bims-curels 2024-09-15 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–09–15
ten papers selected by
Cure Mito Foundation

Unilateral Hearing Loss and Auditory Asymmetry in Mitochondrial Disease: A Scoping Review.
Cascade testing in mitochondrial diseases: a cross-sectional retrospective study.
Pregnancy in women with mitochondrial disease-A literature review and suggested guidance for preconception and pregnancy care.
[Mitochondrial diseases and urolithiasis: Is there an association? Literature review about 2 cases].
Variant load of mitochondrial DNA in single human mesenchymal stem cells.
Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.
Characterization of two iPSC lines from patients with maternally inherited leigh (MILS) and neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome carrying the MT-ATP6 m.8993 T>G mutation at different degrees of heteroplasmy.
The small steps that lead to big impact: translating therapeutics from idea to reality for the CDKL5 deficiency disorder community.
A Novel m.1636A > G Variant in Mitochondrial TV Gene Might Cause New Phenotype of Mitochondrial Disease in a 2-Year Old Chinese Boy.
Is this really Empowerment? Enhancing our understanding of empowerment in patient and public involvement within clinical research.

J Clin Med. 2024 Aug 26. pii: 5044. [Epub ahead of print]13(17):

Unilateral Hearing Loss and Auditory Asymmetry in Mitochondrial Disease: A Scoping Review.

Marianna Manuelli, Andrea Migliorelli, Chiara Bianchini, Francesco Stomeo, Stefano Pelucchi, Elisabetta Genovese, Daniele Monzani, Silvia Palma, Andrea Ciorba.

  Background/Objectives: Mitochondrial transfer RNA mutations are one of the most important causes of hereditary hearing loss in humans. In most cases, its presentation is bilateral and symmetrical; however, there are numerous cases of single-sided presentation or asymmetrical onset described in the literature that may represent a diagnostic challenge. The aim of this review is to present the evidence of auditory asymmetry in mitochondrial diseases, highlighting the possible presence of cases with atypical presentation. Methods: A review of the English literature to date on hearing loss and mitochondrial diseases was performed using PubMed, Scopus, and Google Scholar databases. The literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines for scoping review. Results: A total of 10 full-text articles were included in this review, comprising 25 patients with single-sided or asymmetrical hearing loss associated with mitochondrial disease. Conclusions: Sensorineural hearing loss due to mitochondrial disease can represent a complex diagnostic challenge in cases of asymmetric or unilateral presentation. It is critical to recognize this clinical variant and to diagnose it in daily clinical practice.

Keywords:  deafness; hearing loss; mitochondrial disease; unilateral hearing loss

DOI:  https://doi.org/10.3390/jcm13175044
BMC Neurol. 2024 Sep 13. 24(1): 343

Cascade testing in mitochondrial diseases: a cross-sectional retrospective study.

Sameen Haque, Karen Crawley, Deborah Schofield, Rupendra Shrestha, Carolyn M Sue.

   BACKGROUND: Cascade testing can offer improved surveillance and timely introduction of clinical management for the at-risk biological relatives. Data on cascade testing and costs in mitochondrial diseases are lacking. To address this gap, we performed a cross-sectional retrospective study to provide a framework for cascade testing in mitochondrial diseases, to estimate the eligibility versus real-time uptake of cascade testing and to evaluate the cost of the genetic diagnosis of index cases and the cost of predictive cascade testing.
METHODS: Data was collected through retrospective chart review. The variant inheritance pattern guided the identification of eligible first-degree relatives: (i) Males with mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) - siblings and mothers. (ii) Females with mtDNA SNVs - siblings, mothers and offspring. (iii) Autosomal Dominant (AD) nuclear DNA (nDNA) variants - siblings, offspring and both parents. (iv) Autosomal Recessive (AR) nDNA variants - siblings.
RESULTS: We recruited 99 participants from the Adult Mitochondrial Disease Clinic in Sydney. The uptake of cascade testing was 55.2% in the mtDNA group, 55.8% in the AD nDNA group and 0% in AR nDNA group. Of the relatives in mtDNA group who underwent cascade testing, 65.4% were symptomatic, 20.5% were oligosymptomatic and 14.1% were asymptomatic. The mean cost of cascade testing for eligible first-degree relatives (mtDNA group: $694.7; AD nDNA group: $899.1) was lower than the corresponding index case (mtDNA group: $4578.4; AD nDNA group: $5715.1) (p < 0.001).
CONCLUSION: The demand for cascade testing in mitochondrial diseases varies according to the genotype and inheritance pattern. The real-time uptake of cascade testing can be influenced by multiple factors. Early diagnosis of at-risk biological relatives of index cases through cascade testing, confirms the diagnosis in those who are symptomatic and facilitates implementation of surveillance strategies and clinical care at an early stage of the disease.

