[Review] Mitochondrial disease in adults: recent advances and future promise

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Mitochondrial diseases.

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Consensus-based statements for the management of mitochondrial stroke-like episodes.

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Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes presenting before 50 years of age: when a stroke is not just a stroke.

JAMA Neurol. 73: 604-6064.Hikmat O Naess K Engvall M et al.

Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases.

J Inherit Metab Dis. 43: 726-7365.Sinnecker T Andelova M Mayr M et al.

Diagnosis of adult-onset MELAS syndrome in a 63-year-old patient with suspected recurrent strokes: a case report.

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Late-onset MELAS syndrome with mtDNA 14453G→A mutation masquerading as an acute encephalitis: a case report.

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The diagnosis of posterior reversible encephalopathy syndrome.

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Epilepsy in adults with mitochondrial disease: a cohort study.

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Mitochondrial epilepsy: a cross-sectional nationwide Italian survey.

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Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: a clinical and molecular genetic review.

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Expanded phenotypic spectrum of the m.8344A→G “MERRF” mutation: data from the German mitoNET registry.

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Phenotypic heterogeneity of the 8344A→G mtDNA “MERRF” mutation.

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Leigh syndrome: one disorder, more than 75 monogenic causes.

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A multicenter study on Leigh syndrome: disease course and predictors of survival.

Orphanet J Rare Dis. 9: 5215.Ng YS Martikainen MH Gorman GS et al.

Pathogenic variants in MT-ATP6: a United Kingdom-based mitochondrial disease cohort study.

Ann Neurol. 86: 310-31516.Carelli V d'Adamo P Valentino ML et al.

Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion.

Brain. 139: e1817.

Leber hereditary optic neuropathy.

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Changes in choroidal thickness follow the RNFL changes in Leber's hereditary optic neuropathy.

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Ocular motility findings in chronic progressive external ophthalmoplegia.

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Neuromuscular junction abnormalities in mitochondrial disease: an observational cohort study.

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Diagnosis of ‘possible’ mitochondrial disease: an existential crisis.

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Peripheral neuropathy in mitochondrial disorders.

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Dysphagia, malnutrition and gastrointestinal problems in patients with mitochondrial disease caused by the m3243A>G mutation.

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Heterogeneity of coenzyme Q10 deficiency: patient study and literature review.

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Late-onset thymidine kinase 2 deficiency: a review of 18 cases.

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Both mitochondrial DNA and mitonuclear gene mutations cause hearing loss through cochlear dysfunction.

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OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation.

Brain. 138: 563-57628.

Dominant optic atrophy: novel OPA1 mutations and revised prevalence estimates.

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Syndromic parkinsonism and dementia associated with OPA1 missense mutations.

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Genetics of mitochondrial diseases: identifying mutations to help diagnosis.

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New diagnostic pathways for mitochondrial disease.

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Pathogenic mtDNA mutations causing mitochondrial myopathy: the need for muscle biopsy.

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Mitochondrial myopathy induces a starvation-like response.

Hum Mol Genet. 19: 3948-395834.Kalko SG Paco S Jou C et al.

Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies.

BMC Genomics. 15: 9135.Formichi P Cardone N Taglia I et al.

Fibroblast growth factor 21 and grow differentiation factor 15 are sensitive biomarkers of mitochondrial diseases due to mitochondrial transfer-RNA mutations and mitochondrial DNA deletions.

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FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study.

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Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders.

Ann Neurol. 78: 814-82338.Lehtonen JM Auranen M Darin N et al.

Diagnostic value of serum biomarkers FGF21 and GDF15 compared to muscle sample in mitochondrial disease.

J Inherit Metab Dis. 44: 469-48039.

Accuracy of FGF-21 and GDF-15 for the diagnosis of mitochondrial disorders: a meta-analysis.

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Growth differentiation factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy.

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Expanding and validating the biomarkers for mitochondrial diseases.

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Serum biomarkers in primary mitochondrial disorders.

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Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions.

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Mitochondrial DNA replication defects disturb cellular dNTP pools and remodel one-carbon metabolism.

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Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers.

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Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy.

Cell Metab. 31: 1078-109047.Varhaug KN Nido GS de Coo I et al.

Using urine to diagnose large-scale mtDNA deletions in adult patients.

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Maternally inherited mitochondrial DNA disease in consanguineous families.

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De novo mtDNA point mutations are common and have a low recurrence risk.

J Med Genet. 54: 73-8350.Frazier AE Thorburn DR Compton AG

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology.

J Biol Chem. 294: 5386-539551.Tan J Wagner M Stenton SL et al.

Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases.

