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Background and Objectives: Mitochondrial diseases (MDs) are the commonest group of heritable metabolic disorders. Phenotypic diversity can make molecular diagnosis challenging, and causative genetic variants may reside in either mitochondrial or nuclear DNA. A single comprehensive genetic diagnostic test would be highly useful and transform the field. We applied whole-genome sequencing (WGS) to evaluate the variant detection rate and diagnostic capacity of this technology with a view to simplifying and improving the MD diagnostic pathway., Methods: Adult patients presenting to a specialist MD clinic in Sydney, Australia, were recruited to the study if they satisfied clinical MD (Nijmegen) criteria. WGS was performed on blood DNA, followed by clinical genetic analysis for known pathogenic MD-associated variants and MD mimics., Results: Of the 242 consecutive patients recruited, 62 participants had "definite," 108 had "probable," and 72 had "possible" MD classification by the Nijmegen criteria. Disease-causing variants were identified for 130 participants, regardless of the location of the causative genetic variants, giving an overall diagnostic rate of 53.7% (130 of 242). Identification of causative genetic variants informed precise treatment, restored reproductive confidence, and optimized clinical management of MD., Discussion: Comprehensive bigenomic sequencing accurately detects causative genetic variants in affected MD patients, simplifying diagnosis, enabling early treatment, and informing the risk of genetic transmission., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

This document provides consensus-based recommendations for general physicians and primary care physicians who diagnose and manage patients with mitochondrial diseases (MD). It builds on previous international guidelines, with particular emphasis on clinical management in the Australian setting. This statement was prepared by a working group of medical practitioners, nurses and allied health professionals with clinical expertise and experience in managing Australian patients with MD. As new treatments and management plans emerge, these consensus-based recommendations will continue to evolve, but current standards of care are summarised in this document., (© 2021 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Mitochondrial diseases are some of the most common inherited neurometabolic disorders, and major progress has been made in our understanding, diagnosis, and treatment of these conditions in the past 5 years. Development of national mitochondrial disease cohorts and international collaborations has changed our knowledge of the spectrum of clinical phenotypes and natural history of mitochondrial diseases. Advances in high-throughput sequencing technologies have altered the diagnostic algorithm for mitochondrial diseases by increasingly using a genetics-first approach, with more than 350 disease-causing genes identified to date. While the current management strategy for mitochondrial disease focuses on surveillance for multisystem involvement and effective symptomatic treatment, new endeavours are underway to find better treatments, including repurposing current drugs, use of novel small molecules, and gene therapies. Developments made in reproductive technology offer women the opportunity to prevent transmission of DNA-related mitochondrial disease to their children., Competing Interests: Declaration of interests GSG reports grants from the Wellcome Trust, the UK Medical Research Council (MRC), and Lily Foundation, during the conduct of the study; and grants from Stealth Therapeutics, Reneo, Julius Clinical (Khondrion), Neurovive, and AMO Pharma, outside the submitted work. TK reports grants and personal fees from Santhera Pharmaceuticals and Chiesi GmbH; and grants from Gensight Biologics and Stealth Biotherapeutics, outside the submitted work. CK reports personal fees from Santhera, Sanofi Genzyme, Hormosan, Novartis, and Roche; and personal fees and other from Stealth Biotherapeutics, outside the submitted work. RM reports grants from Wellcome and the MRC, during the conduct of the study; consultancy fees from Minovia Therapeutics and Reneo to the institution; and personal fees from Eisai, outside the submitted work. AS reports grants from the Jane and Aatos Erkko Foundation and Business Finland; and personal fees from Khondrion, outside the submitted work; AS also has a patent pending for NAD concentration measurement and a patent pending for multibiomarkers for mitochondrial disease. RWT reports grants from the Wellcome Trust, the MRC, and the Lily Foundation, during the conduct of the study. DRT reports grants from the Australian National Health and Medical Research Council (NHMRC) and the US Department of Defense, during the conduct of the study. DMT reports grants from the Wellcome Trust, the MRC, and the National Institute for Health Research (NIHR); and personal fees from Khondrion, Imel, Pretzel therapeutics, and Nanna therapeutics, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: The utility of genome sequencing (GS) in the diagnosis of suspected pediatric mitochondrial disease (MD) was investigated., Methods: An Australian cohort of 40 pediatric patients with clinical features suggestive of MD were classified using the modified Nijmegen mitochondrial disease severity scoring into definite (17), probable (17), and possible (6) MD groups. Trio GS was performed using DNA extracted from patient and parent blood. Data were analyzed for single-nucleotide variants, indels, mitochondrial DNA variants, and structural variants., Results: A definitive MD gene molecular diagnosis was made in 15 cases and a likely MD molecular diagnosis in a further five cases. Causative mitochondrial DNA (mtDNA) variants were identified in four of these cases. Three potential novel MD genes were identified. In seven cases, causative variants were identified in known disease genes with no previous evidence of causing a primary MD. Diagnostic rates were higher in patients classified as having definite MD., Conclusion: GS efficiently identifies variants in MD genes of both nuclear and mitochondrial origin. A likely molecular diagnosis was identified in 67% of cases and a definitive molecular diagnosis achieved in 55% of cases. This study highlights the value of GS for a phenotypically and genetically heterogeneous disorder like MD.