Keywords:  Cascade screening; Cascade testing; Genetic predisposition to disease; Genetic testing; Mitochondrial diseases; Neuromuscular diseases; Pedigree

DOI:  https://doi.org/10.1186/s12883-024-03850-6
Aust N Z J Obstet Gynaecol. 2024 Sep 11.

Pregnancy in women with mitochondrial disease-A literature review and suggested guidance for preconception and pregnancy care.

Lisa Hui, Pema Hayman, Ali Buckland, Michael C Fahey, David A Mackey, Andrew J Mallett, Daniel R Schweitzer, Clare P Stuart, Wai Yan Yau, John Christodoulou.

  Mitochondrial donation to reduce the risk of primary mitochondrial disease transmission from mother to child is now permitted under Australian law as part of a clinical trial. The energy demands of pregnancy have the potential to worsen mitochondrial disease symptoms and severity in affected women. We conducted a systematic literature review on mitochondrial disease in pregnancy; five cohort studies and 19 case reports were included. For many women with mitochondrial disease, pregnancy does not have a negative effect on health status. However, serious adverse outcomes may occur. We provide suggested guidelines for preconception counselling and antenatal care.

Keywords:  assisted reproductive techniques; genetics; mitochondrial disease; pregnancy; pregnancy complications

DOI:  https://doi.org/10.1111/ajo.13874
Rev Med Chil. 2024 Jan;pii: S0034-98872024000100111. [Epub ahead of print]152(1): 111-118

[Mitochondrial diseases and urolithiasis: Is there an association? Literature review about 2 cases].

Renato Navarro Capone, Alvaro Bofill, Lucas López, Gastón Astroza Eulufi.

Urolithiasis corresponds to the formation of stones in the urinary tract. It is a multifactorial metabolic disorder; its formation is related to oxidative stress and inflammatory processes. The mitochondria, for its part, is an intracellular organelle that plays a role in the regulation of intracellular oxidative stress and intracellular calcium homeostasis, both processes related to urolithiasis. Mitochondrial diseases are diverse pathologies that compromise different organs, including the urinary system.
MATERIALS: Two cases of patients with mitochondrial diseases under study are presented who debuted with urinary symptoms with septic shock caused by a ureterolithiasis complicated by urinary infection.
RESULTS: Different pathophysiological mechanisms have been proposed in the literature that relate the different mitochondrial diseases with the presence of urolithiasis. We divide them into direct damage mechanisms, that is, the dysfunctional mitochondria would act actively in the formation of urolithiasis, and indirect damage, in which the consequences of mitochondrial diseases in the urinary organs would be responsible for the lithiasis.
DISCUSSION: There are various reports of patients who have been studied for urolithiasis in the context of mitochondrial diseases. Among them, the possible pathophysiological associations reported are collected.
CONCLUSION: Mitochondrial diseases are part of a group of pathologies whose characteristics have not been fully studied. They have a complex relationship with urolithiasis, despite not having been able to demonstrate causality. Studying them in this area would open a door to new treatments and prevention.

DOI: https://doi.org/10.4067/s0034-98872024000100111
Sci Rep. 2024 09 09. 14(1): 20989

Variant load of mitochondrial DNA in single human mesenchymal stem cells.

Daniel Hipps, Angela Pyle, Anna L R Porter, Philip F Dobson, Helen Tuppen, Conor Lawless, Oliver M Russell, Doug M Turnbull, David J Deehan, Gavin Hudson.

