bims-curels Biomed News
on Leigh syndrome
Issue of 2024–08–04
twelve papers selected by
Cure Mito Foundation
  1. Demographic characteristics, diagnostic challenges, treatment patterns, and caregiver burden of mitochondrial diseases: a retrospective cross-sectional study.
  2. Co-creating and hosting PxP: a conference about patient engagement in research for and by patient partners.
  3. Mitochondrial DNA disorders in neuromuscular diseases in diverse populations.
  4. Cranial and spinal nerve enhancement in SURF1-associated Leigh syndrome.
  5. Two novel SUCLA2 variants cause mitochondrial DNA depletion syndrome, type 5 in two siblings.
  6. Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA.
  7. Safety and efficacy of deoxycytidine/deoxythymidine combination therapy in POLG-related disorders: 6-month interim results of an open-label, single arm, phase 2 trial.
  8. The role of the TSC Alliance in advancing therapy development: a patient organization perspective.
  9. Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea (Diabetes Metab J 2024;48:482-6).
  10. Rare disease diagnosis using knowledge guided retrieval augmentation for ChatGPT.
  11. Distinct Imaging Markers of Leigh's Disease Linked to SURF1 Mutation: A Pediatric Case Study.
  12. Digital endpoints in clinical trials: emerging themes from a multi-stakeholder Knowledge Exchange event.
  1. Orphanet J Rare Dis. 2024 Aug 02. 19(1): 287
    Demographic characteristics, diagnostic challenges, treatment patterns, and caregiver burden of mitochondrial diseases: a retrospective cross-sectional study.
    Xutong Zhao, Meng Yu, Wei Zhang, Yue Hou, Yun Yuan, Zhaoxia Wang.
       BACKGROUND: This study aimed to explore the demographic characteristics, diagnostic challenges, treatment patterns, and caregiver burden of mitochondrial diseases.
    METHODS: This retrospective cross-sectional study enrolled patients diagnosed with mitochondrial diseases from the Department of Neurology at Peking University First Hospital between January 2010 and December 2021. A questionnaire covering demographic characteristics, diagnostic dilemma, treatment, economic aspects, and caregiver stress was administered, and disability was assessed using the modified Rankin Scale (mRS).
    RESULTS: A total of 183 patients (mean age: 16 (IQR: 12-25), 49.72% males) were enrolled, including 124 pediatric patients and 59 adult patients. MELAS (106. 57.92%) and Leigh syndrome (37, 20.22%) were predominant among the mitochondrial disease subtypes. Among them, 132 (72.13%) patients were initially misdiagnosed with other diseases, 58 (31.69%) patients visited 2 hospitals before confirmed as mitochondrial disease, and 39 (21.31%) patients visited 3 hospitals before confirmed as mitochondrial disease. Metabolic modifiers were the most common type of drugs used, including several dietary supplements such as L-carnitine (117, 63.93%), Coenzyme Q10 (102, 55.74%), idebenone (82, 44.81%), and vitamins (99, 54.10%) for proper mitochondrial function. Mothers are the primary caregivers for both children (36.29%) and adults (38.98%). The mRS score ranged from 0 to 5, 92.35% of the patients had different degrees of disability due to mitochondrial disease. The average monthly treatment cost was 3000 RMB for children and 3100 RMB for adults.
    CONCLUSIONS: This study provided valuable insights into the characteristics and challenges of mitochondrial diseases, which underscores the need for improved awareness, diagnostic efficiency, and comprehensive support for patients and caregivers.
    Keywords:  Caregiver burden; Demographics; Diagnostic challenges; Disease burden; Mitochondrial disease; Treatment patterns
    DOI:  https://doi.org/10.1186/s13023-024-03289-5
  2. Res Involv Engagem. 2024 Jul 29. 10(1): 77
    Co-creating and hosting PxP: a conference about patient engagement in research for and by patient partners.
    Dawn P Richards, Hetty Mulhall, Joletta Belton, Savia de Souza, Trudy Flynn, Alex Haagaard, Linda Hunter, Amy Price, Sara Riggare, Janice Tufte, Rosie Twomey, Karim M Khan.