Mitochondrial disease presents with a wide spectrum of clinical manifestations that may appear at any age and cause multisystem dysfunction. A broad spectrum of movement disorders can manifest in mitochondrial diseases including ataxia, Parkinsonism, myoclonus, dystonia, choreoathetosis, spasticity, tremor, tic disorders and restless legs syndrome. There is marked heterogeneity of movement disorder phenotypes, even in patients with the same genetic mutation. Moreover, the advent of new technologies, such as next-generation sequencing, is likely to identify novel causative genes, expand the phenotype of known disease genes and improve the genetic diagnosis in these patients. Identification of the underlying genetic basis of the movement disorder is also a crucial step to allow for targeted therapies to be implemented as well as provide the basis for a better understanding of the molecular pathophysiology of the disease process. The aim of this review is to discuss the spectrum of movement disorders associated with mitochondrial disease.

Mitochondrial diseases collectively describe a diverse group of heritable disorders that invariably affect mitochondrial respiratory chain function and cellular energy production. Together they represent the most common cause of inherited metabolic disease, may present at any age, have a wide spectrum of clinical manifestations, may be insidious in onset, and potentially have high morbidity and mortality. Due to the presence of mitochondria in all nucleated cells, mitochondrial disease can affect many different tissues, with single or multiple systems being involved. This leads to highly variable presentations, making the diagnosis of mitochondrial diseases challenging. Recent advances in biomarker and genetic testing, coupled with emerging treatments and reproductive options, hold great promise for improving the clinical identification and management of this highly mutable disease group., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.

SLC39A8 variants have recently been reported to cause a type II congenital disorder of glycosylation (CDG) in patients with intellectual disability and cerebellar atrophy. Here we report a novel SLC39A8 variant in siblings with features of Leigh-like mitochondrial disease. Two sisters born to consanguineous Lebanese parents had profound developmental delay, dystonia, seizures and failure to thrive. Brain MRI of both siblings identified bilateral basal ganglia hyperintensities on T2-weighted imaging and cerebral atrophy. CSF lactate was elevated in patient 1 and normal in patient 2. Respiratory chain enzymology was only performed on patient 1 and revealed complex IV and II + III activity was low in liver, with elevated complex I activity. Complex IV activity was borderline low in patient 1 muscle and pyruvate dehydrogenase activity was reduced. Whole genome sequencing identified a homozygous Chr4(GRCh37):g.103236869C>G; c.338G>C; p.(Cys113Ser) variant in SLC39A8, located in one of eight regions identified by homozygosity mapping. SLC39A8 encodes a manganese and zinc transporter which localises to the cell and mitochondrial membranes. Patient 2 blood and urine manganese levels were undetectably low. Transferrin electrophoresis of patient 2 serum revealed a type II CDG defect. Oral supplementation with galactose and uridine led to improvement of the transferrin isoform pattern within 14 days of treatment initiation. Oral manganese has only recently been added to the treatment. These results suggest SLC39A8 deficiency can cause both a type II CDG and Leigh-like syndrome, possibly via reduced activity of the manganese-dependent enzymes β-galactosyltransferase and mitochondrial manganese superoxide dismutase.

