bims-curels 2024-03-17 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–03–17
eight papers selected by
Cure Mito Foundation

Digenic Leigh syndrome on the background of the m.11778G>A Leber hereditary optic neuropathy variant.
The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study.
"There was No Opportunity to Express Good or Bad": Perspectives From Patient Focus Groups on Patient Experience in Clinical Trials.
Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation.
A systematic review of real-world evidence (RWE) supportive of new drug and biologic license application approvals in rare diseases.
Revisiting the Mitochondrial Function and Communication in Neurodegenerative Diseases.
Elderly onset of MELAS carried an M.3243A >G mutation in a female with deafness and visual deficits: A case report.
The role of registries in improving health and bridging healthcare, research, education, innovation and development: a research department perspective.

Brain. 2024 Mar 13. pii: awae057. [Epub ahead of print]

Digenic Leigh syndrome on the background of the m.11778G>A Leber hereditary optic neuropathy variant.

Beryll Blickhäuser, Sarah L Stenton, Christiane M Neuhofer, Elisa Floride, Victoria Nesbitt, Carl Fratter, Johannes Koch, Birgit Kauffmann, Claudia Catarino, Lea Dewi Schlieben, Robert Kopajtich, Valerio Carelli, Alfredo A Sadun, Robert McFarland, Fang Fang, Chiara La Morgia, Stéphanie Paquay, Marie Cécile Nassogne, Daniele Ghezzi, Costanza Lamperti, Saskia Wortmann, Jo Poulton, Thomas Klopstock, Holger Prokisch.

  Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterised by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA (mtDNA) genes and more than 100 nuclear genes, most often related to mitochondrial complex I (CI) dysfunction. Rarely, LSS has been reported in association with primary Leber hereditary optic neuropathy (LHON) variants of the mtDNA, coding for CI subunits (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4, and m.14484T>C in MT-ND6). The underlying mechanism by which these variants manifest as LSS, a severe neurodegenerative disease, as opposed to the LHON phenotype of isolated optic neuropathy, remains an open question. Here, we analyse the exome sequencing of six probands with LSS carrying primary LHON variants, and report digenic co-occurrence of the m.11778G>A variant with damaging heterozygous variants in nuclear disease genes encoding CI subunits as a plausible explanation. Our findings suggest a digenic mechanism of disease for m.11778G>A-associated LSS, consistent with recent reports of digenic disease in individuals manifesting with LSS due to biallelic variants in the recessive LHON-associated disease gene DNAJC30 in combination with heterozygous variants in CI subunits.

Keywords:  Leber hereditary optic neuropathy (LHON); Leigh syndrome spectrum (LSS); digenic inheritance; mitochondrial complex I (CI)

DOI:  https://doi.org/10.1093/brain/awae057
Front Cell Dev Biol. 2024 ;12 1331351

The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study.

C Nogueira, C Pereira, L Silva, Mateus Laranjeira, A Lopes, R Neiva, E Rodrigues, T Campos, E Martins, A Bandeira, M Coelho, M Magalhães, J Damásio, A Gaspar, P Janeiro, A Levy Gomes, A C Ferreira, S Jacinto, J P Vieira, L Diogo, H Santos, C Mendonça, L Vilarinho.

  Introduction: Rare disorders that are genetically and clinically heterogeneous, such as mitochondrial diseases (MDs), have a challenging diagnosis. Nuclear genes codify most proteins involved in mitochondrial biogenesis, despite all mitochondria having their own DNA. The development of next-generation sequencing (NGS) technologies has revolutionized the understanding of many genes involved in the pathogenesis of MDs. In this new genetic era, using the NGS approach, we aimed to identify the genetic etiology for a suspected MD in a cohort of 450 Portuguese patients. Methods: We examined 450 patients using a combined NGS strategy, starting with the analysis of a targeted mitochondrial panel of 213 nuclear genes, and then proceeding to analyze the whole mitochondrial DNA. Results and Discussion: In this study, we identified disease-related variants in 134 (30%) analyzed patients, 88 with nuclear DNA (nDNA) and 46 with mitochondrial DNA (mtDNA) variants, most of them being pediatric patients (66%), of which 77% were identified in nDNA and 23% in mtDNA. The molecular analysis of this cohort revealed 72 already described pathogenic and 20 novel, probably pathogenic, variants, as well as 62 variants of unknown significance. For this cohort of patients with suspected MDs, the use of a customized gene panel provided a molecular diagnosis in a timely and cost-effective manner. Patients who cannot be diagnosed after this initial approach will be further selected for whole-exome sequencing. Conclusion: As a national laboratory for the study and research of MDs, we demonstrated the power of NGS to achieve a molecular etiology, expanding the mutational spectrum and proposing accurate genetic counseling in this group of heterogeneous diseases without therapeutic options.