      Research projects, initiatives and conferences that include patients as partners rather than as participants are becoming more common. Including patients as partners (what we will call 'patient partners') is an approach called patient engagement or involvement in research, and we will call it patient engagement throughout this paper. Patient engagement moves traditional health research conferences and events to include a broader audience for their knowledge exchange and community building efforts, beyond academics and healthcare professionals. However, there are few examples of conferences where patients are given the opportunity to fully lead. Our conference went beyond patient engagement - it was patient-led. Patient partners conceived, planned, and decided on all aspects of a virtual conference.We present the work and processes we undertook throughout 2023 to create and produce a free conference called "PxP: For patients, by patients" or PxP for short, with a tagline of "Partnering to make research stronger." PxP was patient-led and about patient engagement in research rather than a specific disease or condition. PxP was supported by the Canadian Institutes of Health Research Institute of Musculoskeletal Health and Arthritis. The PxP website, known as the PxP Hub, now houses the conference recordings along with resources about patient engagement in research. These resources were recommended by the PxP Steering Committee members, speakers, and others who attended the 2023 conference. Here we lead you through how the idea for PxP was generated; how the international patient partner Steering Committee was convened and supported; how PxP was brought to life over nine months; the PxP 3-day event and feedback collected to improve future efforts; trade-offs, challenges and learnings; and resources required to support this type of event. We close with what the future holds for PxP in 2024 and beyond.It's time to elevate patients into leadership roles for conferences and events, and we encourage you to adopt the PxP ethos by using or adapting our approach and resources to support your opportunity.
    Keywords:  Co-production; Consumer involvement; Patient and public involvement; Patient author; Patient engagement in research; Patient partner; Patient-led conference; PatientsIncluded; Service user research
    DOI:  https://doi.org/10.1186/s40900-024-00603-0
  3. Ann Clin Transl Neurol. 2024 Aug 02.
    Mitochondrial DNA disorders in neuromuscular diseases in diverse populations.
    ICGNMD Consortium
      Neuromuscular features are common in mitochondrial DNA (mtDNA) disorders. The genetic architecture of mtDNA disorders in diverse populations is poorly understood. We analysed mtDNA variants from whole-exome sequencing data in neuromuscular patients from South Africa, Brazil, India, Turkey and Zambia. In 998 individuals, there were two definite diagnoses, two possible diagnoses and eight secondary findings. Surprisingly, common pathogenic mtDNA variants found in people of European ancestry were very rare. Whole-exome or -genome sequencing from undiagnosed patients with neuromuscular symptoms should be re-analysed for mtDNA variants, but the landscape of pathogenic mtDNA variants differs around the world.
    DOI:  https://doi.org/10.1002/acn3.52141
  4. Pediatr Radiol. 2024 Jul 27.
    Cranial and spinal nerve enhancement in SURF1-associated Leigh syndrome.
    Mhairi Dupré, Richard Warne, Peter Shipman, Maina Kava, Twinkle Ghia, Lily Loughman, Rahul Lakshmanan.
      A 23-month-old boy with poor growth, developmental delay, and hypotonia presented with acute onset of ataxia and fatigue. Magnetic resonance imaging (MRI) of the brain and spinal cord was performed as part of diagnostic work-up. MRI showed bilateral symmetrical lesions in basal ganglia, midbrain, and brainstem consistent with Leigh syndrome. Signal abnormalities were also present within the cervical cord, with enhancement of multiple cranial, spinal, and cauda equina nerve roots. Genetic testing confirmed compound heterozygosity for two pathogenic variants in SURF1 implicated in Leigh syndrome. Whilst nerve root enhancement has been described in other mitochondrial disorders, we believe this is the first published case of both cranial and spinal nerve root enhancement in Leigh syndrome.
    Keywords:   SURF1 ; Leigh syndrome; Magnetic resonance imaging; Mitochondrial disorders; Nerve enhancement; Pediatric
    DOI:  https://doi.org/10.1007/s00247-024-06005-4
  5. Front Neurol. 2024 ;15 1394150
    Two novel SUCLA2 variants cause mitochondrial DNA depletion syndrome, type 5 in two siblings.
    Xiaohuan Zhang, Guo Zhang, Li Cao, Wenjing Zhou, Chang Tan, Shi Ma, Jiyun Yang.
      Mitochondrial DNA depletion syndrome (MDS), characterized by succinate-CoA ligase deficiency and loss of mitochondrial DNA (mtDNA), is caused by specific variants in nuclear genes responsible for mtDNA maintenance. SUCLA2-related mitochondrial DNA depletion syndrome, type 5 (MTDPS-5), presents as a rare, severe early progressive encephalomyopathy. This report investigates a new family exhibiting clinical manifestations of MTDPS-5 and elucidates the genetic basis of this disorder. In two affected siblings, a novel maternally inherited nonsense variant [c.1234C>T (p.Arg412*)] in the SUCLA2 gene and a unique paternally inherited indel variant (g.48569263-48571020del1758insATGA) were identified. Additionally, the siblings exhibited blood mtDNA content lower than 33% compared to age-matched controls. These findings underscore the importance of assessing SUCLA2 variants in patients with severe early progressive encephalomyopathy, even in the absence of methylmalonic aciduria or mtDNA loss, thereby broaden the mutational spectrum of this gene.