Objective: To directly compare the diagnostic utility of growth differentiation factor-15 (GDF-15) with our previous fibroblast growth factor-21 (FGF-21) findings in the same adult mitochondrial disease cohort., Methods: Serum GDF-15 levels were measured using a quantitative ELISA. Statistical analyses of GDF-15 data were compared with our published FGF-21 findings., Results: Median serum GDF-15 concentrations were elevated in patients with mitochondrial disease and differed between all experimental groups, mirroring group results for FGF-21. There was a difference between patients diagnosed by muscle biopsy and genetic diagnosis, suggesting that serum GDF-15 measurement may be more broadly specific for mitochondrial disease than for muscle manifesting mitochondrial disease, in contrast to FGF-21. GDF-15 showed a markedly higher diagnostic odds ratio when compared with FGF-21 (75.3 vs 45.7), was a better predictor of disease based on diagnostic sensitivity (77.8% vs 68.5%), and outperformed FGF-21 on receiver operating characteristic curve analysis (area under the curve 94.1% vs 91.1%). Combining both biomarkers did not improve the area under the curve remarkably over GDF-15 alone. GDF-15 was the best predictor of mitochondrial disease (p < 0.002) following multivariate logistic regression analysis., Conclusions: GDF-15 outperforms FGF-21 as an indicator of mitochondrial diseases. Our data suggest that GDF-15 is generally indicative of inherited mitochondrial disease regardless of clinical phenotype, whereas FGF-21 seems to be more indicative of mitochondrial disease when muscle manifestations are present., Classification of Evidence: This study provides Class III evidence that serum GDF-15 accurately distinguishes patients with mitochondrial diseases from those without them., (© 2016 American Academy of Neurology.)

Background: The diagnosis of mitochondrial disease requires a complex synthesis of clinical, biochemical, histological, and genetic investigations. An expanding number of mitochondrial diseases are being recognized, despite their phenotypic diversity, largely due to improvements in methods to detect mutations in affected individuals and the discovery of genes contributing to mitochondrial function. Improved understanding of the investigational pitfalls and the development of new laboratory methodologies that lead to a molecular diagnosis have necessitated the field to rapidly adopt changes to its diagnostic approach., Scope of Review: We review the clinical, investigational and genetic challenges that have resulted in shifts to the way we define and diagnose mitochondrial disease. Incorporation of changes, including the use of fibroblast growth factor 21 (FGF-21) and next generation sequencing techniques, may allow affected patients access to earlier molecular diagnosis and management., Major Conclusions: There have been important shifts in the diagnostic paradigm for mitochondrial disease. Diagnosis of mitochondrial disease is no longer reliant on muscle biopsy alone, but should include clinical assessment accompanied by the use of serological biomarkers and genetic analysis. Because affected patients will be defined on a molecular basis, oligosymptomatic mutation carriers should be included in the spectrum of mitochondrial disease. Use of new techniques such as the measurement of serum FGF-21 levels and next-generation-sequencing protocols should simplify the diagnosis of mitochondrial disease., General Significance: Improvements in the diagnostic pathway for mitochondrial disease will result in earlier, cheaper and more accurate methods to identify patients with mitochondrial disease. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To prospectively determine the reliability and validity of serum fibroblast growth factor 21 (FGF-21) as a biomarker for mitochondrial disease in a cross-sectional cohort of adults with mitochondrial disease from a specialist primary care and tertiary referral clinic., Methods: We recruited 140 subjects, including 54 adults with mitochondrial disease, 20 patients with nonmitochondrial neuromuscular disease, and 66 control subjects, between November 2011 and October 2012. We compared serum FGF-21 concentrations to classical biomarkers, serum creatine kinase, lactate, pyruvate, and lactate to pyruvate ratio, to determine its validity and reliability as a biomarker of mitochondrial disease. We determined the sensitivity, odds ratio (OR), and overall reliability of FGF-21 as a marker of mitochondrial disease using statistical analyses., Results: Median serum FGF-21 concentrations were significantly elevated in patients with mitochondrial disease and differed significantly between all experimental groups. FGF-21 showed a markedly higher diagnostic OR (45.7 [95% confidence interval = 12.6-166.5], p < 0.0001) when compared to other biomarkers and was the best predictor of disease according to sensitivity and receiver operating characteristic curve analysis. After multivariate logistic regression analysis controlling for potential confounders, FGF-21 was the only measured parameter capable of predicting mitochondrial disease., Conclusion: This prospective study establishes serum FGF-21 levels as a sensitive biomarker of mitochondrial disease and demonstrates that they are the best predictor of this disorder when compared to serum levels of classical indicators: creatine kinase, lactate, pyruvate, and the lactate to pyruvate ratio.

