome: A Comparative Study. Pediatr Neurol. 2022 Nov;136:56-63. doi: 10.1016/j.pediatrneurol.2022.08.006. Epub 2022 Aug 29.

Almannai M, El-Hattab AW, Azamian MS, Ali M, Scaglia F. Mitochondrial DNA maintenance defects: potential therapeutic strategies. Mol Genet Metab. 2022 Sep-Oct;137(1-2):40-48. doi: 10.1016/j.ymgme.2022.07.003. Epub 2022 Jul 6. PMID: 35914366.

Mitochondrial DNA maintenance defects (MDMDs) are a group of disorders characterized by mitochondrial DNA (mtDNA) depletions and/or multiple deletions. These disorders most often affect the brain, liver, skeletal muscle, peripheral nerves, and gastrointestinal tract. As with other mitochondrial disorders, treatment options for MDMDs are currently limited. Recent progress in MDMD research includes the development of model organisms, improved understanding of their pathophysiology, and a better knowledge of their natural history. This progress has led to an increasing number of preclinical studies, as well as existing and planned clinical trials. In this review paper, researchers discuss current studies and trials, including potential new therapeutic options for MDMDs.

Gokcan H, Bedoyan JK, Isayev O. Simulations of Pathogenic E1α Variants: Allostery and Impact on Pyruvate Dehydrogenase Complex-E1 Structure and Function. J Chem Inf Model. 2022 Jul 25;62(14):3463-3475. doi: 10.1021/acs.jcim.2c00630. Epub 2022 Jul 7.

Pernice WM, Eyaid W, Gc JB, Brown ZP, Juanola-Falgarona M, Torres-Torronteras J, Sommerville EW, Hellebrekers DM, Blakely EL, Donaldson A, van de Laar I, Leu CS, Marti R, Frank J, Tanji K, Koolen DA, Rodenburg RJ, Chinnery PF, Smeets HJM, Gorman GS, Bonnen PE, Taylor RW, Hirano M. RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis. J Clin Invest.. 2022 Jul 1;132(13):e145660. doi: 10.1172/JCI145660. PMID: 35617047; PMCID: PMC9246377.

Mitochondrial DNA depletion/deletions syndromes (MDDS) are a group of inherited disorders in which copies of the DNA (genetic material) within mitochondria (specialized cell structures that produce energy) are severely reduced in number. MDDS are frequently caused by defects in nucleoside and nucleotide metabolism, which is critical for mitochondrial DNA replication. In this study, researchers report five individuals from four families who presented with ptosis (eyelid drooping), ophthalmoplegia (eye muscle weakness), other clinical manifestations, and multiple mitochondrial DNA deletions in muscle. The team identified three variants in the gene RRM1, which affect ribonucleotide reductase protein structure and function, leading to impairment of de novo nucleotide synthesis. These results reveal that both recessive and dominant RRM1 variants cause MDDS. Additionally, these findings demonstrate that elements of the de novo nucleotide synthesis pathway may lead to MDDS.

Emmanuele V, Ganesh J, Vladutiu G, Haas R, Kerr D, Saneto RP, Cohen BH, Van Hove JLK, Scaglia F, Hoppel C, Rosales XQ, Barca E, Buchsbaum R, Thompson JL, DiMauro S, Hirano M; North American Mitochondrial Disease Consortium (NAMDC). Time to harmonize mitochondrial syndrome nomenclature and classification: A consensus from the North American Mitochondrial Disease Consortium (NAMDC). Mol Genet Metab. 2022 Jun;136(2):125-131. doi: 10.1016/j.ymgme.2022.05.001. Epub 2022 May 13.

Ganapathi M, Friocourt G, Gueguen N, Friederich MW, Le Gac G, Okur V, Loaëc N, Ludwig T, Ka C, Tanji K, Marcorelles P, Theodorou E, Lignelli-Dipple A, Voisset C, Walker MA, Briere LC, Bourhis A, Blondel M, LeDuc C, Hagen J, Cooper C, Muraresku C, Ferec C, Garenne A, Lelez-Soquet S, Rogers CA, Shen Y, Strode DK, Bizargity P, Iglesias A, Goldstein A, High FA, Network UD, Sweetser DA, Ganetzky R, Van Hove JLK, Procaccio V, Le Marechal C, Chung WK. A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families. J Inherit Metab Dis. 2022 May 27. doi: 10.1002/jimd.12526. Online ahead of print.

Karaa A, MacMullen LE, Campbell JC, Christodoulou J, Cohen BH, Klopstock T, Koga Y, Lamperti C, van Maanen R, McFarland R, Parikh S, Rahman S, Scaglia F, Sherman AV, Yeske P, Falk MJ. Community Consensus Guidelines to Support FAIR Data Standards in Clinical Research Studies in Primary Mitochondrial Disease. Adv Genet (Hoboken). 2022 Mar;3(1):2100047. doi: 10.1002/ggn2.202100047. Epub 2021 Dec 19.

Yang JH, Friederich MW, Ellsworth KA, Frederick A, Foreman E, Malicki D, Dimmock D, Lenberg J, Prasad C, Yu AC, Anthony Rupar C, Hegele RA, Manickam K, Koboldt DC, Crist E, Choi SS, Farhan SMK, Harvey H, Sattar S, Karp N, Wong T, Haas R, Van Hove JLK, Wigby K. Expanding the phenotypic and molecular spectrum of NFS1-related disorders that cause functional deficiencies in mitochondrial and cytosolic iron-sulfur cluster containing enzymes. Hum Mutat. 2022 Mar;43(3):305-315. doi: 10.1002/humu.24330. Epub 2022 Jan 19.

Carelli V, Hirano M, Enríquez JA, Chinnery PF. Implications of mitochondrial DNA mutations in human induced pluripotent stem cells. Nat Rev Genet. 2022 Feb;23(2):69-70. doi: 10.1038/s41576-021-00430-z.

Ducich NH, Mears JA, Bedoyan JK. Solvent accessibility of E1α and E1β residues with known missense mutations causing pyruvate dehydrogenase complex (PDC) deficiency: Impact on PDC-E1 structure and function. J Inherit Metab Dis. 2022 Jan 17. doi: 10.1002/jimd.12477. Online ahead of print.