    Keywords:  MTDPS-5; NGS; SUCLA2; mitochondrial DNA; mitochondrial succinate-CoA ligase; rare disease
    DOI:  https://doi.org/10.3389/fneur.2024.1394150
  6. Nat Aging. 2024 Jul 29.
    Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA.
    Yanfei Ru, Xiaoling Deng, Jiatong Chen, Leping Zhang, Zhe Xu, Qunyu Lv, Shiyun Long, Zijian Huang, Minghua Kong, Jing Guo, Min Jiang.
      Mitochondrial diseases, caused mainly by pathogenic mitochondrial DNA (mtDNA) mutations, pose major challenges due to the lack of effective treatments. Investigating the patterns of maternal transmission of mitochondrial diseases could pave the way for preventive approaches. In this study, we used DddA-derived cytosine base editors (DdCBEs) to generate two mouse models, each haboring a single pathogenic mutation in complex I genes (ND1 and ND5), replicating those found in human patients. Our findings revealed that both mutations are under strong purifying selection during maternal transmission and occur predominantly during postnatal oocyte maturation, with increased protein synthesis playing a vital role. Interestingly, we discovered that maternal age intensifies the purifying selection, suggesting that older maternal age may offer a protective effect against the transmission of deleterious mtDNA mutations, contradicting the conventional notion that maternal age correlates with increased transmitted mtDNA mutations. As collecting comprehensive clinical data is needed to understand the relationship between maternal age and transmission patterns in humans, our findings may have profound implications for reproductive counseling of mitochondrial diseases, especially those involving complex I gene mutations.
    DOI:  https://doi.org/10.1038/s43587-024-00672-6
  7. EClinicalMedicine. 2024 Aug;74 102740
    Safety and efficacy of deoxycytidine/deoxythymidine combination therapy in POLG-related disorders: 6-month interim results of an open-label, single arm, phase 2 trial.
    Heather Pekeles, Saoussen Berrahmoune, Christelle Dassi, Anthony C T Cheung, Tommy Gagnon, Paula J Waters, Ralf Eberhard, Daniela Buhas, Kenneth A Myers.
       Background: DNA polymerase gamma (POLG)-related disorders are a group of rare neurodegenerative mitochondrial diseases caused by pathogenic variants in POLG, the gene encoding POLG. Patients may experience a range of signs and symptoms, including seizures, vision loss, myopathy, neuropathy, developmental impairment or regression, and liver failure. The diseases follow a progressive, degenerative course, with most affected individuals dying within 3 months-12 years of diagnosis. At present, there are no effective treatments for POLG-related disorders.
    Methods: In this study we report the interim 6-month data from a long term open-label, single arm phase 2 trial, in which we assessed the safety and efficacy of combination therapy with deoxycytidine and deoxythymidine (dC/dT) in children with POLG-related disorders. dC/dT was given enterally in powder form, dissolved in water. The primary outcome measures included Newcastle Mitochondrial Disease Scale (NMDS) score, serum growth differentiation factor 15 (GDF-15; a biomarker of mitochondrial dysfunction), electroencephalography (EEG), seizure diary, and blood and urine tests to assess end organ and mitochondrial function. Secondary outcome measures included recording of all adverse events to evaluate the safety of the intervention. The trial is registered with ClinicalTrials.gov, NCT04802707 (https://clinicaltrials.gov/ct2/show/NCT04802707). Data were collected from 14 October, 2021 to 13 December, 2023.
    Findings: We present 6-month interim data from the first ten people with POLG-related disorders enrolled in the trial, six with Alpers-Huttenlocher syndrome, two with ataxia-neuropathy spectrum, and two who do not fit into a classical POLG-related phenotype. During the 6 months of treatment, NMDS score improved from a mean of 27.3 at baseline to 20.7 at 6 months (estimated difference 6.0; 95% CI 2.5-∞). GDF-15 values remained stable or decreased in all patients; the mean decreased from 1031 pg/ml to 729 pg/ml (estimated difference 200; 95% CI 12-∞). 8/10 patients had abnormal baseline EEG; improvement in EEG was seen in 5 of these 8. There were no significant changes in other blood and urine testing. Regarding adverse events, two patients experienced diarrhea that spontaneously resolved.