EBioMedicine. 5410273052.Gorman GS Schaefer AM Ng Y et al.

Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease.

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Comprehensive mitochondrial genome analysis by massively parallel sequencing.

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Mitochondrial DNA mutation analysis from exome sequencing-A more holistic approach in diagnostics of suspected mitochondrial disease.

J Inherit Metab Dis. 42: 909-91755.Grady JP Pickett SJ Ng YS et al.

mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A→G mitochondrial disease.

EMBO Mol Med. 10e826256.Ng YS Thompson K Loher D et al.

Novel MT-ND gene variants causing adult-onset mitochondrial disease and isolated complex I deficiency.

Front Genet. 11: 2457.Thompson K Collier JJ Glasgow RIC et al.

Recent advances in understanding the molecular genetic basis of mitochondrial disease.

J Inherit Metab Dis. 43: 36-5058.Rath S Sharma R Gupta R et al.

MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations.

Nucleic Acids Res. 49: D1541-D154759.Tankard RM Bennett MF Degorski P Delatycki MB Lockhart PJ Bahlo M

Detecting expansions of tandem repeats in cohorts sequenced with short-read sequencing data.

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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.

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Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests.

Eur J Hum Genet. 27: 1197-121462.Kalia S Adelman K Bale S et al.

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

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Resolution of disease phenotypes resulting from multilocus genomic variation.

N Engl J Med. 376: 21-3164.Frazier AE Vincent AE Turnbull DM Thorburn DR Taylor RW

Assessment of mitochondrial respiratory chain enzymes in cells and tissues.

Methods Cell Biol. 155: 121-15665.Warren C McDonald D Capaldi R et al.

Decoding mitochondrial heterogeneity in single muscle fibres by imaging mass cytometry.

Sci Rep. 101533666.Grady JP Campbell G Ratnaike T et al.

Disease progression in patients with single, large-scale mitochondrial DNA deletions.

Brain. 137: 323-33467.Cummings BB Marshall JL Tukiainen T et al.

Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.

Sci Transl Med. 9 ()eaal520968.Nesbitt V Pitceathly RDS Turnbull DM et al.

The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A→G mutation—implications for diagnosis and management.

J Neurol Neurosurg Psychiatry. 84: 936-93869.Mancuso M Orsucci D Angelini C et al.

The m.3243A→G mitochondrial DNA mutation and related phenotypes: a matter of gender?.

J Neurol. 261: 504-51070.Pickett SJ Grady JP Ng YS et al.

Phenotypic heterogeneity in m.3243A→G mitochondrial disease: the role of nuclear factors.

Ann Clin Transl Neurol. 5: 333-34571.de Laat P Rodenburg RR Roeleveld N Koene S Smeitink JA Janssen MC

Six-year prospective follow-up study in 151 carriers of the mitochondrial DNA 3243 A>G variant.

J Med Genet. 58: 48-5572.Stendel C Neuhofer C Floride E et al.

Delineating MT-ATP6-associated disease: from isolated neuropathy to early onset neurodegeneration.

Neurol Genet. 6: e39373.Mancuso M Orsucci D Angelini C et al.

Redefining phenotypes associated with mitochondrial DNA single deletion.

J Neurol. 262: 1301-130974.Hikmat O Naess K Engvall M et al.

Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases.

J Inherit Metab Dis. 43: 726-73675.Garone C Taylor RW Nascimento A et al.

Retrospective natural history of thymidine kinase 2 deficiency.

J Med Genet. 55: 515-52176.Corazza G Pagan C Hardy G et al.

MyoNeuroGastroIntestinal encephalopathy: natural history and means for early diagnosis.

Gastroenterology. 156: 1525-152777.Sofou K de Coo IFM Ostergaard E et al.

Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients.

J Med Genet. 55: 21-2778.Martikainen MH Ng YS Gorman GS et al.

Clinical, genetic, and radiological features of extrapyramidal movement disorders in mitochondrial disease.

JAMA Neurol. 73: 668-67479.Mancuso M Orsucci D Angelini C et al.

Myoclonus in mitochondrial disorders.

Mov Disord. 29: 722-72880.Heighton JN Brady LI Sadikovic B Bulman DE Tarnopolsky MA

Genotypes of chronic progressive external ophthalmoplegia in a large adult-onset cohort.

Mitochondrion. 49: 227-23181.Orsucci D Angelini C Bertini E et al.

Revisiting mitochondrial ocular myopathies: a study from the Italian Network.

J Neurol. 264: 1777-178482.Feeney CL Lim AZ Fagan E et al.

A case-comparison study of pregnant women with mitochondrial disease: what to expect?.

