bims-curels 2024-12-01 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–12–01
thirteen papers selected by
Cure Mito Foundation

LNC-ing Genetics in Mitochondrial Disease.
Uncommon case of mitochondrial disease: Mild amyotrophy of the legs and symmetrical lipomatosis of the arms.
Mutations in mitochondrial ATAD3 gene and disease, lessons from in vivo models.
Advancing Research Alongside Patient Partners: Next-Generation Best Practices for Effective Collaboration in Health Research.
Chimeric mitochondrial RNA transcripts predict mitochondrial genome deletion mutations in mitochondrial genetic diseases and aging.
The clinical utility in hospital-wide use of growth differentiation factor 15 as a biomarker for mitochondrial DNA-related disorders.
Disease registries and rare disorders: The virtuous example of mitochondrial medicine.
Exploring the journey to genomic testing and genetic services: A qualitative study of parental perspectives of children with rare conditions.
How to establish and sustain a disease registry: insights from a qualitative study of six disease registries in the UK.
Mitochondrial Mutations in Cardiovascular Diseases: Preliminary Findings.
A micro-costing study of mass-spectrometry based quantitative proteomics testing applied to the diagnostic pipeline of mitochondrial and other rare disorders.
Analysis of mitochondrial DNA replisome in autism spectrum disorder: Exploring the role of replisome genes.
"I just don't know enough": Australian perspectives on community involvement in health and medical research.

Noncoding RNA. 2024 Nov 15. pii: 57. [Epub ahead of print]10(6):

LNC-ing Genetics in Mitochondrial Disease.

Rick Kamps, Emma Louise Robinson.

  Primary mitochondrial disease (MD) is a group of rare genetic diseases reported to have a prevalence of 1:5000 and is currently without a cure. This group of diseases includes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), Leber's hereditary optic neuropathy (LHON), Leigh syndrome (LS), Kearns-Sayre syndrome (KSS), and myoclonic epilepsy and ragged-red fiber disease (MERRF). Additionally, secondary mitochondrial dysfunction has been implicated in the most common current causes of mortality and morbidity, including cardiovascular disease (CVD) and cancer. Identifying key genetic contributors to both MD and secondary mitochondrial dysfunction may guide clinicians to assess the most effective treatment course and prognosis, as well as informing family members of any hereditary risk of disease transmission. Identifying underlying genetic causes of primary and secondary MD involves either genome sequencing (GS) or small targeted panel analysis of known disease-causing nuclear- or mitochondrial genes coding for mitochondria-related proteins. Due to advances in GS, the importance of long non-coding RNA (lncRNA) as functional contributors to the pathophysiology of MD is being unveiled. A limited number of studies have thus far reported the importance of lncRNAs in relation to MD causation and progression, and we are entering a new area of attention for clinical geneticists in specific rare malignancies. This commentary provides an overview of what is known about the role of lncRNAs as genetic and molecular contributors to disease pathophysiology and highlights an unmet need for a deeper understanding of mitochondrial dysfunction in serious human disease burdens.

Keywords:  biomarkers; disease coding and non-coding variants; genome sequencing (GS); long non-coding RNA (lncRNA); mitochondrial disease (MD); multiomics

DOI:  https://doi.org/10.3390/ncrna10060057
J Inherit Metab Dis. 2024 Nov 26.

Uncommon case of mitochondrial disease: Mild amyotrophy of the legs and symmetrical lipomatosis of the arms.

Leslie Bercu, Patrizia Amati-Bonneau, Valérie Desquiret-Dumas, Vincent Procaccio, François Maillot.



Keywords:  lipomatosis; mitochondial diseases; mitochondrial DNA mutations

DOI:  https://doi.org/10.1002/jimd.12820
Front Neurosci. 2024 ;18 1496142

Mutations in mitochondrial ATAD3 gene and disease, lessons from in vivo models.

Marcel Brügel, Ann-Sophie Kiesel, Tobias B Haack, Susana Peralta.