Mutations in ATP13A2 cause autosomal-recessive parkinsonism (Kufor-Rakeb syndrome; KRS). Because several other parkinsonism-associated proteins have been connected to mitochondrial function and mitophagy, we studied the impact of endogenous mutations in ATPase type 13A2 (ATP13A2) on mitochondria in fibroblasts from KRS patients compared with controls. In patients, we detected decreased adenosine triphosphate (ATP) synthesis rates, increased mitochondrial DNA levels, a higher frequency of mitochondrial DNA lesions, increased oxygen consumption rates, and increased fragmentation of the mitochondrial network. Importantly, overexpression of wild-type ATP13A2 rescued the respiration phenotype. These findings collectively suggest that ATP13A2 contributes to the maintenance of a healthy mitochondrial pool, supporting the hypothesis that impaired mitochondrial clearance represents an important pathogenic mechanism underlying KRS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The discovery that defects in mitochondria and mitochondrial DNA could cause human disease has led to the development of a rapidly expanding group of disorders known as mitochondrial disease. Mitochondrial disease is so named because of the common feature of impaired mitochondrial function. The main function of the mitochondrion is to produce energy for the cell in the form of ATP. ATP is generated by the respiratory chain, a series of complex proteins that are located in the mitochondrial membrane, and are encoded for by both the mitochondrial and nuclear genomes. Consequently, mitochondrial disease can be caused by mutations in either mitochondrial or nuclear DNA. Given the distribution of mitochondria throughout the body, the specific properties of mitochondrial DNA, and the mitochondrion's dependence on nuclear genes for its normal function, the clinical presentation of mitochondrial disease can be highly variable. Thus, familiarity with typical clinical presentations and knowledge of the genes that contribute to mitochondrial function will aid the clinician in the recognition, diagnosis, and management of patients with this group of diverse disorders., (© Thieme Medical Publishers.)

A 3 1/2-year-old boy presented with megaloblastic anemia and recurrent episodes of severe lactic acidosis and coma. At age 4 years, he developed sepsis and died; postmortem examination failed to show any gross abnormality in any tissue. Biochemical analysis of muscle showed decreased activities for all respiratory chain enzymes except complex II. Muscle histochemistry revealed diffuse cytochrome c oxidase deficiency. Southern blot analysis of mitochondrial DNA from muscle, liver, and blood showed a heteroplasmic single mitochindrial DNA deletion of 2.4 kb, which removed the genes for cytochrome c oxidase I and II and the transfer ribonucleic acid genes for serine and aspartic acid. Single large-scale deletions in mitochondrial DNA have been associated with Pearson's syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. This patient's presentation is unusual and suggests an overlap between Pearson's syndrome and Kearns-Sayre syndrome.

Objectives: To further characterize mtDNA defects associated with autistic features, especially the A3243G mtDNA mutation and mtDNA depletion.Study design Five patients with autistic spectrum disorders and family histories of mitochondrial DNA diseases were studied. We performed mtDNA analysis in all patients and magnetic resonance spectroscopy in three., Results: Three patients manifested isolated autistic spectrum features and two had additional neurologic symptoms. Two patients harbored the A3243G mutation. In two others, the A3243G mutation was not found in accessible tissues but was present in tissues from their mothers. The fifth patient had 72% mtDNA depletion in skeletal muscle., Conclusions: Autistic spectrum disorders with or without additional neurologic features can be early presentations of the A3243G mtDNA mutation and can be a prominent clinical manifestation of mtDNA depletion. Mitochondrial dysfunction should be considered in patients who have autistic features and associated neurologic findings or who have evidence of maternal inheritance.