Berardo A, Domínguez-González C, Engelstad K, Hirano M. Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies. J Neuromuscul Dis. 2022;9(2):225-235. doi: 10.3233/JND-210786.

Lopez-Gomez C, Sanchez-Quintero MJ, Lee EJ, Kleiner G, Tadesse S, Xie J, Akman HO, Gao G, Hirano M. Synergistic Deoxynucleoside and Gene Therapies for Thymidine Kinase 2 Deficiency. Ann Neurol. 2021 Oct;90(4):640-652. doi: 10.1002/ana.26185. Epub 2021 Aug 13.

Friederich MW, Geddes GC, Wortmann SB, Punnoose A, Wartchow E, Knight KM, Prokisch H, Creadon-Swindell G, Mayr JA, Van Hove JLK. Pathogenic variants in MRPL44 cause infantile cardiomyopathy due to a mitochondrial translation defect. Mol Genet Metab. 2021 Aug;133(4):362-371. doi: 10.1016/j.ymgme.2021.06.001. Epub 2021 Jun 10.

Saneto RP, Patrick KE, Perez FA. Homoplasmy of the m. 8993 T>G variant in a patient without MRI findings of Leigh syndrome, ataxia or retinal abnormalities. Mitochondrion. 2021 Jul;59:58-62. doi: 10.1016/j.mito.2021.04.010. Epub 2021 Apr 22.

Zolkipli-Cunningham Z, Naviaux JC, Nakayama T, Hirsch CM, Monk JM, Li K, Wang L, Le TP, Meinardi S, Blake DR, Naviaux RK. Metabolic and behavioral features of acute hyperpurinergia and the maternal immune activation mouse model of autism spectrum disorder. PLoS One. 2021 Mar 18;16(3):e0248771. doi: 10.1371/journal.pone.0248771. eCollection 2021.

Hirano M, Carelli V, De Giorgio R, Pironi L, Accarino A, Cenacchi G, D'Alessandro R, Filosto M, Martí R, Nonino F, Pinna AD, Baldin E, Bax BE, Bolletta A, Bolletta R, Boschetti E, Cescon M, D'Angelo R, Dotti MT, Giordano C, Gramegna LL, Levene M, Lodi R, Mandel H, Morelli MC, Musumeci O, Pugliese A, Scarpelli M, Siniscalchi A, Spinazzola A, Tal G, Torres-Torronteras J, Vignatelli L, Zaidman I, Zoller H, Rinaldi R, Zeviani M. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. J Inherit Metab Dis. 2021 Mar;44(2):376-387. doi: 10.1002/jimd.12300. Epub 2020 Sep 8.

Hirano M, Berardo A, Barca E, Emmanuele V, Quinzii C, Simpson CV, Engelstad K, Rosales XQ, Thompson JLP. Regulatory environment for novel therapeutic development in mitochondrial diseases. J Inherit Metab Dis. 2021 Mar;44(2):292-300. doi: 10.1002/jimd.12353. Epub 2021 Jan 4.

Murali CN, Soler-Alfonso C, Loomes KM, Shah AA, Monteil D, Padilla CD, Scaglia F, Ganetzky R. TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation. Mol Genet Metab. 2021 Feb;132(2):146-153. doi: 10.1016/j.ymgme.2021.01.005. Epub 2021 Jan 14.

Kripps KA, Friederich MW, Chen T, Larson AA, Mirsky DM, Wang Y, Tanji K, Knight KM, Wong LJ, Van Hove JLK. A novel acceptor stem variant in mitochondrial tRNA(Tyr) impairs mitochondrial translation and is associated with a severe phenotype. Mol Genet Metab. 2020 Dec;131(4):398-404. doi: 10.1016/j.ymgme.2020.11.006. Epub 2020 Nov 24.

McCormick EM, Lott MT, Dulik MC, Shen L, Attimonelli M, Vitale O, Karaa A, Bai R, Pineda-Alvarez DE, Singh LN, Stanley CM, Wong S, Bhardwaj A, Merkurjev D, Mao R, Sondheimer N, Zhang S, Procaccio V, Wallace DC, Gai X, Falk MJ. Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation. Hum Mutat. 2020 Dec;41(12):2028-2057. doi: 10.1002/humu.24107. Epub 2020 Nov 10.

Knight KM, Shelkowitz E, Larson AA, Mirsky DM, Wang Y, Chen T, Wong LJ, Friederich MW, Van Hove JLK. The mitochondrial DNA variant m.9032T > C in MT-ATP6 encoding p.(Leu169Pro) causes a complex mitochondrial neurological syndrome. Mitochondrion. 2020 Nov;55:8-13. doi: 10.1016/j.mito.2020.08.009. Epub 2020 Sep 12.

Falkenberg M, Hirano M. Editing the Mitochondrial Genome. N Engl J Med. 2020 Oct 8;383(15):1489-1491. doi: 10.1056/NEJMcibr2025332.

Almannai M, El-Hattab AW, Ali M, Soler-Alfonso C, Scaglia F. Clinical trials in mitochondrial disorders, an update. Mol Genet Metab. 2020 Sep-Oct;131(1-2):1-13. doi: 10.1016/j.ymgme.2020.10.002. Epub 2020 Oct 6.

Bedoyan JK, Hage R, Shin HK, Linard S, Ferren E, Ducich N, Wilson K, Lehman A, Schillaci LA, Manickam K, Mori M, Bartholomew D, DeBrosse S, Cohen B, Parikh S, Kerr D. Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other mitochondrial disorders associated with congenital lactic acidosis and newborn screening prospects. JIMD Rep. 2020 Aug 16;56(1):70-81. doi: 10.1002/jmd2.12153. eCollection 2020 Nov.

Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy. J Cachexia Sarcopenia Muscle. 2020 Aug;11(4):909-918. doi: 10.1002/jcsm.12559. Epub 2020 Feb 25.