  Pathogenic variants in the ATAD3 gene cluster have been associated with different neurodevelopmental disorders showing clinical symptoms like global developmental delay, muscular hypotonia, cardiomyopathy, congenital cataracts, and cerebellar atrophy. ATAD3A encodes for a mitochondrial ATPase whose function is unclear and has been considered one of the five most common nuclear genes associated with mitochondrial diseases in childhood. However, the mechanism causing ATAD3-associated disorders is still unknown. In vivo models have been used to identify ATAD3 function. Here we summarize the features of mouse models with ATAD3 loss of function and Drosophila models overexpressing pathogenic ATAD3 variants. We discuss how these models have contributed to our understanding of ATAD3 function and the pathomechanism of the ATAD3-associated disease.

Keywords:  ATAD3; animal model; cholesterol; mitochondrial disease; mtDNA depletion and deletion; neurodegeneration

DOI:  https://doi.org/10.3389/fnins.2024.1496142
Curr Oncol. 2024 Nov 07. 31(11): 6956-6978

Advancing Research Alongside Patient Partners: Next-Generation Best Practices for Effective Collaboration in Health Research.

Ally C Farrell, Jessica A Lawson, Ovarian Cancer Canada's Patient Partners In Research Team, Alison Ross, Alicia A Tone.

  Ovarian Cancer Canada's Patient Partners in Research (PPiR) is a national volunteer-based program that trains and connects individuals with lived ovarian cancer (OC) experience to diverse research opportunities, to maximize the clinical relevance and real-life impact of OC research in Canada. A steadily increasing demand for patient partners to be involved as research team members and decision-makers led us to co-develop with the PPiR team a series of "best practices" for researcher-patient partnerships. This framework formalizes our evolving approach to patient engagement and begins to address challenges that can arise in research settings focused on less commonly diagnosed yet significant and fatal diseases such as OC: (1) Start early. (2) Foster collaboration among the entire research team. (3) Establish expectations and communicate regularly. (4) Report impact of patient partner contributions. (5) Ensure adequate resources. While there are ongoing challenges associated with patient engagement that need to be addressed, data collected from an anonymous survey of Canadian OC researchers show a marked improvement in perceived benefits of patient engagement over time and validate the best practices presented herein. Developed in the context of OC research, these best practices can be adapted to a variety of health research settings with similar challenges.

Keywords:  best practices; ovarian cancer research; patient engagement; patient partner; patient partner–researcher relationship; patient-oriented research

DOI:  https://doi.org/10.3390/curroncol31110513
Genome Res. 2024 Nov 27. pii: gr.279072.124. [Epub ahead of print]

Chimeric mitochondrial RNA transcripts predict mitochondrial genome deletion mutations in mitochondrial genetic diseases and aging.

Amy R Vandiver, Allen Herbst, Paul Stothard, Jonathan Wanagat.

While it is well understood that mitochondrial DNA (mtDNA) deletion mutations cause incurable diseases and contribute to aging, little is known about the transcriptional products that arise from these DNA structural variants. We hypothesized that mitochondrial genomes containing deletion mutations express chimeric mitochondrial RNAs. To test this, we analyzed human and rat RNA sequencing data to identify, quantitate, and characterize chimeric mitochondrial RNAs. We observed increased chimeric mitochondrial RNA frequency in samples from patients with mitochondrial genetic diseases and in samples from aged humans. The spectrum of chimeric mitochondrial transcripts reflected the known pattern of mtDNA deletion mutations. To test the hypothesis that mtDNA deletions induce chimeric RNA transcripts, we treated 18 mo and 34 mo rats with guanidinopropionic acid to induce high levels of skeletal muscle mtDNA deletion mutations. With mtDNA deletion induction, we demonstrate that the chimeric mitochondrial transcript frequency also increased and correlated strongly with an orthogonal DNA-based mutation assay performed on identical samples. Further, we show that the frequency of chimeric mitochondrial transcripts predicts expression of both nuclear and mitochondrial genes central to mitochondrial function, demonstrating the utility of these events as metrics of age-induced metabolic change. Mapping and quantitation of chimeric mitochondrial RNAs provides an accessible, orthogonal approach to DNA-based mutation assays, offers a potential method for identifying mitochondrial pathology in widely accessible datasets, and opens a new area of study in mitochondrial genetics and transcriptomics.

