bims-curels 2024-03-03 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024‒03‒03
twelve papers selected by
Cure Mito Foundation

The Application of Brain Organoid for Drug Discovery in Mitochondrial Diseases.
Lack of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile-onset brainstem neurodegenerative disease with early lethality.
mitoTALEN reduces the mutant mtDNA load in neurons.
Embracing the unknown: investigating medical communication around uncertainty and the implications on patient and family well-being.
Late-onset mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and the role of serial imaging.
Sustaining connections: feasibility and impact of long-term virtual patient engagement.
Mitochondrial DNA competition: starving out the mutant genome.
Bilateral cochlear implants in a MELAS patient.
Analysis of the first ten years of FDA's rare pediatric disease priority review voucher program: designations, diseases, and drug development.
MtDNA deletions and aging.
What you do not need to tell a patient.
Genetic and bioinformatic analyses reveal transcriptional networks underlying dual genomic coordination of mitochondrial biogenesis.

Int J Biochem Cell Biol. 2024 Feb 27. pii: S1357-2725(24)00047-5. [Epub ahead of print] 106556

The Application of Brain Organoid for Drug Discovery in Mitochondrial Diseases.

Kristina Xiao Liang.

  Mitochondrial diseases are difficult to treat due to the complexity and multifaceted nature of mitochondrial dysfunction. Brain organoids are three-dimensional (3D) structures derived from human pluripotent stem cells designed to mimic brain-like development and function. Brain organoids have received a lot of attention in recent years as powerful tools for modeling human diseases, brain development, and drug screening. Screening compounds for mitochondrial diseases using brain organoids could provide a more physiologically relevant platform for drug discovery. Brain organoids offer the possibility of personalized medicine because they can be derived from patient-specific cells, allowing testing of drugs tailored to specific genetic mutations. In this article, we highlight how brain organoids offer a promising avenue for screening compounds for mitochondrial diseases and address the challenges and limitations associated with their use. We hope this review will provide new insights into the further progress of brain organoids for mitochondrial screening studies.

Keywords:  Brain organoid; drug discovery; drug screening; iPSCs; mitochondrial diseases

DOI:  https://doi.org/10.1016/j.biocel.2024.106556
Orphanet J Rare Dis. 2024 Feb 28. 19(1): 92

Lack of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile-onset brainstem neurodegenerative disease with early lethality.

Firas Abu Hanna, Yoav Zehavi, Eran Cohen-Barak, Morad Khayat, Nasim Warwar, Roni Shreter, Richard J Rodenburg, Ronen Spiegel.

  BACKGROUND: Congenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among them, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Biallelic pathogenic variants in NDUFAF2, encoding the nuclear assembly CI factor NDUFAF2, were initially reported to cause progressive encephalopathy beginning in infancy. Since the initial report in 2005, less than a dozen patients with NDUFAF2-related disease have been reported.METHODS: Clinical, biochemical, and neuroradiological features of four new patients residing in Northern Israel were collected during 2016-2022 at Emek Medical Center. Enzymatic activities of the five respiratory-chain complexes were determined in isolated fibroblast mitochondria by spectrophotometric methods. Western blot analyses were conducted with anti-human NDUFAF2 antibody; antibody against the mitochondrial marker VDAC1 was used as a loading control. Genetic studies were performed by chromosome microarray analysis using Affymetrix CytoScan 750 K arrays.
RESULTS: All four patients presented with infantile-onset growth retardation, ophthalmological impairments with nystagmus, strabismus (starting between 5 and 9 months), and further progressed to life-threatening episodes of apnea usually triggered by trivial febrile illnesses (between 10 and 18 months) with gradual loss of acquired developmental milestones (3 of 4 patients). Serial magnetic-resonance imaging studies in two of the four patients showed a progressive pattern of abnormal T2-weighted hyperintense signals involving primarily the brainstem, the upper cervical cord, and later, the basal ganglia and thalami. Magnetic-resonance spectroscopy in one patient showed an increased lactate peak. Disease progression was marked by ventilatory dependency and early lethality. 3 of the 4 patients tested, harbored a homozygous 142-kb partial interstitial deletion that omits exons 2-4 of NDUFAF2. Mitochondrial CI activity was significantly decreased in the only patient tested. Western blot analysis disclosed the absence of NDUFAF2 protein compared to normal controls. In addition, we reviewed all 10 previously reported NDUFAF2-deficient cases to better characterize the disease.
CONCLUSIONS: Biallelic loss-of-function mutations in NDUFAF2 result in a distinctive phenotype in the spectrum of Leigh syndrome with clinical and neuroradiological features that are primarily attributed to progressive brainstem damage.