    Interpretation: dC/dT is a promising treatment option for people with POLG-related disorders. Further research is needed to assess the long-term safety and efficacy in POLG-related disorders, as well as safety and efficacy in other mitochondrial DNA depletion disorders.
    Funding: This study was primarily funded by the Liam Foundation, with additional funding from the Savoy Foundation, Grand Défi Pierre Lavoie Foundation, and Fonds de Recherche du Québec - Santé.
    Keywords:  Deoxycytidine; Deoxynucleosides; Deoxythymidine; POLG; Thymidine
    DOI:  https://doi.org/10.1016/j.eclinm.2024.102740
  8. Ther Adv Rare Dis. 2024 Jan-Dec;5:5 26330040241265411
    The role of the TSC Alliance in advancing therapy development: a patient organization perspective.
    Steven L Roberds, Zoë Fuchs, Elizabeth M Cassidy, Samantha Metzger, Ayat Abi, Ashley J Pounders, Dean J Aguiar.
      Tuberous sclerosis complex (TSC) is a genetic disease leading to malformations, or tubers, in the cerebral cortex and growth of tumors, most frequently in the brain, heart, kidneys, skin, and lungs. Changes in the brain caused by TSC usually have the biggest negative impact on quality of life. Approximately 85% of individuals with TSC have epilepsy, and TSC-associated neuropsychiatric disorders (TAND) affect nearly all individuals with TSC in some way. TSC Alliance's research strategy is built upon both funding and catalyzing research. Through grants, the organization provides funding directly to researchers through a competitive application process. The organization has also built a set of resources available to researchers worldwide, including a Natural History Database, Biosample Repository, and Preclinical Consortium. These resources catalyze research because they are available to qualified academic or industry researchers around the world, enabling an almost unlimited number of scientists to access data and resources to enable and accelerate research on TSC. This research strategy continues to be shaped by the needs and priorities of the TSC community, working toward a future where everyone affected by TSC can live their fullest lives.
    Keywords:  TSC Alliance; patient engagement; patient-centered research; research strategy; translational research; tuberous sclerosis complex
    DOI:  https://doi.org/10.1177/26330040241265411
  9. Diabetes Metab J. 2024 Jul;48(4): 818-819
    Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea (Diabetes Metab J 2024;48:482-6).
    Eun Hoo Rho, Soo Heon Kwak.
      
    DOI:  https://doi.org/10.4093/dmj.2024.0154
  10. J Biomed Inform. 2024 Jul 29. pii: S1532-0464(24)00120-5. [Epub ahead of print] 104702
    Rare disease diagnosis using knowledge guided retrieval augmentation for ChatGPT.
    Charlotte Zelin, Wendy K Chung, Mederic Jeanne, Gongbo Zhang, Chunhua Weng.
      Although rare diseases individually have a low prevalence, they collectively affect nearly 400 million individuals around the world. On average, it takes five years for an accurate rare disease diagnosis, but many patients remain undiagnosed or misdiagnosed. As machine learning technologies have been used to aid diagnostics in the past, this study aims to test ChatGPT's suitability for rare disease diagnostic support with the enhancement provided by Retrieval Augmented Generation (RAG). RareDxGPT, our enhanced ChatGPT model, supplies ChatGPT with information about 717 rare diseases from an external knowledge resource, the RareDis Corpus, through RAG. In RareDxGPT, when a query is entered, the three documents most relevant to the query in the RareDis Corpus are retrieved. Along with the query, they are returned to ChatGPT to provide a diagnosis. Additionally, phenotypes for thirty different diseases were extracted from free text from PubMed's Case Reports. They were each entered with three different prompt types: "prompt", "prompt + explanation" and "prompt + role play." The accuracy of ChatGPT and RareDxGPT with each prompt was then measured. With "Prompt", RareDxGPT had a 40 % accuracy, while ChatGPT 3.5 got 37 % of the cases correct. With "Prompt + Explanation", RareDxGPT had a 43 % accuracy, while ChatGPT 3.5 got 23 % of the cases correct. With "Prompt + Role Play", RareDxGPT had a 40 % accuracy, while ChatGPT 3.5 got 23 % of the cases correct. To conclude, ChatGPT, especially when supplying extra domain specific knowledge, demonstrates early potential for rare disease diagnosis with adjustments.
    Keywords:  Diagnostic Decision Support; Generative AI; Large Language Models; Rare Disease
    DOI:  https://doi.org/10.1016/j.jbi.2024.104702
  11. Am J Case Rep. 2024 Jul 31. 25 e944514
    Distinct Imaging Markers of Leigh's Disease Linked to SURF1 Mutation: A Pediatric Case Study.