DOI: https://doi.org/10.1101/gr.279072.124
J Inherit Metab Dis. 2024 Nov 24.

The clinical utility in hospital-wide use of growth differentiation factor 15 as a biomarker for mitochondrial DNA-related disorders.

Andrea Cortés Fernández, Jane Estrella, Devin Oglesbee, Austin A Larson, Johan L K Van Hove.

  Clinical recognition of primary mitochondrial disorders (PMD) is difficult due to the clinical and genetic heterogeneity. Whereas lactate has low sensitivity and specificity, in structured clinical studies growth differentiation factor 15 (GDF15) has shown promise with elevations in mitochondrial DNA (mtDNA)-related PMD, but its specificity has been questioned. In a tertiary care hospital-wide study, medical records were retrospectively reviewed from 418 cases where GDF15 levels were obtained by clinicians. Patients were classified into patients with PMD due to mtDNA-related defects (mtDNA maintenance, mtDNA deletions, and mtDNA-encoded tRNA variants), PMD due to structural defects or other nuclear causes, and in non-mitochondrial disease. Patients with liver disease or systemic critical illness were excluded. GDF15 was assayed in a clinical laboratory with a cutoff of 750 ng/L. There were 38 mtDNA-related PMD (GDF15 >750 pg/mL in 76%), 35 other nuclear DNA-encoded PMD or structural subunits (31% elevated GDF15), 309 non-mitochondrial disorders (13% elevated GDF15). Based on the highest Youden J-index, the optimal cut-off value to identify these target mtDNA-related disorders was 815 pg/mL, with sensitivity 76%, specificity 88%, positive predictive value of 41% and negative predictive value of 97%. At this optimized cutoff level, mtDNA-encoded PMD patients had elevated GDF15 in 76%, nuclear DNA-encoded PMD in 26%, and non-mitochondrial disorders in 11% of patients. Thus, in a real-life clinical setting, after excluding abnormal liver function and critical illness, GDF15 had good clinical utility increasing the odds at predicting mtDNA-related primary mitochondrial disorders 14-fold, but not for structural or other nuclear-encoded primary mitochondrial disorders.

Keywords:  biomarker; mitochondrial DNA deletion; mitochondrial DNA maintenance disorder; mitochondrial tRNAs

DOI:  https://doi.org/10.1002/jimd.12821
Exp Neurol. 2024 Nov 25. pii: S0014-4886(24)00399-6. [Epub ahead of print] 115073

Disease registries and rare disorders: The virtuous example of mitochondrial medicine.

Daniele Orsucci, Elena Caldarazzo Ienco, Piervito Lopriore, Michelangelo Mancuso.

  Primary mitochondrial disorders (PMDs) are an extraordinarily complex group of rare disorders caused by impairment of the mitochondrial electron transport chain, or respiratory chain. Studying genotype-phenotype relationships in PMDs is a complex task. The clinical variability is large even in individuals with the same genotype, and the statistical power is low in single-center studies because of their rarity. To better define the clinical phenotypes associated with PMDs, in the last 15 years a significant multicenter effort has led to nation-wide studies on large cohorts of patients. Many national registries of mitochondrial patients have been developed in recent years, and now there is a strong effort towards international (and even global) registries. This review will revise the notable advances obtained with such studies in recent years, and will discuss the actual developments and future perspectives.

Keywords:  CPEO; Disease registries; MELAS; MERRF; Primary mitochondrial diseases; Primary mitochondrial myopathies

DOI:  https://doi.org/10.1016/j.expneurol.2024.115073
J Genet Couns. 2024 Nov 29.

Exploring the journey to genomic testing and genetic services: A qualitative study of parental perspectives of children with rare conditions.

Amy Clark, Courtney K Wallingford, Molly Krause, Heather Renton, Tatiane Yanes, Chris Jacobs, Gemma Brett, Aideen McInerney-Leo.