Keywords:   NDUFAF2 gene; Leigh syndrome; Mitochondrial disease; Optic neuropathy; Oxidative phosphorylation

DOI:  https://doi.org/10.1186/s13023-024-03094-0
Mol Ther Nucleic Acids. 2024 Mar 12. 35(1): 102132

mitoTALEN reduces the mutant mtDNA load in neurons.

Sandra R Bacman, Jose Domingo Barrera-Paez, Milena Pinto, Derek Van Booven, James B Stewart, Anthony J Griswold, Carlos T Moraes.

  Mutations within mtDNA frequently give rise to severe encephalopathies. Given that a majority of these mtDNA defects exist in a heteroplasmic state, we harnessed the precision of mitochondrial-targeted TALEN (mitoTALEN) to selectively eliminate mutant mtDNA within the CNS of a murine model harboring a heteroplasmic mutation in the mitochondrial tRNA alanine gene (m.5024C>T). This targeted approach was accomplished by the use of AAV-PHP.eB and a neuron-specific synapsin promoter for effective neuronal delivery and expression of mitoTALEN. We found that most CNS regions were effectively transduced and showed a significant reduction in mutant mtDNA. This reduction was accompanied by an increase in mitochondrial tRNA alanine levels, which are drastically reduced by the m.5024C>T mutation. These results showed that mitochondrial-targeted gene editing can be effective in reducing CNS-mutant mtDNA in vivo, paving the way for clinical trials in patients with mitochondrial encephalopathies.

Keywords:  AAV-PHPeB; CNS; MT: RNA/DNA editing; TALEN; gene therapy; heteroplasmy; mitochondria

DOI:  https://doi.org/10.1016/j.omtn.2024.102132
Orphanet J Rare Dis. 2024 Feb 26. 19(1): 37

Embracing the unknown: investigating medical communication around uncertainty and the implications on patient and family well-being.

Leisha Devisetti.

Rare diseases present immense challenges to physicians, patients, and the healthcare system at large due to a scarcity of research and knowledge in the field. This contributes to uncertainty surrounding rare diseases, which can hinder the management of these chronic conditions. An analysis of my family's experience battling my mother's ameloblastic carcinoma highlights the difficulties in communicating the uncertainty around rare diseases and their damaging effects on our family's well-being. Here, we will recognize the importance of acknowledging uncertainty during diagnoses and advocating for enhanced detection strategies. The goal of this article is to emphasize that effective medical communication around rare diseases, accessibility to accurate information, proper services, and a shift toward a culture that prioritizes patient well-being are critical for improving health outcomes for rare disease patients.

DOI: https://doi.org/10.1186/s13023-024-03050-y
BMJ Case Rep. 2024 Feb 27. pii: e259102. [Epub ahead of print]17(2):

Late-onset mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and the role of serial imaging.

Robert Ambrogetti, Ethan Kavanagh, Khalid ElTayeb.

  Mitochondria are essential for human metabolic function. Over 350 genetic mutations are associated with mitochondrial diseases, which are inherited in a matrilineal fashion. In mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), defective mitochondrial function and resultant impaired cellular energy production compromise vascular perfusion in affected tissues. Early diagnostic criteria suggested the diagnosis should be considered in those under 40. However, a broader range of phenotypes are now recognised, including those that present for the first time later in life. The primary presenting feature in MELAS is a stroke-like episode invariably resulting in patients undergoing neuroradiological imaging. We present a case of a woman with a first presentation of a stroke-like episode and seizures in her 40s who was eventually diagnosed with MELAS. We detail her clinical presentation, treatment and diagnosis, emphasising the role of serial imaging in her diagnosis.

Keywords:  Epilepsy and seizures; Genetics; Neuro genetics; Neurology

DOI:  https://doi.org/10.1136/bcr-2023-259102
Res Involv Engagem. 2024 Feb 24. 10(1): 28

Sustaining connections: feasibility and impact of long-term virtual patient engagement.

Kelsey Stefanik-Guizlo, Claire Allen, Sarah Brush, Jessica Mogk, Starette Canada, Marina Peck, Kathryn Ramos, Karen Volpe, Paula Lozano.