Keywords:  mitochondrial DNA; mitochondrial diseases; next-generation sequencing; nuclear DNA; nuclear genes; oxidative phosphorylation; respiratory chain

DOI:  https://doi.org/10.3389/fcell.2024.1331351
J Patient Exp. 2024 ;11 23743735241237684

"There was No Opportunity to Express Good or Bad": Perspectives From Patient Focus Groups on Patient Experience in Clinical Trials.

Patrick Boyd, Elizabeth A Sternke, David J Tite, Kristopher Morgan.

  To understand how patients perceive their experiences leading up to, during, and after a clinical trial, and the relationship these experiences had with future willingness to participate, we conducted 3 focus groups with patients who had prior clinical trial involvement (n = 25). Discussion topics included clinical trial discovery, enrollment, communication, trust, patient-centricity, and future enrollment. Patient focus groups revealed a variety of motivations for enrolling in clinical trials (eg, altruism, efficacious treatment, curiosity, desperation, etc.). Patients learned about clinical trials through trusted sources (eg, primary care physicians, patient advocacy groups) and social media. Access and uncertainty about clinical trials were barriers to enrollment. Patient-centric communication and attention given to disease states and symptom severity were valued and made patients feel genuinely cared about. Post-trial follow up and being informed of trial results were inconsistently reported by patients. Critically, patients described frustration with an overall lack of patient experience measurement. Patients identified a need to measure experiences before, during, and after clinical trials and emphasized that doing so would facilitate patient trust and overall experience.

Keywords:  clinician-patient relationship; communication; patient feedback; patient satisfaction; trust

DOI:  https://doi.org/10.1177/23743735241237684
Cells. 2024 Feb 27. pii: 410. [Epub ahead of print]13(5):

Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation.

Kuldeep Tripathi, Dorit Ben-Shachar.

  Mitochondria, the energy suppliers of the cells, play a central role in a variety of cellular processes essential for survival or leading to cell death. Consequently, mitochondrial dysfunction is implicated in numerous general and CNS disorders. The clinical manifestations of mitochondrial dysfunction include metabolic disorders, dysfunction of the immune system, tumorigenesis, and neuronal and behavioral abnormalities. In this review, we focus on the mitochondrial role in the CNS, which has unique characteristics and is therefore highly dependent on the mitochondria. First, we review the role of mitochondria in neuronal development, synaptogenesis, plasticity, and behavior as well as their adaptation to the intricate connections between the different cell types in the brain. Then, we review the sparse knowledge of the mechanisms of exogenous mitochondrial uptake and describe attempts to determine their half-life and transplantation long-term effects on neuronal sprouting, cellular proteome, and behavior. We further discuss the potential of mitochondrial transplantation to serve as a tool to study the causal link between mitochondria and neuronal activity and behavior. Next, we describe mitochondrial transplantation's therapeutic potential in various CNS disorders. Finally, we discuss the basic and reverse-translation challenges of this approach that currently hinder the clinical use of mitochondrial transplantation.

Keywords:  CNS; mitochondria; mitochondria and behavior; mitochondrial transplantation; neural development and function; neuropsychiatric disorders

DOI:  https://doi.org/10.3390/cells13050410
Orphanet J Rare Dis. 2024 Mar 12. 19(1): 117

A systematic review of real-world evidence (RWE) supportive of new drug and biologic license application approvals in rare diseases.

Shailja Vaghela, Kaniz Afroz Tanni, Geetanjoli Banerjee, Vanja Sikirica.

   BACKGROUND: Real-world evidence (RWE) generated using real-world data (RWD) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This systematic review evaluated the use of RWD for non-oncologic RD therapies with orphan drug designation (ODD) to support efficacy outcomes in regulatory application packages to the US Food and Drug Administration (FDA). New drug applications (NDAs) and biologic license applications (BLAs) submitted between January 2017 and October 2022 were obtained from publicly available FDA drug approval websites. NDAs and BLAs of non-oncologic RD therapies were screened, and manually reviewed using RWE-related keywords. Quantitative summary of number/proportion of study types was provided, whereas qualitative synthesis focused on key categories of output assessing the use of RWD in overall drug approval process, including agency's feedback on its strengths and key challenges.
RESULTS: A total of 868 NDAs and BLAs were identified, of which 243 were screened for non-oncologic RDs with ODD, and 151 were subsequently reviewed for the RWD used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications met the review inclusion criteria. Most (19; 95%) applications used only retrospective RWD, while one (5%) collected RWD both retrospectively and prospectively. RWD studies included natural history including registry-based/retrospective historical controls (14; 70%), retrospective medical chart-reviews (4; 20%), and external RWD controls from other studies (2; 10%). The FDA generally accepted RWD studies demonstrating a large effect size despite the noted concerns and criticisms. However, the agency expressed concerns about overall quality and comparability of RWD with trial data for some applications, including RWD study designs with respect to differences in patients' baseline characteristics, missing information, and potential bias and measurement errors.
CONCLUSIONS: This systematic review highlights potential benefits of appropriately conducted RWE studies in RD, which can strengthen the clinical evidence for efficacy comparison and contextualization to support product approval efforts, particularly when a large magnitude of effect is observed for the new intervention. Nonetheless, quality and completeness of RWD and its comparability with trial data remain areas of concern that can serve as valuable learnings for advancing future science and regulatory approvals.