  Despite affecting a small portion of the population, rare conditions have a significant impact, collectively affecting around 300 million people worldwide. Historically, early diagnosis has been impeded by failure to recognize rare conditions and order/refer for appropriate genomic testing. The advancements in genome sequencing offer a more agnostic and accelerated approach to the identification and diagnosis of rare disorders, potentially improving health outcomes, reducing the impact of disability, and reducing financial and psychological burdens on families. Due to the complex nature of these conditions, early engagement with genomic testing and clinical genetics services is key to facilitating a diagnosis. This qualitative exploration aimed to understand the journey to genomic testing and services and identify the supports families need during the diagnostic period. We conducted semi-structured interviews with 24 parents of children with a rare condition. Interviews were analyzed using inductive reflexive thematic analysis. Three themes of the parent experience were identified (1) the need for a streamlined pathway through the healthcare system, (2) the value of healthcare professionals who listen to parents, believed them, and partnered with them, and (3) the power of accurate diagnosis. Our findings indicate that providing direct and timely access to genomic testing for patients with a suspected rare condition could alleviate psychological and financial stressors. Genetic counselors are adept at supporting families affected by rare conditions and are optimally placed to facilitate timely access to genomic testing. Improving timely access may be facilitated through educating primary care physicians and embedding genetic counselors in pediatric settings.

Keywords:  diagnostic odyssey; genetics services; lived experience; parents; rare condition; rare disease; referral practice

DOI:  https://doi.org/10.1002/jgc4.1996
BMC Med Inform Decis Mak. 2024 Nov 28. 24(1): 361

How to establish and sustain a disease registry: insights from a qualitative study of six disease registries in the UK.

Edmund Stubbs, Josephine Exley, Raphael Wittenberg, Nicholas Mays.

   BACKGROUND: The advent of new chronic conditions such as long COVID-19 raises the question of whether and, if so, how best to establish new disease registries for such conditions. Prompted by the potential need for a long COVID-19 registry, we examined experiences of existing UK disease registries to understand barriers and enablers to establishing and sustaining a register, and how these have changed over time.
METHODS: We undertook semi-structured interviews between November 2022 and April 2023 with individuals representing six disease registries that collect individual-level longitudinal data on people diagnosed with a chronic condition.
RESULTS: Registries examined were developed by a few individuals, usually clinicians, to gain a greater understanding of the disease. Patient voices were largely absent from initial agenda setting processes, but, over time, all registries sought to increase patient involvement. Securing long-term funding was cited as the biggest challenge; due to limited funds, one of the registries examined no longer actively recruits patients. Charities devoted to the diseases in question were key funders, though most registries also sought commercial opportunities. Inclusion on the NIHR Clinical Research Network Portfolio was also considered a vital resource to support recruitment and follow-up of participants. All registries have sought to minimise the primary data collected to reduce the burden on clinicians and patients, increasingly relying on linkage to other data sources. Several registries have developed consent procedures that enable participants to be contacted for additional data collection. In some cases, the initial patient consent and data sharing permissions obtained had limited the flexibility to adapt the registry to changing data needs. Finally, there was a need to foster buy-in from the community of patients and clinicians who provide and/or use the data.
CONCLUSION: We identified six key considerations when establishing a sustainable disease registry: (1) include a diverse set of stakeholders; (2) involve patients at every stage; (3) collect a core data set for all participants; (4) ensure the data system is flexible and interoperable with the wider data landscape; (5) anticipate changing data needs over time; and (6) identify financial opportunities to sustain the registry's activities for the long term.

Keywords:  Chronic conditions; Disease registry; Health research data and infrastructure; Long COVID-19; Patient registry

DOI:  https://doi.org/10.1186/s12911-024-02775-x
Genes (Basel). 2024 Nov 08. pii: 1442. [Epub ahead of print]15(11):

Mitochondrial Mutations in Cardiovascular Diseases: Preliminary Findings.

Anastasios Papageorgiou, Fragkiski-Ioanna Sofiou, Panagiotis Lembessis, Lubomir L Traikov, Nina-Rafailia Karela, Dimitrios C Angouras, Anastassios Philippou.