    Rama Krishna Narra, Reshma Vemuri.
      BACKGROUND Leigh disease (LD) is a rare progressive mitochondrial neurodegenerative disorder characterized by subacute necrotizing encephalopathy and symmetrical spongiform lesions in the brain. Cytochrome C oxidase deficiencies due to SURF1 Cytochrome C Oxidase Assembly Factor (SURF1) gene mutations are seen only in 15% of LD cases. Consideration of these genetic mutations in young patients is crucial for early diagnosis, intervention, and further genetic counseling. Although only a few cases of the SURF1 mutation have been reported, there are anecdotal case reports describing imaging features. CASE REPORT We report a case of a 2-year-old boy with developmental delay, hypotonia, involuntary movements, shortness of breath, and reduced activity since age 6 months. On blood examination there was mildly elevated lactate levels and increased lactate to pyruvate ratio and cerebrospinal fluid lactate levels. Magnetic resonance imaging findings showed symmetrical lesions in the dentate nucleus, subthalamic nucleus, midbrain (substantia nigra, periaqueductal gray matter), posterolateral pons, and olivary nucleus of the medulla extending into the cervical spinal cord, with mild elevation of the lactate peak on magnetic resonance spectroscopy. CONCLUSIONS These findings prompted further genetic analysis, which indicated a mitochondrial type IV deficiency with the SURF1 gene defect, an intranuclear type 1 mutation (MC4DN1) (OMIM 220110). Treatment is usually supportive with vitamins supplementation and physiotherapy, and genetic counseling of the parents is mandatory.
    DOI:  https://doi.org/10.12659/AJCR.944514
  12. Trials. 2024 Aug 03. 25(1): 521
    Digital endpoints in clinical trials: emerging themes from a multi-stakeholder Knowledge Exchange event.
    Mia S Tackney, Amber Steele, Joseph Newman, Marie-Christine Fritzsche, Federica Lucivero, Zarnie Khadjesari, Jennifer Lynch, Rosemary A Abbott, Vicki S Barber, James R Carpenter, Bethan Copsey, Elin H Davies, William G Dixon, Lisa Fox, Javier González, Jessica Griffiths, Chloe H L Hinchliffe, Magdalena A Kolanko, Dylan McGagh, Aryelly Rodriguez, George Roussos, Karen B E So, Louise Stanton, Mark Toshner, Frances Varian, Paula R Williamson, Belay B Yimer, Sofía S Villar.
       BACKGROUND: Digital technologies, such as wearable devices and smartphone applications (apps), can enable the decentralisation of clinical trials by measuring endpoints in people's chosen locations rather than in traditional clinical settings. Digital endpoints can allow high-frequency and sensitive measurements of health outcomes compared to visit-based endpoints which provide an episodic snapshot of a person's health. However, there are underexplored challenges in this emerging space that require interdisciplinary and cross-sector collaboration. A multi-stakeholder Knowledge Exchange event was organised to facilitate conversations across silos within this research ecosystem.
    METHODS: A survey was sent to an initial list of stakeholders to identify potential discussion topics. Additional stakeholders were identified through iterative discussions on perspectives that needed representation. Co-design meetings with attendees were held to discuss the scope, format and ethos of the event. The event itself featured a cross-disciplinary selection of talks, a panel discussion, small-group discussions facilitated via a rolling seating plan and audience participation via Slido. A transcript was generated from the day, which, together with the output from Slido, provided a record of the day's discussions. Finally, meetings were held following the event to identify the key challenges for digital endpoints which emerged and reflections and recommendations for dissemination.
    RESULTS: Several challenges for digital endpoints were identified in the following areas: patient adherence and acceptability; algorithms and software for devices; design, analysis and conduct of clinical trials with digital endpoints; the environmental impact of digital endpoints; and the need for ongoing ethical support. Learnings taken for next generation events include the need to include additional stakeholder perspectives, such as those of funders and regulators, and the need for additional resources and facilitation to allow patient and public contributors to engage meaningfully during the event.
    CONCLUSIONS: The event emphasised the importance of consortium building and highlighted the critical role that collaborative, multi-disciplinary, and cross-sector efforts play in driving innovation in research design and strategic partnership building moving forward. This necessitates enhanced recognition by funders to support multi-stakeholder projects with patient involvement, standardised terminology, and the utilisation of open-source software.
    Keywords:  Clinical trials; Digital endpoints; Digital health technology; Multi-stakeholder engagement
    DOI:  https://doi.org/10.1186/s13063-024-08356-7
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