BJOG. 126: 1380-138983.Ng YS Feeney C Schaefer AM et al.

Pseudo-obstruction, stroke, and mitochondrial dysfunction: a lethal combination.

Ann Neurol. 80: 686-69284.Ng YS Grady JP Lax NZ et al.

Sudden adult death syndrome in m.3243A→G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.

Eur Heart J. 37: 2552-255985.Sissler M González-Serrano LE Westhof E

Recent advances in mitochondrial aminoacyl-tRNA synthetases and disease.

Trends Mol Med. 23: 693-70886.Poulton J Steffann J Burgstaller J McFarland R

243rd ENMC international workshop: developing guidelines for management of reproductive options for families with maternally inherited mtDNA disease, Amsterdam, the Netherlands, 22–24 March 2019.

Neuromuscul Disord. 29: 725-73387.De Vries MC Brown DA Allen ME et al.

Safety of drug use in patients with a primary mitochondrial disease: an international Delphi-based consensus.

J Inherit Metab Dis. 43: 800-81888.Hirano M Carelli V De Giorgio R et al.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): position paper on diagnosis, prognosis, and treatment by the MNGIE International Network.

J Inherit Metab Dis. 44: 376-38789.Shen L Diroma MA Gonzalez M et al.

MSeqDR: a centralized knowledge repository and bioinformatics web resource to facilitate genomic investigations in mitochondrial disease.

Hum Mutat. 37: 540-54890.Mancuso M McFarland R Klopstock T Hirano M

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. 27: 1126-113791.Klopstock T Yu-Wai-Man P Dimitriadis K et al.

A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy.

Brain. 134: 2677-268692.Catarino CB von Livonius B Priglinger C et al.

Real-world clinical experience with idebenone in the treatment of Leber hereditary optic neuropathy.

J Neuroophthalmol. 405586593.Koga Y Povalko N Inoue E et al.

Therapeutic regimen of L-arginine for MELAS: 9-year, prospective, multicenter, clinical research.

J Neurol. 265: 2861-287494.Ohsawa Y Hagiwara H Nishimatsu SI et al.

Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial.

J Neurol Neurosurg Psychiatry. 90: 529-53695.Ng YS Lax NZ Maddison P et al.

MT-ND5 mutation exhibits highly variable neurological manifestations at low mutant load.

EBioMedicine. 30: 86-9396.Stefanetti RJ Blain A Jimenez-Moreno C et al.

Measuring the effects of exercise in neuromuscular disorders: a systematic review and meta-analyses.

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Aerobic exercise training in patients with mtDNA-related mitochondrial myopathy.

Front Physiol. 11: 34998.Traschütz A Schirinzi T Laugwitz L et al.

Clinico-genetic, imaging and molecular delineation of COQ8A-ataxia: a multicenter study of 59 patients.

Ann Neurol. 88: 251-26399.Distelmaier F Haack TB Wortmann SB Mayr JA Prokisch H

Treatable mitochondrial diseases: cofactor metabolism and beyond.

Brain. 140: e11100.Russell OM Gorman GS Lightowlers RN Turnbull DM

Mitochondrial diseases: hope for the future.

Cell. 181: 168-188101.

Strategies for fighting mitochondrial diseases.

J Intern Med. 287: 665-684102.

Mitochondrial neurogastrointestinal encephalomyopathy: approaches to diagnosis and treatment.

J Transl Genet Genom. 4: 1-16103.Domínguez-González C Madruga-Garrido M Mavillard F et al.

Deoxynucleoside therapy for thymidine kinase 2-deficient myopathy.

Ann Neurol. 86: 293-303104.Yu-Wai-Man P Newman NJ Carelli V et al.

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy.

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Therapeutic manipulation of mtDNA heteroplasmy: a shifting perspective.

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A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing.

Nature. 583: 631-637107.Gorman GS McFarland R Stewart J Feeney C Turnbull DM

Mitochondrial donation: from test tube to clinic.

Lancet. 392: 1191-1192108.Luo S Valencia CA Zhang J et al.

Biparental inheritance of mitochondrial DNA in humans.

Proc Natl Acad Sci USA. 115: 13039-13044109.Wei W Pagnamenta AT Gleadall N et al.

Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans.

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Biparental inheritance of mitochondrial DNA in humans is not a common phenomenon.

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Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck.

Hum Mol Genet. 25: 1031-1041112.Greenfield A Braude P Flinter F Lovell-Badge R Ogilvie C Perry ACF

Assisted reproductive technologies to prevent human mitochondrial disease transmission.

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Heritable human genome editing.

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