Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project

Karaa, Amel; Rahman, Shamima; Lombès, Anne; Yu‐Wai‐Man, Patrick; Sheikh, Muniza; Alai-Hansen, Sherita; Cohen, Bruce H.; Dimmock, David; Emrick, Lisa; Falk, Marni J.; McCormack, Shana E.; Mirsky, David M.; Moore, T.; Parikh, Sumit; Shoffner, John M.; Taivassalo, Tanja; Tarnopolsky, Mark A.; Tein, Ingrid; Odenkirchen, Joanne; Goldstein, Amy

doi:10.1007/s10545-017-0035-5

Cited by 15 publications

(16 citation statements)

References 15 publications

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“…Clinicians and researchers are making strides to combat this problem, such as developing clear and widely used diagnostic criteria, 2 , 3 , 9 and perfecting genetic testing. 4 , 10 Patients with mitochondrial disease, through Patient Advocacy Groups or as individuals, are raising awareness of these diseases. Yet, because of the rarity and diffuse nature of mitochondrial diseases, the difficulty of diagnosis is not likely to go away any time soon.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic odyssey of patients with mitochondrial disease

et al. 2018

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ObjectiveTo document the complex “diagnostic odyssey” of patients with mitochondrial disease.MethodsWe analyzed data from 210 Rare Diseases Clinical Research Network Contact Registry participants who were patients with a biochemical deficiency or self-reported diagnosis of mitochondrial disease, or their caregivers.ResultsParticipants saw an average of 8.19 clinicians (SD 8.0, median 5). The first clinician consulted about symptoms was typically a primary care physician (56.7%), although 35.2% of participants initially sought a specialist. Of note, 55.2% of participants received their diagnosis from a neurologist, 18.2% from a clinical geneticist, and 11.8% from a metabolic disease specialist. A majority of the participants (54.6%) received 1 or more nonmitochondrial diagnoses before their final mitochondrial diagnosis. In their pursuit of a diagnosis, 84.8% of participants received blood tests, 71% a muscle biopsy, 60.5% MRI, and 38.6% urine organic acids. In addition, 39.5% of the participants underwent mitochondrial DNA sequencing, 19% sequencing of nuclear gene(s), and 11.4% whole-exome sequencing.ConclusionsThe diagnostic odyssey of patients with mitochondrial disease is complex and burdensome. It features multiple consultations and tests, and, often, conflicting diagnoses. These reflect disease variety, diagnostic uncertainty, and clinician unfamiliarity. The current survey provides an important benchmark. Its replication at appropriate intervals will assist in tracking changes that may accompany increased popularity of exome testing, more rigorous diagnostic criteria, increased patient reported outcome activity, and trials for promising therapies.

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Section: Discussionmentioning

confidence: 99%

Diagnostic odyssey of patients with mitochondrial disease

et al. 2018

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“…102 The availability of numerous animal models has facilitated testing of novel therapies for mitochondrial disease. 103 Several national mitochondrial cohorts have been established and international consortia have begun to perform natural history studies, 91,104-106 set up Delphi panels to establish outcome measures for mitochondrial disease, 107,108 and document current standard practices for monitoring and management. 109 International collaboration will likely pave the way for relatively large clinical trials, even for the rarest genetic disorders, although innovative trial designs will be needed for ultra-rare disorders.…”

Section: Translational Medicinementioning

confidence: 99%

Mitochondrial medicine in the omics era

Rahman¹,

2018

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Mitochondria are dynamic bioenergetic organelles whose maintenance requires around 1500 proteins from two genomes. Mutations in either the mitochondrial or nuclear genome can disrupt a plethora of cellular metabolic and homoeostatic functions. Mitochondrial diseases represent one of the most common and severe groups of inherited genetic disorders, characterised by clinical, biochemical, and genetic heterogeneity, diagnostic odysseys, and absence of disease-modifying curative therapies. This Review aims to discuss recent advances in mitochondrial biology and medicine arising from widespread use of high-throughput omics technologies, and also includes a broad discussion of emerging therapies for mitochondrial disease. New insights into both bioenergetic and biosynthetic mitochondrial functionalities have expedited the genetic diagnosis of primary mitochondrial disorders, and identified novel mitochondrial pathomechanisms and new targets for therapeutic intervention. As we enter this new era of mitochondrial medicine, underpinned by global unbiased approaches and multifaceted investigation of mitochondrial function, omics technologies will continue to shed light on unresolved mitochondrial questions, paving the way for improved outcomes for patients with mitochondrial diseases.

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“…It is germane to note that, in the USA, the National Institute of Neurological Disorders and Stroke have developed the common data elements for clinical research in mitochondrial disease project ‘to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies’ (Karaa et al 2017, 2018). Common data elements for ME/CFS are being developed along the lines of the following 11 domains: baseline/covariate; fatigue; post-exertional malaise; sleep; pain; neurologic/cognitive/CNS imaging; autonomic; neuroendocrine; immune; quality of life/functional status/activity; and biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

et al. 2019

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A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation. The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.

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Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project

Cited by 15 publications

References 15 publications

Diagnostic odyssey of patients with mitochondrial disease

Diagnostic odyssey of patients with mitochondrial disease

Mitochondrial medicine in the omics era

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

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