PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families

Guimier, Anne; Achleitner, Melanie T.; Bellaing, Anne Moreau de; Edwards, Matthew S.; Pontual, Loïc de; Mittal, Kirti; Dunn, Kyla; Grove, Megan E.; Tysoe, Carolyn; Dimartino, Clémantine; Cameron, Jessie M.; Kanthi, Anil; Shukla, Anju; Broek, Florence van den; Chatterjee, Diptendu; Alston, Charlotte L.; Knowles, Charlotte V; Brett, Laura; Till, Jan; Homfray, Tessa; French, Paul M. W.; Spentzou, Georgia; Elserafy, Noha; Lichkus, Kate; Sankaran, Bindu Parayil; Kennedy, Hannah; George, Peter M.; Kidd, Alexa; Wortmann, Saskia B.; Fisk, Dianna G.; Koopmann, Tamara T.; Rafiq, Muhammad; Merker, Jason D.; Parikh, Sumith; Ahimaz, Priyanka; Weintraub, Robert G.; Alan, S; Turner, C. David; Ellaway, Carolyn; Phillips, Liza K.; Thorburn, David R.; Chung, Wendy K.; Kana, Sajel L; Faye-Petersen, Ona; Thompson, Michelle L.; Janin, Alexandre; McLeod, Karen; McGowan, Ruth; McFarland, Robert; Girisha, Katta M.; Morris-Rosendahl, Deborah; Hurst, Anna; Turner, Claire; Hamilton, Robert M.; Taylor, Robert W.; Bajolle, Fanny; Gordon, Christopher T; Amiel, Jeanne; Mayr, Johannes A.; Doudney, Kit

doi:10.1016/j.gim.2022.02.002

Cited by 4 publications

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“…Third, alcohol appears to be poorly tolerated and associated with symptom onset in some patients with mtDNA defects [97][98][99] , but the basis for alcohol intolerance remains unknown. Alcohol itself causes hypermetabolism in healthy individuals-increasing whole-body REE by as much as 16%, and inhibiting lipid oxidation by 31-36% 100,101 .…”

Section: Discussionmentioning

confidence: 99%

OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases

et al. 2023

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Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases.

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Section: Discussionmentioning

confidence: 99%

OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases

et al. 2023

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“…Third, alcohol appears to be poorly tolerated and associated with symptom onset in some patients with mtDNA defects [95][96][97] , but the basis for alcohol intolerance remains unknown. Alcohol itself causes hypermetabolism in healthy individuals -increasing whole-body REE by as much as 16%, and inhibiting lipid oxidation by 31-36% 98,99 .…”

Section: Discussionmentioning

confidence: 99%

“…Second , as noted above, severely affected patients with mitochondrial disease are usually thin, which may be attributable to not only reduced energy intake or to intestinal malabsorption, but to chronic hypermetabolism, effectively burning excess ingested calories, preventing the accumulation of excess adiposity and muscle mass. Third , alcohol appears to be poorly tolerated and associated with symptom onset in some patients with mtDNA defects 95–97 , but the basis for alcohol intolerance remains unknown. Alcohol itself causes hypermetabolism in healthy individuals – increasing whole-body REE by as much as 16%, and inhibiting lipid oxidation by 31-36% 98, 99 .…”

Section: Discussionmentioning

confidence: 99%

OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases

Sturm

Karan

Monzel

et al. 2021

Preprint

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Patients with primary mitochondrial diseases present with fatigue and multi-system disease, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. Integrating data from 17 cohorts of patients with mitochondrial diseases (n=690), we find that clinical mitochondrial disorders increase resting energy expenditure, a state termed hypermetabolism. In a longitudinal cellular model of primary patient-derived fibroblasts from multiple donors, we show that genetic and pharmacological disruptions of oxidative phosphorylation (OxPhos) similarly trigger increased energy consumption in a cell-autonomous manner, despite near-normal OxPhos coupling efficiency. Hypermetabolism was associated with mtDNA instability, activation of the integrated stress response, increased extracellular secretion of age-related cytokines and metabokines including GDF15, as well as an accelerated rate of telomere erosion and epigenetic aging, and a reduced Hayflick limit. Finally, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations to OxPhos dysfunction. Hypermetabolism, or the increased energetic cost of living in mitochondrial diseases, has important biological and clinical implications.

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“…PPA2 infantile sudden cardiac failure (ISCF; MIM#617222) was identified postmortem . There is a frequent association between ISCF and neonatal sudden cardiac death, and it has been treated with cardioverter defibrillator implant and heart transplant . Rapid WGS during either of 2 prior pediatric ICU admissions may have been followed by diagnosis and consideration of these interventions …”

Section: Resultsmentioning

confidence: 99%

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

et al. 2023

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ImportanceUnderstanding the causes of infant mortality shapes public health, surveillance, and research investments. However, the association of single-locus (mendelian) genetic diseases with infant mortality is poorly understood.ObjectiveTo determine the association of genetic diseases with infant mortality.Design, Setting, and ParticipantsThis cohort study was conducted at a large pediatric hospital system in San Diego County (California) and included 546 infants (112 infant deaths [20.5%] and 434 infants [79.5%] with acute illness who survived; age, 0 to 1 year) who underwent diagnostic whole-genome sequencing (WGS) between January 2015 and December 2020. Data analysis was conducted between 2015 and 2022.ExposureInfants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation.Main Outcomes and MeasuresProportion of infant deaths associated with single-locus genetic diseases.ResultsAmong 112 infant deaths (54 girls [48.2%]; 8 [7.1%] African American or Black, 1 [0.9%] American Indian or Alaska Native, 8 [7.1%] Asian, 48 [42.9%] Hispanic, 1 [0.9%] Native Hawaiian or Pacific Islander, and 34 [30.4%] White infants) in San Diego County between 2015 and 2020, single-locus genetic diseases were the most common identifiable cause of infant mortality, with 47 genetic diseases identified in 46 infants (41%). Thirty-nine (83%) of these diseases had been previously reported to be associated with childhood mortality. Twenty-eight death certificates (62%) for 45 of the 46 infants did not mention a genetic etiology. Treatments that can improve outcomes were available for 14 (30%) of the genetic diseases. In 5 of 7 infants in whom genetic diseases were identified postmortem, death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission.Conclusions and RelevanceIn this cohort study of 112 infant deaths, the association of genetic diseases with infant mortality was higher than previously recognized. Strategies to increase neonatal diagnosis of genetic diseases and immediately implement treatment may decrease infant mortality. Additional study is required to explore the generalizability of these findings and measure reduction in infant mortality.

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PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families

Cited by 4 publications

References 0 publications

OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases

OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases

OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

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