  Background/Objectives: Mitochondria are the main organelles for ATP synthesis able to produce energy for several different cellular activities. Cardiac cells require high amounts of energy and, thus, they contain a high number of mitochondria. Consequently, mitochondrial dysfunction in these cells is a crucial factor for the development of cardiovascular diseases. Mitochondria constitute central regulators of cellular metabolism and energy production, producing approximately 90% of the cells' energy needs in the form of ATP via oxidative phosphorylation. The mitochondria have their own circular, double-stranded DNA encoding 37 genes. Any mitochondrial DNA sequence anomaly may result in defective oxidative phosphorylation and lead to cardiac dysfunction. Methods: In this study, we investigated the potential association between mitochondrial DNA mutation and cardiovascular disease. Cardiac tissue and serum samples were collected from seven patients undergoing coronary artery bypass grafting. Total DNA was extracted from cardiac muscle tissue specimens and serum and each sample was subjected to polymerase chain reaction (PCR) to amplify the NADH dehydrogenase 1 (ND1) gene, which is part of the mitochondrial complex I enzyme complex and was screened for mutations. Results: We identified one patient with a homoplasmic A to G substitution mutation in cardiac tissue DNA and two patients with heteroplasmic A3397G mutation in serum DNA. Specifically, amplicon sequence analysis revealed a homoplasmic A3397G substitution in the ND1 gene in a tissue sample of the patient with ID number 1 and a heteroplasmic mutation in A3397G in serum samples of patients with ID numbers 3 and 6, respectively. The A to G substitution changes the amino acid from methionine (ATA) to valine (GTA) at position 31 of the ND1 gene. Conclusions: The detection of this novel mutation in patients with coronary artery disease may contribute to our understanding of the association between mitochondrial dysfunction and the disease, implying that mitochondria may be key players in the pathogenesis of cardiovascular diseases.

Keywords:  ND1 gene; coronary artery disease; mitochondrial DNA

DOI:  https://doi.org/10.3390/genes15111442
Orphanet J Rare Dis. 2024 Nov 29. 19(1): 443

A micro-costing study of mass-spectrometry based quantitative proteomics testing applied to the diagnostic pipeline of mitochondrial and other rare disorders.

Francisco Santos Gonzalez, Daniella H Hock, David R Thorburn, Dylan Mordaunt, Nicholas A Williamson, Ching-Seng Ang, David A Stroud, John Christodoulou, Ilias Goranitis.

   BACKGROUND: Mass spectrometry-based quantitative proteomics has a demonstrated utility in increasing the diagnostic yield of mitochondrial disorders (MDs) and other rare diseases. However, for this technology to be widely adopted in routine clinical practice, it is crucial to accurately estimate delivery costs. Resource use and unit costs required to undertake a proteomics test were measured and categorized into consumables, equipment, and labor. Unit costs were aggregated to obtain a total cost per patient, reported in 2023 Australian dollars (AUD). Probabilistic and deterministic sensitivity analysis were conducted to evaluate parameter uncertainty and identify key cost drivers.
RESULTS: The mean cost of a proteomics test was $897 (US$ 607) per patient (95% CI: $734-$1,111). Labor comprised 53% of the total costs. At $342 (US$ 228) per patient, liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was the most expensive non-salary component. An integrated analysis pipeline where all the standard analysis are performed automatically, as well as discounts or subsidized LC-MS/MS equipment or consumables can lower the cost per test.
CONCLUSIONS: Proteomics testing provide a lower-cost option and wider application compared to respiratory chain enzymology for mitochondrial disorders and potentially other functional assays in Australia. Our analysis suggests that streamlining and automating workflows can reduce labor costs. Using PBMC samples may be a cheaper and more efficient alternative to generating fibroblasts, although their use has not been extensively tested yet. Use of fibroblasts could potentially lower costs when fibroblasts are already available by avoiding the expense of isolating PBMCs. A joint evaluation of the health and economic implications of proteomics is now needed to support its introduction to routine clinical care.

Keywords:  Functional genomics; Health economics; Micro-costing; Mitochondrial disorders; Proteomics

DOI:  https://doi.org/10.1186/s13023-024-03462-w
Autism Res. 2024 Nov 29.