Dominguez-Gonzalez C, Badosa C, Madruga-Garrido M, Martí I, Paradas C, Ortez C, Diaz-Manera J, Berardo A, Alonso-Pérez J, Trifunov S, Cuadras D, Kalko SG, Blázquez-Bermejo C, Cámara Y, Martí R, Mavillard F, Martin MA, Montoya J, Ruiz-Pesini E, Villarroya J, Montero R, Villarroya F, Artuch R, Hirano M, Nascimento A, Jimenez-Mallebrera C. Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy. Sci Rep. 2020 Jun 22;10(1):10111. doi: 10.1038/s41598-020-66940-8.

Shen L, McCormick EM, Muraresku CC, Falk MJ, Gai X. Clinical Bioinformatics in Precise Diagnosis of Mitochondrial Disease. Clin Lab Med. 2020 Jun;40(2):149-161. doi: 10.1016/j.cll.2020.02.002.

Kripps K, Nakayuenyongsuk W, Shayota BJ, Berquist W, Gomez-Ospina N, Esquivel CO, Concepcion W, Sampson JB, Cristin DJ, Jackson WE, Gilliland S, Pomfret EA, Kueht ML, Pettit RW, Sherif YA, Emrick LT, Elsea SH, Himes R, Hirano M, Van Hove JLK, Scaglia F, Enns GM, Larson AA. Successful liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Mol Genet Metab. 2020 May;130(1):58-64. doi: 10.1016/j.ymgme.2020.03.001. Epub 2020 Mar 6.

Barca E, Long Y, Cooley V, Schoenaker R, Emmanuele V, DiMauro S, Cohen BH, Karaa A, Vladutiu GD, Haas R, Van Hove JLK, Scaglia F, Parikh S, Bedoyan JK, DeBrosse SD, Gavrilova RH, Saneto RP, Enns GM, Stacpoole PW, Ganesh J, Larson A, Zolkipli-Cunningham Z, Falk MJ, Goldstein AC, Tarnopolsky M, Gropman A, Camp K, Krotoski D, Engelstad K, Rosales XQ, Kriger J, Grier J, Buchsbaum R, Thompson JLP, Hirano M. Mitochondrial diseases in North America: An analysis of the NAMDC Registry. Neurol Genet. 2020 Mar 2;6(2):e402. doi: 10.1212/NXG.0000000000000402. eCollection 2020 Apr.

Berardo A, Emmanuele V, Vargas W, Tanji K, Naini A, Hirano M. Leber hereditary optic neuropathy plus dystonia, and transverse myelitis due to double mutations in MT-ND4 and MT-ND6. J Neurol. 2020 Mar;267(3):823-829. doi: 10.1007/s00415-019-09619-z. Epub 2019 Nov 27.

Friederich MW, Perez FA, Knight KM, Van Hove RA, Yang SP, Saneto RP, Van Hove JLK. Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement. Mol Genet Metab. 2020 Mar;129(3):236-242. doi: 10.1016/j.ymgme.2019.12.013. Epub 2019 Dec 30.

Saneto RP. Mitochondrial diseases: expanding the diagnosis in the era of genetic testing. J Transl Genet Genom. 2020;4:384-428. doi: 10.20517/jtgg.2020.40. Epub 2020 Sep 29.

Rosales XQ, Thompson JLP, Haas R, Van Hove JLK, Karaa A, Krotoski D, Engelstad K, Buchsbaum R, DiMauro S, Hirano M; North American Mitochondrial Disease Consortium. The North American mitochondrial disease registry. J Transl Genet Genom. 2020;4:81-90. doi: 10.20517/jtgg.2020.12. Epub 2020 Apr 28.

Rosenberg BJ, Hirano M, Quinzii CM, Colantuoni E, Needham DM, Lederer DJ, Baldwin MR. Growth differentiation factor-15 as a biomarker of strength and recovery in survivors of acute respiratory failure. Thorax. 2019 Nov;74(11):1099-1101. doi: 10.1136/thoraxjnl-2019-213621. Epub 2019 Sep 18.

de Barcelos IP, Emmanuele V, Hirano M. Advances in primary mitochondrial myopathies. Curr Opin Neurol. 2019 Oct;32(5):715-721. doi: 10.1097/WCO.0000000000000743.

Sturm G, Cardenas A, Bind MA, Horvath S, Wang S, Wang Y, Hägg S, Hirano M, Picard M. Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts. Epigenetics. 2019 Oct;14(10):961-976. doi: 10.1080/15592294.2019.1626651. Epub 2019 Jun 12.

Lopez-Gomez C, Hewan H, Sierra C, Akman HO, Sanchez-Quintero MJ, Juanola-Falgarona M, Tadesse S, Tanji K, Konofagou EE, Hirano M. Bioavailability and cytosolic kinases modulate response to deoxynucleoside therapy in TK2 deficiency. EBioMedicine. 2019 Aug;46:356-367. doi: 10.1016/j.ebiom.2019.07.037. Epub 2019 Aug 2.

Domínguez-González C, Madruga-Garrido M, Mavillard F, Garone C, Aguirre-Rodríguez FJ, Donati MA, Kleinsteuber K, Martí I, Martín-Hernández E, Morealejo-Aycinena JP, Munell F, Nascimento A, Kalko SG, Sardina MD, Álvarez Del Vayo C, Serrano O, Long Y, Tu Y, Levin B, Thompson JLP, Engelstad K, Uddin J, Torres-Torronteras J, Jimenez-Mallebrera C, Martí R, Paradas C, Hirano M. Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy. Ann Neurol. 2019 Aug;86(2):293-303. doi: 10.1002/ana.25506. Epub 2019 Jun 17.

Bedoyan JK, Hecht L, Zhang S, Tarrant S, Bergin A, Demirabis D, Wang E, Shin H, Grahame GJ, DeBrosse SD, Hoppel CL, Kerr DS, Berry GT. A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency. JIMD Rep. 2019 Jun 17;48(1):26-35.

Haas RH. Mitochondrial Dysfunction in Aging and Diseases of Aging. Biology (Basel). 2019 Jun 17;8(2):48. doi: 10.3390/biology8020048.

Barcelos IP, Haas RH. CoQ10 and Aging. Biology (Basel). 2019 May 11;8(2):28. doi: 10.3390/biology8020028.