  Heteroplasmic mitochondrial DNA (mtDNA) variants accumulate as humans age, particularly in the stem-cell compartments, and are an important contributor to age-related disease. Mitochondrial dysfunction has been observed in osteoporosis and somatic mtDNA pathogenic variants have been observed in animal models of osteoporosis. However, this has never been assessed in the relevant human tissue. Mesenchymal stem cells (MSCs) are the progenitors to many cells of the musculoskeletal system and are critical to skeletal tissues and bone vitality. Investigating mtDNA in MSCs could provide novel insights into the role of mitochondrial dysfunction in osteoporosis. To determine if this is possible, we investigated the landscape of somatic mtDNA variation in MSCs through a combination of fluorescence-activated cell sorting and single-cell next-generation sequencing. Our data show that somatic heteroplasmic variants are present in individual patient-derived MSCs, can reach high heteroplasmic fractions and have the potential to be pathogenic. The identification of somatic heteroplasmic variants in MSCs of patients highlights the potential for mitochondrial dysfunction to contribute to the pathogenesis of osteoporosis.

Keywords:  Bone disease; Mesenchymal stem cells; Osteoporosis; Somatic mtDNA variation

DOI:  https://doi.org/10.1038/s41598-024-71822-4
Adv Sci (Weinh). 2024 Sep 12. e2401856

Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.

Lihao Jin, Dingyi Gan, Wentao He, Na Wu, Shuchenlu Xiang, Yinsheng Wei, Gilbert Eriani, Yanchun Ji, Min-Xin Guan, Meng Wang.

  Leber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNAGlu 14693A>G and ND6 14484T>C mutations in three Chinese families affected by LHON is investigated. The m.14693A>G mutation nearly abolishes the pseudouridinylation at position 55 of tRNAGlu, leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the ND6 14484T>C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual-mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.

Keywords:  apoptosis; leber's hereditary optic neuropathy; mitochondrial tRNA mutation; mitophagy; phenotypic expression

DOI:  https://doi.org/10.1002/advs.202401856
Stem Cell Res. 2024 Sep 06. pii: S1873-5061(24)00245-9. [Epub ahead of print]81 103547

Characterization of two iPSC lines from patients with maternally inherited leigh (MILS) and neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome carrying the MT-ATP6 m.8993 T>G mutation at different degrees of heteroplasmy.

Anna Maria Haschke, Sebastian Diecke, Markus Schuelke.

Human-derived experimental systems such as induced pluripotent stem cell (iPSC)-derived models are useful tools to study mechanisms and potential therapeutic approaches for mitochondrial disorders. Here, we generated two iPSC lines from fibroblasts of patients carrying mutations at MT-ATP6 (m.8993 T>G). One patient with 96 % heteroplasmy suffered from Neuropathy, Ataxia, and Retinitis pigmentosa (NARP) syndrome, while the other patient with a homoplasmic mutation suffered from Maternally Inherited Leigh Syndrome (MILS). For reprogramming, we delivered reprogramming factors using Sendai virus and evaluated the pluripotency characteristics of the derived iPSCs. The degree of heteroplasmy remained stable after reprogramming.

DOI: https://doi.org/10.1016/j.scr.2024.103547
Ther Adv Rare Dis. 2024 Jan-Dec;5:5 26330040241275673

The small steps that lead to big impact: translating therapeutics from idea to reality for the CDKL5 deficiency disorder community.

Amanda Jaksha, Marissa Bishop, Karen Utley, Heidi L Grabenstatter.

  Despite the unmet needs of patients living with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) and the challenges facing a rare population with small patient numbers, now is a time of unprecedented opportunities to turn scientific breakthroughs into safe and effective treatments for families of CDD patients. New data collected for over a decade and an evolution in genetics technologies have resulted in transformational new treatments currently in development for CDD. This progress is in great part due to the patient advocacy efforts early on to drive development of stakeholder research tools necessary to de-risk industry entry into the CDD space, family participation in longitudinal natural history studies, and a robust caregiver-reported database. Cumulatively, these efforts offered new insights into CDD, specifically patterns in disease progression, helped identify the most burdensome symptoms to patients and caregivers, improved clinical trial design, and reduced financial barriers for therapeutic development for potential industry partners. This paper documents the growth of a small patient community through relationship building and collaboration. The International Foundation for CDKL5 Research is mindful of ongoing challenges namely the long research timelines, high development and production costs, and inequitable access to approved therapies. Therefore, sustaining strong early resources while recognizing opportunities that engagement, advocacy, and funding can accelerate progress remains at the heart of the agile foundation strategy.

