Research priorities for mitochondrial disorders: Current landscape and patient and professional views

Thomas, Rhys H.; Hunter, Amy; Butterworth, Lyndsey; Feeney, Catherine; Graves, Tracey D.; Holmes, Sarah; Hossain, Pushpa; Lowndes, Jo; Sharpe, Jenny; Upadhyaya, Sheela; Varhaug, Kristin Nielsen; Votruba, Marcela; Wheeler, Russell L.; Staley, Kristina; Rahman, Shamima

doi:10.1002/jimd.12521

Cited by 9 publications

(5 citation statements)

References 36 publications

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“…One participant said their disease was triggered by a well-defined period of intense stress, whereas others stated their mitochondrial disease symptoms and moods are entirely independent of each other. This heterogeneity in perspectives aligns well with the range of responses to the main mood-symptom SHES question, as well as with previous findings that research questions about stress/mental health in mitochondrial disease research are polarizing, with some patients viewing it as essential and some as irrelevant (Thomas et al, 2022). Moreover, some participants noted that the SHES survey could not fully capture how they experience their symptoms and mood interacting.…”

Section: Discussionsupporting

confidence: 84%

Perceived association of mood and symptom severity in adults with mitochondrial diseases

Kelly,

Junker,

Englestad

et al. 2024

Preprint

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Individuals with genetic mitochondrial diseases suffer from multisystemic symptoms that vary in severity from day-to-day and week-to-week, but the underlying causes of symptomatic fluctuations are not understood. Based upon observations that: i) patients and their families frequently report that stressful life events either trigger exacerbations of existing symptoms or the onset of new symptoms, ii) psychological states and stress hormones influence mitochondrial energy production capacity, and iii) epidemiological reports document a robust connection between traumatic/stressful life events and various neurologic disorders, we hypothesized that mitochondrial disease symptom severity may vary according to participant's mood. To investigate this we administered the Stress, Health and Emotion Survey (SHES) in 70 adults (majority white (84%) cisgender women (83%), ages 18-74) with self-reported mitochondrial diseases (MELAS, 18%; CPEO, 17%; Complex I deficiency, 13%). Participants rated the severity of each of their symptom(s) over the past year on either good or bad days. On days marked by more stress, sadness and other negative emotions, some but not all symptoms were reported to be worse, including fatigue, exercise intolerance, brain fog, and fine motor coordination. By contrast, on days marked by happiness and calmness, participants reported these and other symptoms to be better, or less severe. Other symptoms including diminished sweating, hearing problems, and dystonia were in general unrelated to mood. Thus, some individuals living with mitochondrial diseases, at times perceive a connection between their mood and symptom severity. These preliminary associative results constitute an initial step towards developing more comprehensive models of the factors that influence the clinical course of mitochondrial diseases.

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Section: Discussionsupporting

confidence: 84%

Perceived association of mood and symptom severity in adults with mitochondrial diseases

Kelly,

Junker,

Englestad

et al. 2024

Preprint

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“…Understanding disease heterogeneity is a clear priority for mitochondrial disease patients, which is ultimately where research into nuclear modifiers of mtDNA disease will have the biggest, tangible impact 58 . Our results show that the factors likely to have the biggest impact are those that affect severe neurological phenotypes associated with MELAS syndrome, have prepared the way for their future identification and have demonstrated the importance of assembling large well-phenotyped patient cohorts for mtDNA diseases.…”

Section: Discussionmentioning

confidence: 99%

Defining the nuclear genetic architecture of a common maternally inherited mitochondrial disorder

Boggan

Franklin

et al. 2022

Preprint

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Maternally inherited mitochondrial diseases are caused by pathogenic mitochondrial (mt)DNA variants. Affecting individuals at any age, they are often multi-systemic and manifest extreme clinical variability. We have very little understanding of the cause of this heterogeneity, which makes disease diagnosis and prognosis exceptionally challenging. This is clearly demonstrated by disease caused by m.3243A>G, the most common pathogenic mtDNA variant. m.3243A>G can cause a severe syndrome characterised by mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS), but individuals who carry m.3243A>G may be asymptomatic or present with any number of a range of phenotypes. There is strong evidence for the presence of nuclear factors that modify phenotype; we set out to characterise the nature of this nuclear involvement using genetic linkage analysis. We assembled a multi-centre cohort of well-characterised patients and their maternal relatives, comprising 76 pedigrees, and characterised the nuclear genetic landscape of m.3243A>G-related disease phenotypes using non-parametric genetic linkage analysis. We considered eight of the most common m.3243A>G-related phenotypes, accounted for known risk factors using logistic regression, and determined empirical significance using simulation to identify regions of the nuclear genome most likely to contain disease modifying variants. We identified significant genetic linkage to encephalopathy on chromosome 7q22, and suggestive regions for encephalopathy, stroke-like episodes and psychiatric involvement on chromosomes 1, 5, 6, 11 and 13. These findings suggest that these neurological features are likely to be influenced by a small number of nuclear factors with a relatively large effect size. In contrast, no linkage regions were identified for cerebellar ataxia, migraine, diabetes mellitus, hearing impairment or chronic progressive external ophthalmoplegia. The genetic architecture of the nuclear factors influencing disease related to m.3243A>G differs between phenotypes. Severe and cardinal neurological features of MELAS are likely to be strongly influenced by a small number of nuclear genes, whereas the nuclear influence over other phenotypic presentations is more likely to be polygenic and complex in nature, composed of a larger number of factors that each exert a small effect. These results will inform strategies for future studies to identify the genes and pathways that influence clinical heterogeneity in m.3243A>G-related disease, with the ultimate aim of better understanding disease development and progression.

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“…and 'why are people with the same genetic mutation affected so differently in mitochondrial disease?' [89]. While the answer to these questions is complex, immune functions appear to be one potent contributor to both onset and severity of genetic mitochondrial disease.…”

Section: Immunologic Stress As a Possible Catalyst For Symptomsmentioning

confidence: 99%

The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence

Hanaford

Johnson

2022

Orphanet J Rare Dis

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Background Genetic mitochondrial diseases represent a significant challenge to human health. These diseases are extraordinarily heterogeneous in clinical presentation and genetic origin, and often involve multi-system disease with severe progressive symptoms. Mitochondrial diseases represent the most common cause of inherited metabolic disorders and one of the most common causes of inherited neurologic diseases, yet no proven therapeutic strategies yet exist. The basic cell and molecular mechanisms underlying the pathogenesis of mitochondrial diseases have not been resolved, hampering efforts to develop therapeutic agents. Main body In recent pre-clinical work, we have shown that pharmacologic agents targeting the immune system can prevent disease in the Ndufs4(KO) model of Leigh syndrome, indicating that the immune system plays a causal role in the pathogenesis of at least this form of mitochondrial disease. Intriguingly, a number of case reports have indicated that immune-targeting therapeutics may be beneficial in the setting of genetic mitochondrial disease. Here, we summarize clinical and pre-clinical evidence suggesting a key role for the immune system in mediating the pathogenesis of at least some forms of genetic mitochondrial disease. Conclusions Significant clinical and pre-clinical evidence indicates a key role for the immune system as a significant in the pathogenesis of at least some forms of genetic mitochondrial disease.

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Research priorities for mitochondrial disorders: Current landscape and patient and professional views

Cited by 9 publications

References 36 publications

Perceived association of mood and symptom severity in adults with mitochondrial diseases

Perceived association of mood and symptom severity in adults with mitochondrial diseases

Defining the nuclear genetic architecture of a common maternally inherited mitochondrial disorder

The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence

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