Domínguez-González C, Hernández-Laín A, Rivas E, Hernández-Voth A, Sayas Catalán J, Fernández-Torrón R, Fuiza-Luces C, García García J, Morís G, Olivé M, Miralles F, Díaz-Manera J, Caballero C, Méndez-Ferrer B, Martí R, García Arumi E, Badosa MC, Esteban J, Jimenez-Mallebrera C, Encinar AB, Arenas J, Hirano M, Martin MÁ, Paradas C. Late-onset thymidine kinase 2 deficiency: a review of 18 cases. Orphanet J Rare Dis. 2019 May 6;14(1):100. doi: 10.1186/s13023-019-1071-z.

Ganetzky RD, Stendel C, McCormick EM, Zolkipli-Cunningham Z, Goldstein AC, Klopstock T, Falk MJ. MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases. Hum Mutat. 2019 May;40(5):499-515. doi: 10.1002/humu.23723. Epub 2019 Mar 4.

Triska P, Kaneva K, Merkurjev D, Sohail N, Falk MJ, Triche TJ Jr, Biegel JA, Gai X. Landscape of Germline and Somatic Mitochondrial DNA Mutations in Pediatric Malignancies. Cancer Res. 2019 Apr 1;79(7):1318-1330. doi: 10.1158/0008-5472.CAN-18-2220. Epub 2019 Feb 1.

Kubota A, Juanola-Falgarona M, Emmanuele V, Sanchez-Quintero MJ, Kariya S, Sera F, Homma S, Tanji K, Quinzii CM, Hirano M. Cardiomyopathy and altered integrin-actin signaling in Fhl1 mutant female mice. Hum Mol Genet. 2019 Jan 15;28(2):209-219. doi: 10.1093/hmg/ddy299.

Larson AA, Balasubramaniam S, Christodoulou J, Burrage LC, Marom R, Graham BH, Diaz GA, Glamuzina E, Hauser N, Heese B, Horvath G, Mattman A, van Karnebeek C, Lane Rutledge S, Williamson A, Estrella L, Van Hove JKL, Weisfeld-Adams JD. Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6. Mitochondrion. 2019 Jan;44:58-64. doi: 10.1016/j.mito.2018.01.001. Epub 2018 Jan 4.

McCormick EM, Zolkipli-Cunningham Z, Falk MJ. Mitochondrial disease genetics update: recent insights into the molecular diagnosis and expanding phenotype of primary mitochondrial disease. Curr Opin Pediatr. 2018 Dec;30(6):714-724. doi: 10.1097/MOP.0000000000000686.

Kleiner G, Barca E, Ziosi M, Emmanuele V, Xu Y, Hidalgo-Gutierrez A, Qiao C, Tadesse S, Area-Gomez E, Lopez LC, Quinzii CM. CoQ(10) supplementation rescues nephrotic syndrome through normalization of H(2)S oxidation pathway. Biochim Biophys Acta Mol Basis Dis. 2018 Nov;1864(11):3708-3722. doi: 10.1016/j.bbadis.2018.09.002. Epub 2018 Sep 6.

Barca E, Ganetzky RD, Potluri P, Juanola-Falgarona M, Gai X, Li D, Jalas C, Hirsch Y, Emmanuele V, Tadesse S, Ziosi M, Akman HO, Chung WK, Tanji K, McCormick EM, Place E, Consugar M, Pierce EA, Hakonarson H, Wallace DC, Hirano M, Falk MJ. USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis. Hum Mol Genet. 2018 Oct 1;27(19):3305-3312. doi: 10.1093/hmg/ddy231.

Siegmund SE, Grassucci R, Carter SD, Barca E, Farino ZJ, Juanola-Falgarona M, Zhang P, Tanji K, Hirano M, Schon EA, Frank J, Freyberg Z. Three-Dimensional Analysis of Mitochondrial Crista Ultrastructure in a Patient with Leigh Syndrome by In Situ Cryoelectron Tomography. iScience. 2018 Aug 31;6:83-91. doi: 10.1016/j.isci.2018.07.014. Epub 2018 Jul 20.

Hoff KE, DeBalsi KL, Sanchez-Quintero MJ, Longley MJ, Hirano M, Naini AB, Copeland WC. Characterization of the human homozygous R182W POLG2 mutation in mitochondrial DNA depletion syndrome. PLoS One. 2018 Aug 29;13(8):e0203198. doi: 10.1371/journal.pone.0203198. eCollection 2018.

Garone C, Taylor RW, Nascimento A, Poulton J, Fratter C, Domínguez-González C, Evans JC, Loos M, Isohanni P, Suomalainen A, Ram D, Hughes MI, McFarland R, Barca E, Lopez Gomez C, Jayawant S, Thomas ND, Manzur AY, Kleinsteuber K, Martin MA, Kerr T, Gorman GS, Sommerville EW, Chinnery PF, Hofer M, Karch C, Ralph J, Cámara Y, Madruga-Garrido M, Domínguez-Carral J, Ortez C, Emperador S, Montoya J, Chakrapani A, Kriger JF, Schoenaker R, Levin B, Thompson JLP, Long Y, Rahman S, Donati MA, DiMauro S, Hirano M. Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet. 2018 Aug;55(8):515-521. doi: 10.1136/jmedgenet-2017-105012. Epub 2018 Mar 30.

Hirano M, Emmanuele V, Quinzii CM. Emerging therapies for mitochondrial diseases. Essays Biochem. 2018 Jul 20;62(3):467-481. doi: 10.1042/EBC20170114. Print 2018 Jul 20.

Torres-Torronteras J, Cabrera-Pérez R, Vila-Julià F, Viscomi C, Cámara Y, Hirano M, Zeviani M, Martí R. Long-Term Sustained Effect of Liver-Targeted Adeno-Associated Virus Gene Therapy for Mitochondrial Neurogastrointestinal Encephalomyopathy. Hum Gene Ther. 2018 Jun;29(6):708-718. doi: 10.1089/hum.2017.133. Epub 2018 Feb 26.