Analysis of mitochondrial DNA replisome in autism spectrum disorder: Exploring the role of replisome genes.

Valentina Rojas, Carlos Carrasco-Gallardo, Lidia Tenorio, Margrethe A Olesen, Victor Tapia, Manuel Carrasco, Patricio Araos, Rodrigo A Quintanilla, Lina M Ruiz.

  Autism spectrum disorder (ASD) is a neurodevelopmental condition often associated with mitochondrial dysfunction, including increased mitochondrial DNA (mtDNA) copy number and impaired energy production. This study investigates the role of the mitochondrial replisome-specifically, the genes TFAM, TWNK, POLG, and TOP1MT-in mtDNA replication and its potential contribution to ASD pathophysiology. We analyzed samples from the oral mucosa of children with ASD and typically developing (TD) controls, assessing mtDNA copy number, gene expression, and protein levels. Our findings revealed a significant increase in mtDNA copy number in the oral mucosa of ASD children, along with partially deleted mtDNA molecules. However, there were no significant changes in the expression of TFAM, TWNK, POLG, or MT-TL1 genes between ASD and TD samples. Additionally, TFAM protein levels, including monomeric, dimeric, and trimeric forms, did not differ significantly. We also observed increased oxidative stress and inflammatory markers in the oral mucosa of ASD children, suggesting that mitochondrial alterations may be linked to inflammation and oxidative damage in ASD. To further investigate the functional impact of TFAM, we overexpressed it in human HEK293 cells and cortical neurons (CN1.4). TFAM overexpression led to increased mtDNA copy number, cell proliferation, and ATP production in HEK293 cells, but did not significantly alter mitochondrial gene expression, protein oxidation, or mtDNA integrity. In CN1.4 neurons, TFAM overexpression increased mitochondrial membrane potential and length, indicating potential changes in mitochondrial dynamics. Overall, our study suggests that while mtDNA alterations are present in ASD, they are not directly driven by changes in mitochondrial replisome gene expression. These findings highlight the complexity of mitochondrial dysfunction in ASD and suggest the need for further investigation into the underlying molecular mechanisms.

Keywords:  ASD; MT‐TL1; POLG; TFAM overexpression; TOPMT1; TWNK; autism; mitochondrial DNA; mtDNA replisome; TFAM

DOI:  https://doi.org/10.1002/aur.3277
Res Involv Engagem. 2024 Nov 28. 10(1): 126

"I just don't know enough": Australian perspectives on community involvement in health and medical research.

Fiona Russo, Isabella Sherburn, Keri Finlay, Jack Nunn, Monica Ferrie, Anne McKenzie, Sean Murray, John Cannings, Greg Pratt, Tiffany Boughtwood.

   BACKGROUND: There is increasing global support from governments and other funding bodies for community involvement in research, alongside a scientific and moral imperative for responsible and ethical research practice. Ninety per cent of Australian patient-led organisations in rare diseases have clearly articulated research priorities, indicating a desire among people affected by disease to be involved in research that impacts their communities. Philanthropic research, which is likely to have predominantly community-minded priorities, is worth over AU$1 billion annually and increased more than 100% between 2007 and 2017.
AIMS: This research aimed to understand public perspectives on community involvement in health-related research activities, and to inform the development of guidelines for genomic researchers to improve this involvement.
METHODS: A 37-question survey was completed by 1,156 members of the Australian public via Dynata. The survey was co-designed by the Involve Australia Working Group of community members within Australian Genomics. Results from 1156 responses were analysed.
RESULTS: Key themes emerging from the survey data that impact potential involvement were low community confidence to contribute, a limited understanding of community involvement, roles and recognition, trust and governance of data, perceived trustworthiness of research funders, and factors related to time and personal resources. A variety of motivations for involvement were also stated.
CONCLUSION: Members of the Australian public are interested in research involvement; however the differences between involvement and participation are poorly understood and a variety of barriers still exist. Researchers must actively reach out into communities and offer opportunities to engage with research and identify community priorities.

Keywords:  Australia; Community; Engagement; Genomic research; Involvement; Perspectives

DOI:  https://doi.org/10.1186/s40900-024-00633-8