  BACKGROUND: Virtual patient engagement has become more common in recent years. Emerging research suggests virtual engagement can increase accessibility for patients managing long-term health conditions and those living in larger geographic areas, but it can also be challenging to establish relationships and maintain engagement over time. Little is known about virtual engagement lasting more than two years, nor about the specific contributions of patients to virtual engagement projects. Here we describe a project where virtual engagement was sustained over a long period of time (3.5 years), measure patients' contributions to the work, and describe the facilitators and challenges of the project using the Valuing All Voices (VAV) patient engagement framework.METHODS: Five researchers recruited four patient partners living with persistent pain to work together virtually on a project to improve care for others with long-term pain. Researchers documented engagement activities and patient partner contributions and categorized them using Carman et al.'s 3 types of engagement. They also collected data via semi-structured group interviews with patient partners about the facilitators and challenges of the project using the VAV framework.
RESULTS: In 3.5 years, patient partners contributed 487 h to the project, averaging 3.0 h per month, and participated in 40 meetings. They contributed to 17 products for patients, health care teams, and researchers. Most products (12 of 17) were created using the more in-depth engagement approaches of involvement or partnership and shared leadership. The group identified facilitators of the project across the five VAV domains of relationship-building, trust, understanding & acceptance, education & communication, and self-awareness, as well as some specific challenges such as keeping track of products across virtual platforms and managing the high volume of project information.
CONCLUSIONS: Long-term virtual patient engagement is feasible and can use more in-depth engagement approaches. Additionally, it can result in substantial contributions from patients in terms of time, effort, and products. These findings can inform future long-term virtual patient engagement efforts and provide insight into how researchers can structure their activities to encourage and maintain deep engagement over time.

Keywords:  Chronic pain; Patient and public involvement; Patient engagement; Virtual engagement

DOI:  https://doi.org/10.1186/s40900-024-00558-2
Trends Pharmacol Sci. 2024 Feb 23. pii: S0165-6147(24)00024-5. [Epub ahead of print]

Mitochondrial DNA competition: starving out the mutant genome.

Antonella Spinazzola, Diego Perez-Rodriguez, Jan Ježek, Ian J Holt.

  High levels of pathogenic mitochondrial DNA (mtDNA) variants lead to severe genetic diseases, and the accumulation of such mutants may also contribute to common disorders. Thus, selecting against these mutants is a major goal in mitochondrial medicine. Although mutant mtDNA can drift randomly, mounting evidence indicates that active forces play a role in the selection for and against mtDNA variants. The underlying mechanisms are beginning to be clarified, and recent studies suggest that metabolic cues, including fuel availability, contribute to shaping mtDNA heteroplasmy. In the context of pathological mtDNAs, remodeling of nutrient metabolism supports mitochondria with deleterious mtDNAs and enables them to outcompete functional variants owing to a replicative advantage. The elevated nutrient requirement represents a mutant Achilles' heel because small molecules that restrict nutrient consumption or interfere with nutrient sensing can purge cells of deleterious mtDNAs and restore mitochondrial respiration. These advances herald the dawn of a new era of small-molecule therapies to counteract pathological mtDNAs.

Keywords:  2-Deoxy-d-glucose; epigenetic rewiring; heteroplasmy; mitochondrial DNA; nutrient metabolism; nutrient signaling

DOI:  https://doi.org/10.1016/j.tips.2024.01.011
Eur Arch Otorhinolaryngol. 2024 Feb 26.

Bilateral cochlear implants in a MELAS patient.

Yung-Chen Sun, Yu-Pu Chou, Pei-Hsuan Ho, Xiang-Xiang Chen, Pey-Yu Chen, Chia-Huei Chu, Hung-Ching Lin.

  BACKGROUND: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disease that affects various systems in the body, particularly the brain, nervous system, and muscles. Among these systems, sensorineural hearing loss is a common additional symptom.METHODS: A 42-year-old female patient with MELAS who experienced bilateral profound deafness and underwent bilateral sequential cochlear implantation (CIs). Speech recognition and subjective outcomes were evaluated.
RESULTS: Following the first CI follow-up, the patient exhibited improved speech recognition ability and decided to undergo the implantation of the second ear just two months after the initial CI surgery. The second CI also demonstrated enhanced speech recognition ability. Subjective outcomes were satisfactory for bilateral CIs.
CONCLUSIONS: MELAS patients receiving bilateral CIs can attain satisfactory post-CI speech recognition, spatial hearing, and sound qualities.

Keywords:  Bilateral cochlear implants; MELAS; Mitochondrial disease; Speech recognition performance; Subjective outcomes

DOI:  https://doi.org/10.1007/s00405-024-08532-0
Orphanet J Rare Dis. 2024 Feb 25. 19(1): 86

Analysis of the first ten years of FDA's rare pediatric disease priority review voucher program: designations, diseases, and drug development.