Shen L, Attimonelli M, Bai R, Lott MT, Wallace DC, Falk MJ, Gai X. MSeqDR mvTool: A mitochondrial DNA Web and API resource for comprehensive variant annotation, universal nomenclature collation, and reference genome conversion. Hum Mutat. 2018 Jun;39(6):806-810. doi: 10.1002/humu.23422. Epub 2018 Apr 6.

Zolkipli-Cunningham Z, Xiao R, Stoddart A, McCormick EM, Holberts A, Burrill N, McCormack S, Williams L, Wang X, Thompson JLP, Falk MJ. Mitochondrial disease patient motivations and barriers to participate in clinical trials. PLoS One. 2018 May 17;13(5):e0197513. doi: 10.1371/journal.pone.0197513. eCollection 2018.

Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. 2018 Apr 3;90(14):e1212-e1221. doi: 10.1212/WNL.0000000000005255. Epub 2018 Mar 2.

Grier J, Hirano M, Karaa A, Shepard E, Thompson JLP. Diagnostic odyssey of patients with mitochondrial disease: Results of a survey. Neurol Genet. 2018 Mar 26;4(2):e230. doi: 10.1212/NXG.0000000000000230. PMID: 29600276; PMCID: PMC5873725.

Gramegna LL, Pisano A, Testa C, Manners DN, D'Angelo R, Boschetti E, Giancola F, Pironi L, Caporali L, Capristo M, Valentino ML, Plazzi G, Casali C, Dotti MT, Cenacchi G, Hirano M, Giordano C, Parchi P, Rinaldi R, De Giorgio R, Lodi R, Carelli V, Tonon C. Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy. AJNR Am J Neuroradiol. 2018 Mar;39(3):427-434. doi: 10.3174/ajnr.A5507. Epub 2018 Jan 18.

Al-Gadi IS, Haas RH, Falk MJ, Goldstein A, McCormack SE. Endocrine Disorders in Primary Mitochondrial Disease. J Endocr Soc. 2018 Feb 19;2(4):361-373. doi: 10.1210/js.2017-00434. eCollection 2018 Apr 1.

Mancuso M, McFarland R, Klopstock T, Hirano M; consortium on Trial Readiness in Mitochondrial Myopathies. International Workshop: Outcome measures and clinical trial readiness in primary mitochondrial myopathies in children and adults. Consensus recommendations. 16-18 November 2016, Rome, Italy. Neuromuscul Disord. 2017 Dec;27(12):1126-1137. doi: 10.1016/j.nmd.2017.08.006. Epub 2017 Sep 8.

Shin HK, Grahame G, McCandless SE, Kerr DS, Bedoyan JK. Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab. 2017 Nov;122(3):61-66. doi: 10.1016/j.ymgme.2017.09.001. Epub 2017 Sep 8.

Lopez-Gomez C, Levy RJ, Sanchez-Quintero MJ, Juanola-Falgarona M, Barca E, Garcia-Diaz B, Tadesse S, Garone C, Hirano M. Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol. 2017 May;81(5):641-652. doi: 10.1002/ana.24922. Epub 2017 May 4.

Bedoyan JK, Yang SP, Ferdinandusse S, Jack RM, Miron A, Grahame G, DeBrosse SD, Hoppel CL, Kerr DS, Wanders RJA. Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab. 2017 Apr;120(4):342-349. doi: 10.1016/j.ymgme.2017.02.002. Epub 2017 Feb 2.

Huang X, Bedoyan JK, Demirbas D, Harris DJ, Miron A, Edelheit S, Grahame G, DeBrosse SD, Wong LJ, Hoppel CL, Kerr DS, Anselm I, Berry GT. Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion. Mol Genet Metab. 2017 Mar;120(3):213-222. doi: 10.1016/j.ymgme.2016.11.005. Epub 2016 Nov 12.

Garone C, Gurgel-Giannetti J, Sanna-Cherchi S, Krishna S, Naini A, Quinzii CM, Hirano M. A Novel SUCLA2 Mutation Presenting as a Complex Childhood Movement Disorder. J Child Neurol. 2017 Feb;32(2):246-250. doi: 10.1177/0883073816666221. Epub 2016 Sep 28.

Kerr DS, Bedoyan JK. Disorders of pyruvate metabolism and the tricarboxylic acid cycle. In Sarafoglou K (ed) Essentials of Pediatric Endocrinology and Metabolism, 2nd Edition, McGraw Hill . 2017

Hirano M, Peters GJ. Advances in purine and pyrimidine metabolism in health and diseases. Nucleosides Nucleotides Nucleic Acids. 2016 Dec;35(10-12):495-501. doi: 10.1080/15257770.2016.1218022.

Al-Mehmadi S, Splitt M; For DDD Study group*, Ramesh V, DeBrosse S, Dessoffy K, Xia F, Yang Y, Rosenfeld JA, Cossette P, Michaud JL, Hamdan FF, Campeau PM, Minassian BA; For CENet Study group‡. FHF1 (FGF12) epileptic encephalopathy. Neurol Genet. 2016 Oct 28;2(6):e115. doi: 10.1212/NXG.0000000000000115. eCollection 2016 Dec.

Pavlakis SG, Hirano M. Mitochondrial Diseases: A Clinical and Molecular History. Pediatr Neurol. 2016 Oct;63:3-5. doi: 10.1016/j.pediatrneurol.2016.05.014. Epub 2016 Jun 2.

Perales-Clemente E, Cook AN, Evans JM, Roellinger S, Secreto F, Emmanuele V, Oglesbee D, Mootha VK, Hirano M, Schon EA, Terzic A, Nelson TJ. Natural underlying mtDNA heteroplasmy as a potential source of intra-person hiPSC variability. EMBO J. 2016 Sep 15;35(18):1979-90. doi: 10.15252/embj.201694892. Epub 2016 Jul 19.

Torres-Torronteras J, Cabrera-Pérez R, Barba I, Costa C, de Luna N, Andreu AL, Barquinero J, Hirano M, Cámara Y, Martí R. Long-Term Restoration of Thymidine Phosphorylase Function and Nucleoside Homeostasis Using Hematopoietic Gene Therapy in a Murine Model of Mitochondrial Neurogastrointestinal Encephalomyopathy. Hum Gene Ther. 2016 Sep;27(9):656-67. doi: 10.1089/hum.2015.160. Epub 2016 May 4.