Keywords:  Biologic license application; New drug application; Orphan drugs; Rare diseases; Real-world data; Real-world evidence; Systematic review; US FDA regulatory approval

DOI:  https://doi.org/10.1186/s13023-024-03111-2
Curr Pharm Des. 2024 Mar 12.

Revisiting the Mitochondrial Function and Communication in Neurodegenerative Diseases.

Nitu L Wankhede, Mayur B Kale, Mohit D Umare, Sanket Lokhande, Aman B Upaganlawar, Pranay Wal, Brijesh G Taksande, Milind J Umekar, Prasanna Shama Khandige, Bhupendra Singh, Vandana Sadananda, Seema Ramniwas, Tapan Behl.

  Neurodegenerative disorders are distinguished by the progressive loss of anatomically or physiologically relevant neural systems. Atypical mitochondrial morphology and metabolic malfunction are found in many neurodegenerative disorders. Alteration in mitochondrial function can occur as a result of aberrant mitochondrial DNA, altered nuclear enzymes that interact with mitochondria actively or passively, or due to unexplained reasons. Mitochondria are intimately linked to the Endoplasmic reticulum (ER), and ER-mitochondrial communication governs several of the physiological functions and procedures that are disrupted in neurodegenerative disorders. Numerous researchers have associated these disorders with ER-mitochondrial interaction disturbance. In addition, aberrant mitochondrial DNA mutation and increased ROS production resulting in ionic imbalance and leading to functional and structural alterations in the brain as well as cellular damage may have an essential role in disease progression via mitochondrial malfunction. In this review, we explored the evidence highlighting the role of mitochondrial alterations in neurodegenerative pathways in most serious ailments, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).

Keywords:  Alzheimer’s disease; Huntington’s disease; Neurodegenerative disorders; Parkinson’s disease; endoplasmic reticulum.; mitochondrial communication

DOI:  https://doi.org/10.2174/0113816128286655240304070740
Clin Case Rep. 2024 Mar;12(3): e8438

Elderly onset of MELAS carried an M.3243A >G mutation in a female with deafness and visual deficits: A case report.

Lin Zijun, Yi Xu, Yang Yujia, Xu Zhiqiang.

   Key Clinical Message: MELAS is a disorder with clinical variability that also responsible for a significant portion of unexplained hereditary or childhood-onset hearing loss. Although patients typically present in childhood, the first stroke-like episode can occur later in life in some patients, potentially related to a lower heteroplasmy level. It is crucial to consider MELAS as a potential cause of stroke-like events if age at presentation and symptoms are atypical, especially among middle-aged patients without vascular risk factors.
Abstract: MELAS syndrome (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) is a rare genetic condition that most patients develop stroke-like episodes before the age of 40. We report a 52-year-old female with a documented 40-year history of progressive sensorineural hearing loss, developed a visual field deficit and stroke-like events in her middle age who finally diagnosed was MELAS. The patient was started on vitamin E, l-carnitine, l-arginine, and coenzyme Q10 that gradually improved before dismissal from the hospital. This case highlights the importance of considering MELAS as a potential cause of stroke-like events if imaging findings are atypical for cerebral infarction, especially among middle-aged patients without vascular risk factors and an unusual cause of progressive sensorineural hearing loss.

Keywords:  MELAS syndrome; case report; epilepsy; mitochondria; stroke‐like episodes; visual deficit

DOI:  https://doi.org/10.1002/ccr3.8438
J Int Med Res. 2024 Mar;52(3): 3000605241233140

The role of registries in improving health and bridging healthcare, research, education, innovation and development: a research department perspective.

Maria Lourdes Posadas-Martinez, Jimena Vicens, Adriana Ruth Dawidowski, Marcela Alejandra Martinez Von Scheidt, Vanina Laura Pagotto, Gabriela Alejandra Blugerman, Monica Gabriela Schpilberg, Adrian Carlos Gadano.

  Health registries are organized systems that collect data on individuals with a particular disease, condition or exposure. The aim of this narrative review was to provide an integrated perspective from the Research Department at the Hospital Italiano de Buenos Aires, Argentina, on how health registries can be used as a bridge between healthcare, research, education, innovation and development while addressing ethical challenges. The review includes a description of the experience of a registry implemented at our institution, which has provided healthcare for 170 years, and is committed to support, education and research. We focus on the potential of health registries to provide better value healthcare by reducing healthcare costs and improving health outcomes and quality of care, and to improve medical knowledge. However, we also acknowledge and discuss the challenges that accompany these achievements, such as that of ethical issues. Through effective collaboration and integration with other healthcare stakeholders, health registries can be a powerful tool to promote better health.

Keywords:  Health registry; development; education; epidemiology; ethics; innovation; patient care; research

DOI:  https://doi.org/10.1177/03000605241233140