Catherine Mease, Kathleen L Miller, Lewis J Fermaglich, Jeanine Best, Gumei Liu, Erika Torjusen.

  BACKGROUND: The Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) Program was enacted in 2012 to support the development of new products for children. Prior to requesting a voucher, applicants can request RPD designation, which confirms their product treats or prevents a rare disease in which the serious manifestations primarily affect children. This study describes the trends and characteristics of these designations. Details of RPD designations are not publicly disclosable; this research represents the first analysis of the RPD designation component of the program.RESULTS: We used an internal US Food and Drug Administration database to analyze all RPD designations between 2013 and 2022. Multiple characteristics were analyzed, including the diseases targeted by RPD designation, whether the product targeted a neonatal disease, product type (drug/biologic), and the level of evidence (preclinical/clinical) to support designation. There were 569 RPD designations during the study period. The top therapeutic areas were neurology (26%, n = 149), metabolism (23%, n = 131), oncology (18%, n = 105). The top diseases targeted by RPD designation were Duchenne muscular dystrophy, neuroblastoma, and sickle cell disease. Neonatology products represented 6% (n = 33), over half were for drug products and 38% were supported by clinical data.
CONCLUSIONS: The RPD PRV program was created to encourage development of new products for children. The results of this study establish that a wide range of diseases have seen development-from rare pediatric cancers to rare genetic disorders. Continued support of product development for children with rare diseases is needed to find treatments for all children with unmet needs.

Keywords:  Children; Designations; Drug development; Food and Drug Administration; Rare pediatric diseases

DOI:  https://doi.org/10.1186/s13023-024-03097-x
Front Aging. 2024 ;5 1359638

MtDNA deletions and aging.

Charlotte Sprason, Trudy Tucker, David Clancy.

  Aging is the major risk factor in most of the leading causes of mortality worldwide, yet its fundamental causes mostly remain unclear. One of the clear hallmarks of aging is mitochondrial dysfunction. Mitochondria are best known for their roles in cellular energy generation, but they are also critical biosynthetic and signaling organelles. They also undergo multiple changes with organismal age, including increased genetic errors in their independent, circular genome. A key group of studies looking at mice with increased mtDNA mutations showed that premature aging phenotypes correlated with increased deletions but not point mutations. This generated an interest in mitochondrial deletions as a potential fundamental cause of aging. However, subsequent studies in different models have yielded diverse results. This review summarizes the research on mitochondrial deletions in various organisms to understand their possible roles in causing aging while identifying the key complications in quantifying deletions across all models.

Keywords:  aging; mitochondria; mitochondrial DNA; mitochondrial DNA deletions; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fragi.2024.1359638
Am J Orthod Dentofacial Orthop. 2024 Mar;pii: S0889-5406(23)00644-3. [Epub ahead of print]165(3): 365-368

What you do not need to tell a patient.

Laurance Jerrold.

DOI: https://doi.org/10.1016/j.ajodo.2023.12.002
bioRxiv. 2024 Jan 29. pii: 2024.01.25.577217. [Epub ahead of print]

Genetic and bioinformatic analyses reveal transcriptional networks underlying dual genomic coordination of mitochondrial biogenesis.

Fan Zhang, Annie Lee, Anna Freitas, Jake Herb, Zongheng Wang, Snigdha Gupta, Zhe Chen, Hong Xu.

Mitochondrial genome encodes handful genes of respiratory chain complexes, whereas all the remaining mitochondrial proteins are encoded on the nuclear genome. However, the mechanisms coordinating these two genomes to control mitochondrial biogenesis remain largely unknown. To identify transcription circuits involved in these processes, we performed a candidate RNAi screen in developing eyes that had reduced mitochondrial DNA contents. We reasoned that impaired mitochondrial biogenesis would synergistically interact with mtDNA deficiency in disrupting tissue development. Over 638 transcription factors annotated in the fly genome, we identified 77 transcription factors that may be involved in mitochondrial genome maintenance and gene expression. Additional genetic and genomic analyses revealed that a novel transcription factor, CG1603, and its upstream factor YL-1 are essential for mitochondrial biogenesis. We constructed a regulator network among positive hits using the published CHIP-seq data. The network analysis revealed extensive connections, and complex hierarchical organization underlying the transcription regulation of mitochondrial biogenesis.

DOI: https://doi.org/10.1101/2024.01.25.577217