Karaa A, Kriger J, Grier J, Holbert A, Thompson JL, Parikh S, Hirano M. Mitochondrial disease patients' perception of dietary supplements' use. Mol Genet Metab. 2016 Sep;119(1-2):100-8. doi: 10.1016/j.ymgme.2016.07.005. Epub 2016 Jul 16.

Barca E, Musumeci O, Montagnese F, Marino S, Granata F, Nunnari D, Peverelli L, DiMauro S, Quinzii CM, Toscano A. Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3. Clin Genet. 2016 Aug;90(2):156-60. doi: 10.1111/cge.12742. Epub 2016 Feb 16.

Saneto RP. Alpers-Huttenlocher syndrome: the role of a multidisciplinary health care team. J Multidiscip Healthc. 2016 Jul 26;9:323-33. doi: 10.2147/JMDH.S84900. eCollection 2016.

Yamada M, Emmanuele V, Sanchez-Quintero MJ, Sun B, Lallos G, Paull D, Zimmer M, Pagett S, Prosser RW, Sauer MV, Hirano M, Egli D. Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes. Cell Stem Cell. 2016 Jun 2;18(6):749-754. doi: 10.1016/j.stem.2016.04.001. Epub 2016 May 19.

Shen L, Diroma MA, Gonzalez M, Navarro-Gomez D, Leipzig J, Lott MT, van Oven M, Wallace DC, Muraresku CC, Zolkipli-Cunningham Z, Chinnery PF, Attimonelli M, Zuchner S, Falk MJ, Gai X. MSeqDR: A Centralized Knowledge Repository and Bioinformatics Web Resource to Facilitate Genomic Investigations in Mitochondrial Disease. Hum Mutat. 2016 Jun;37(6):540-548. doi: 10.1002/humu.22974. Epub 2016 Mar 21.

Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

Engelstad K, Sklerov M, Kriger J, Sanford A, Grier J, Ash D, Egli D, DiMauro S, Thompson JL, Sauer MV, Hirano M. Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy. Hum Reprod. 2016 May;31(5):1058-65. doi: 10.1093/humrep/dew033. Epub 2016 Mar 2.

Marin SE, Saneto RP. Neuropsychiatric Features in Primary Mitochondrial Disease. Neurol Clin. 2016 Feb;34(1):247-94. doi: 10.1016/j.ncl.2015.08.011.

Halter JP, Michael W, Schüpbach M, Mandel H, Casali C, Orchard K, Collin M, Valcarcel D, Rovelli A, Filosto M, Dotti MT, Marotta G, Pintos G, Barba P, Accarino A, Ferra C, Illa I, Beguin Y, Bakker JA, Boelens JJ, de Coo IF, Fay K, Sue CM, Nachbaur D, Zoller H, Sobreira C, Pinto Simoes B, Hammans SR, Savage D, Martí R, Chinnery PF, Elhasid R, Gratwohl A, Hirano M. Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy. Brain. 2015 Oct;138(Pt 10):2847-58. doi: 10.1093/brain/awv226. Epub 2015 Aug 10.

Gonzalez M, Falk MJ, Gai X, Postrel R, Schüle R, Zuchner S. Innovative genomic collaboration using the GENESIS (GEM.app) platform. Hum Mutat. 2015 Oct;36(10):950-6. doi: 10.1002/humu.22836. Epub 2015 Aug 12.

Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R, Anselm I, Cohen BH, Falk MJ, Greene C, Gropman AL, Haas R, Hirano M, Morgan P, Sims K, Tarnopolsky M, Van Hove JL, Wolfe L, DiMauro S. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015 Sep;17(9):689-701. doi: 10.1038/gim.2014.177. Epub 2014 Dec 11.

Ferdinandusse S, Friederich MW, Burlina A, Ruiter J, Coughlin CR, Dishop MK, Gallagher RC, Bedoyan JK, Vaz FM, Waterham HR, Gowan K, Chatfield K, Bennett MJ, Elpeleg O, Van Hove JLK, Wanders RJA. Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis. 2015 Jun 18;10:79.

Navarro-Gomez D, Leipzig J, Shen L, Lott M, Stassen AP, Wallace DC, Wiggs JL, Falk MJ, van Oven M, Gai X. Phy-Mer: a novel alignment-free and reference-independent mitochondrial haplogroup classifier. Bioinformatics. 2015 Apr 15;31(8):1310-2. doi: 10.1093/bioinformatics/btu825. Epub 2014 Dec 12.

Falk MJ, Shen L, Gonzalez M, Leipzig J, Lott MT, Stassen AP, Diroma MA, Navarro-Gomez D, Yeske P, Bai R, Boles RG, Brilhante V, Ralph D, DaRe JT, Shelton R, Terry SF, Zhang Z, Copeland WC, van Oven M, Prokisch H, Wallace DC, Attimonelli M, Krotoski D, Zuchner S, Gai X; MSeqDR Consortium Participants; MSeqDR Consortium participants: Sherri Bale, Jirair Bedoyan, Doron Behar, Penelope Bonnen, Lisa Brooks, Claudia Calabrese, Sarah Calvo, Patrick Chinnery, John Christodoulou, Deanna Church,; Rosanna Clima, Bruce H Cohen, Richard G Cotton, IFM de Coo, Olga Derbenevoa, Johan T den Dunnen, David Dimmock, Gregory Enns, Giuseppe Gasparre,; Amy Goldstein, Iris Gonzalez, Katrina Gwinn, Sihoun Hahn, Richard H Haas, Hakon Hakonarson, Michio Hirano, Douglas Kerr, Dong Li, Maria Lvova, Finley Macrae, Donna Maglott, Elizabeth McCormick, Grant Mitchell, Vamsi K Mootha, Yasushi Okazaki,; Aurora Pujol, Melissa Parisi, Juan Carlos Perin, Eric A Pierce, Vincent Procaccio, Shamima Rahman, Honey Reddi, Heidi Rehm, Erin Riggs, Richard Rodenburg, Yaffa Rubinstein, Russell Saneto, Mariangela Santorsola, Curt Scharfe,; Claire Sheldon, Eric A Shoubridge, Domenico Simone, Bert Smeets, Jan A Smeitink, Christine Stanley, Anu Suomalainen, Mark Tarnopolsky, Isabelle Thiffault, David R Thorburn, Johan Van Hove, Lynne Wolfe, and Lee-Jun Wong. 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 Mar;114(3):388-96. doi: 10.1016/j.ymgme.2014.11.016. Epub 2014 Dec 4.