Keywords:  CDD; CDKL5; DEE; patient advocacy

DOI:  https://doi.org/10.1177/26330040241275673
Mol Neurobiol. 2024 Sep 07.

A Novel m.1636A > G Variant in Mitochondrial TV Gene Might Cause New Phenotype of Mitochondrial Disease in a 2-Year Old Chinese Boy.

Haiyan Yang, Victor Wei Zhang, Liang Ai, Liwen Wu.

  Pathogenic variants of mitochondrial DNA (mtDNA) are associated with a large number of heterogeneous diseases involving multiple systems with which patients may present with a wide range of clinical phenotypes. Clinical data of the proband and his family members were gathered in a retrospective study. Whole-exome sequencing and full-length sequencing of the mitochondrial genome that was performed on peripheral blood, urine, and oral mucosa cells were applied for genetic analysis. In this study, we describe a 2-year-old Chinese boy with global developmental delay, Charcot-Marie-Tooth (CMT) disease, progressive myoclonic epilepsy, paroxysmal arrhythmia, and brain atrophy with elevated blood lactate levels. The clinical manifestations of the patient were improved after metabolic therapy, but the development regressed after infection. The molecular finding of whole-exome sequencing is unremarkable, but the mtDNA genome sequencing of the proband and his monther revealed a de novo novel heteroplasmic variant, m.1636A > G, located next to the highly conserved anticodon loop of tRNA Val (MT-TV) gene. Moreover, the higher levels of mutational load in urinary epithelial cells (19.05%) and oral mucosa cells (20.8%) were detected than that in blood (17.4%). Combined with the phenotypic and molecular genetics analysis of this family, this novel variation was currently considered to be a likely pathogenic variant. Our results added evidence that the de novo m.1636A > G variation in the highly conserved sequence of MT-TV appears to suggest a childhood-onset mitochondrial phenotype of a 2-year-old patient, thus broaden the genotypic interpretation of mitochondrial DNA-related disease.

Keywords:   MT-TV gene; Charcot-Marie-Tooth disease; Global developmental delay; Mitochondrial DNA; Mutation

DOI:  https://doi.org/10.1007/s12035-024-04472-2
BMC Med Res Methodol. 2024 Sep 13. 24(1): 205

Is this really Empowerment? Enhancing our understanding of empowerment in patient and public involvement within clinical research.

Imke Schilling, Ansgar Gerhardus.

   BACKGROUND: There has been a growing push to involve patients in clinical research, shifting from conducting research on, about, or for them to conducting it with them. Two arguments advocate for this approach, known as Patient and Public Involvement (PPI): to improve research quality, appropriateness, relevance, and credibility by including patients' diverse perspectives, and to use PPI to empower patients and democratize research for more equity in research and healthcare. However, while empowerment is a core objective, it is often not clear what is meant by empowerment in the context of PPI in clinical research. This vacancy can lead to insecurities for both patients and researchers and a disconnect between the rhetoric of empowerment in PPI and the reality of its practice in clinical trials. Thus, clarifying the understanding of empowerment within PPI in clinical research is essential to ensure that involvement does not become tokenistic and depletes patients' capacity to advocate for their rights and needs.
METHODS: We explored the historical roots of empowerment, primarily emerging from mid-20th century social movements like feminism and civil rights and reflected the conceptual roots of empowerment from diverse fields to better understand the (potential) role of empowerment in PPI in clinical research including its possibilities and limitations.
RESULTS: Common themes of empowerment in PPI and other fields are participation, challenging power structures, valuing diverse perspectives, and promoting collaboration. On the other hand, themes such as contextual differences in the empowerment objectives, the relationship between empowerment and scientific demands, research expertise, and power asymmetries mark a clear distinction from empowerment in other fields.
CONCLUSION: PPI offers potential for patient empowerment in clinical trials, even when its primary goal may be research quality. Elements like participation, sharing opinions, and active engagement can contribute to patient empowerment. Nonetheless, some expectations tied to empowerment might not be met within the constraints of clinical research. To empower patients, stakeholders must be explicit about what empowerment means in their research, engage in transparent communication about its realistic scope, and continuously reflect on how empowerment can be fostered and sustained within the research process.

Keywords:  Clinical Research; Empowerment; PPI; Patient and public involvement

DOI:  https://doi.org/10.1186/s12874-024-02323-1