Ruhoy IS, Saneto RP. The genetics of Leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet. 2014 Nov 13;7:221-34. doi: 10.2147/TACG.S46176. eCollection 2014.

Balreira A, Boczonadi V, Barca E, Pyle A, Bansagi B, Appleton M, Graham C, Hargreaves IP, Rasic VM, Lochmüller H, Griffin H, Taylor RW, Naini A, Chinnery PF, Hirano M, Quinzii CM, Horvath R. ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency. J Neurol. 2014 Nov;261(11):2192-8. doi: 10.1007/s00415-014-7476-7. Epub 2014 Sep 3.

Deeb KK, Bedoyan JK, Wang R, Sremba L, Schroeder MC, Grahame GJ, Boyer M, McCandless SE, Kerr DS, Zhang S. Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency. Mol Genet Metab. 2014 Aug 28;1:362-367.

Garone C, Garcia-Diaz B, Emmanuele V, Lopez LC, Tadesse S, Akman HO, Tanji K, Quinzii CM, Hirano M. Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. EMBO Mol Med. 2014 Aug;6(8):1016-27. doi: 10.15252/emmm.201404092.

Peverelli L, Gold CA, Naini AB, Tanji K, Akman HO, Hirano M, Dimauro S. Mitochondrial myopathy with dystrophic features due to a novel mutation in the MTTM gene. Muscle Nerve. 2014 Aug;50(2):292-5. doi: 10.1002/mus.24262.

Quinzii CM, Hirano M, DiMauro S. Mutant COQ2 in multiple-system atrophy. N Engl J Med. 2014 Jul 3;371(1):81-2. doi: 10.1056/NEJMc1311763.

Quinzii CM, Emmanuele V, Hirano M. Clinical presentations of coenzyme q10 deficiency syndrome. Mol Syndromol. 2014 Jul;5(3-4):141-6. doi: 10.1159/000360490.

Garcia-Diaz B, Garone C, Barca E, Mojahed H, Gutierrez P, Pizzorno G, Tanji K, Arias-Mendoza F, Quinzii CM, Hirano M. Deoxynucleoside stress exacerbates the phenotype of a mouse model of mitochondrial neurogastrointestinal encephalopathy. Brain. 2014 May;137(Pt 5):1337-49. doi: 10.1093/brain/awu068. Epub 2014 Apr 10.

Torres-Torronteras J, Viscomi C, Cabrera-Pérez R, Cámara Y, Di Meo I, Barquinero J, Auricchio A, Pizzorno G, Hirano M, Zeviani M, Martí R. Gene therapy using a liver-targeted AAV vector restores nucleoside and nucleotide homeostasis in a murine model of MNGIE. Mol Ther. 2014 May;22(5):901-7. doi: 10.1038/mt.2014.6. Epub 2014 Jan 22..

Hirano M. Weighing in on Leber hereditary optic neuropathy: effects of mitochondrial mass. Brain. 2014 Feb;137(Pt 2):308-9. doi: 10.1093/brain/awu005.

Paradas C, Akman HO, Ionete C, Lau H, Riskind PN, Jones DE, Smith TW, Hirano M, Dimauro S. Branching enzyme deficiency: expanding the clinical spectrum. JAMA Neurol. 2014 Jan;71(1):41-7. doi: 10.1001/jamaneurol.2013.4888.

Paradas C, Camaño P, Otaegui D, Oz O, Emmanuele V, DiMauro S, Hirano M. Longitudinal clinical follow-up of a large family with the R357P Twinkle mutation. JAMA Neurol. 2013 Nov;70(11):1425-8. doi: 10.1001/jamaneurol.2013.3185.

Pfeffer G, Horvath R, Klopstock T, Mootha VK, Suomalainen A, Koene S, Hirano M, Zeviani M, Bindoff LA, Yu-Wai-Man P, Hanna M, Carelli V, McFarland R, Majamaa K, Turnbull DM, Smeitink J, Chinnery PF. New treatments for mitochondrial disease-no time to drop our standards. Nat Rev Neurol. 2013 Aug;9(8):474-81. doi: 10.1038/nrneurol.2013.129. Epub 2013 Jul 2.

DiMauro S. Mitochondrial encephalomyopathies--fifty years on: the Robert Wartenberg Lecture. Neurology. 2013 Jul 16;81(3):281-91. doi: 10.1212/WNL.0b013e31829bfe89.

Melià MJ, Kubota A, Ortolano S, Vílchez JJ, Gámez J, Tanji K, Bonilla E, Palenzuela L, Fernández-Cadenas I, Pristoupilová A, García-Arumí E, Andreu AL, Navarro C, Hirano M, Martí R. Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene. Brain. 2013 May;136(Pt 5):1508-17. doi: 10.1093/brain/awt074. Epub 2013 Mar 29.

Saneto RP, Sedensky MM. Mitochondrial disease in childhood: mtDNA encoded. Neurotherapeutics. 2013 Apr;10(2):199-211. doi: 10.1007/s13311-012-0167-0.

Saneto RP, Cohen BH, Copeland WC, Naviaux RK. Alpers-Huttenlocher syndrome. Pediatr Neurol. 2013 Mar;48(3):167-78. doi: 10.1016/j.pediatrneurol.2012.09.014.

Gurgel-Giannetti J, Oliveira G, Brasileiro Filho G, Martins P, Vainzof M, Hirano M. Mitochondrial cardioencephalomyopathy due to a novel SCO2 mutation in a Brazilian patient: case report and literature review. JAMA Neurol. 2013 Feb;70(2):258-61. doi: 10.1001/jamaneurol.2013.595.

Garone C, Rubio JC, Calvo SE, Naini A, Tanji K, Dimauro S, Mootha VK, Hirano M. MPV17 Mutations Causing Adult-Onset Multisystemic Disorder With Multiple Mitochondrial DNA Deletions. Arch Neurol. 2012 Dec;69(12):1648-51. doi: 10.1001/archneurol.2012.405.

Neeve VC, Samuels DC, Bindoff LA, van den Bosch B, Van Goethem G, Smeets H, Lombès A, Jardel C, Hirano M, Dimauro S, De Vries M, Smeitink J, Smits BW, de Coo IF, Saft C, Klopstock T, Keiling BC, Czermin B, Abicht A, Lochmüller H, Hudson G, Gorman GG, Turnbull DM, Taylor RW, Holinski-Feder E, Chinnery PF, Horvath R. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?. Brain. 2012 Dec;135(Pt 12):3614-26. doi: 10.1093/brain/aws298.

Garcia-Diaz B, Barros MH, Sanna-Cherchi S, Emmanuele V, Akman HO, Ferreiro-Barros CC, Horvath R, Tadesse S, El Gharaby N, DiMauro S, De Vivo DC, Shokr A, Hirano M, Quinzii CM. Infantile encephaloneuromyopathy and defective mitochondrial translation are due to a homozygous RMND1 mutation. Am J Hum Genet. 2012 Oct 5;91(4):729-36. doi: 10.1016/j.ajhg.2012.08.019. Epub 2012 Sep 27.

Ash DB, Papadimitriou D, Hays AP, Dimauro S, Hirano M. A novel mutation in PNPLA2 leading to neutral lipid storage disease with myopathy. Arch Neurol. 2012 Sep;69(9):1190-2. doi: 10.1001/archneurol.2011.2600.

Gurgel-Giannetti J, Camargos ST, Cardoso F, Hirano M, DiMauro S. POLG1 Arg953Cys mutation: expanded phenotype and recessive inheritance in a Brazilian family. Muscle Nerve. 2012 Mar;45(3):453-4. doi: 10.1002/mus.22330.

Rahman S, Clarke CF, Hirano M. 176th ENMC International Workshop: diagnosis and treatment of coenzyme Q(1)(0) deficiency. Neuromuscul Disord. Jan 2012;22(1):76-86. PMID: 21723727, PMCID: PMC3222743.

Kurt B, Naini AB, Copeland WC, Lu J, Dimauro S, Hirano M. A novel POLG gene mutation in a patient with SANDO. J Exp Integr Med. 2012;2(2):10.5455/jeim.200312.cr.001. doi: 10.5455/jeim.200312.cr.001.

Marti R, Lopez LC, Hirano M. Assessment of thymidine phosphorylase function: measurement of plasma thymidine (and deoxyuridine) and thymidine phosphorylase activity. Methods Mol Biol. 2012;837:121-133. PMID: 22215544, PMCID: PMC4942128.

Martí R, Dorado B, Hirano M. Measurement of mitochondrial dNTP pools. Methods Mol Biol. 2012;837:135-48. doi: 10.1007/978-1-61779-504-6_9.

Kaufmann P, Engelstad K, Wei Y, Kulikova R, Oskoui M, Sproule DM, Battista V, Koenigsberger DY, Pascual JM, Shanske S, Sano M, Mao X, Hirano M, Shungu DC, Dimauro S, De Vivo DC. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology. 2011 Nov 29;77(22):1965-71. doi: 10.1212/WNL.0b013e31823a0c7f. Epub 2011 Nov 16.

Quinzii CM, Hirano M. Primary and secondary CoQ(10) deficiencies in humans. Biofactors. Sep 2011;37(5):361-365. PMID: 21990098, PMCID: PMC3258494.

Torres-Torronteras J, Gómez A, Eixarch H, Palenzuela L, Pizzorno G, Hirano M, Andreu AL, Barquinero J, Martí R. Hematopoietic gene therapy restores thymidine phosphorylase activity in a cell culture and a murine model of MNGIE. Gene Ther. 2011 Aug;18(8):795-806. doi: 10.1038/gt.2011.24. Epub 2011 Mar 31.

Villarroya J, Lara MC, Dorado B, Garrido M, García-Arumí E, Meseguer A, Hirano M, Vilà MR. Targeted impairment of thymidine kinase 2 expression in cells induces mitochondrial DNA depletion and reveals molecular mechanisms of compensation of mitochondrial respiratory activity. Biochem Biophys Res Commun. 2011 Apr 8;407(2):333-8. doi: 10.1016/j.bbrc.2011.03.018. Epub 2011 Mar 5.

Halter J, Schüpbach W, Casali C, Elhasid R, Fay K, Hammans S, Illa I, Kappeler L, Krähenbühl S, Lehmann T, Mandel H, Marti R, Mattle H, Orchard K, Savage D, Sue CM, Valcarcel D, Gratwohl A, Hirano M. Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach. Bone Marrow Transplant. 2011 Mar;46(3):330-337. doi: 10.1038/bmt.2010.100. Epub 2010 May 3.

Dorado B, Area E, Akman HO, Hirano M. Onset and organ specificity of Tk2 deficiency depends on Tk1 down-regulation and transcriptional compensation. Hum Mol Genet. Jan 1 2011;20(1):155-164. PMID: 20940150, PMCID: PMC3000681.

Villarroya J, Dorado B, Vilà MR, Garcia-Arumí E, Domingo P, Giralt M, Hirano M, Villarroya F. Thymidine kinase 2 deficiency-induced mitochondrial DNA depletion causes abnormal development of adipose tissues and adipokine levels in mice. PLoS One. 2011;6(12):e29691. doi: 10.1371/journal.pone.0029691. Epub 2011 Dec 27.

Tanji K, Kaufmann P, Naini AB, Lu J, Parsons TC, Wang D, Willey JZ, Shanske S, Hirano M, Bonilla E, Khandji A, Dimauro S, Rowland LP. A novel tRNA(Val) mitochondrial DNA mutation causing MELAS. J Neurol Sci. 2008 Jul 15;270(1-2):23-7. doi: 10.1016/j.jns.2008.01.016. Epub 2008 Mar 7.