bims-curels 2023-10-15 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2023‒10‒15
eleven papers selected by
Cure Mito Foundation

The burden of mitochondrial disease with associated seizures: systematic literature reviews of health-related quality of life, utilities, costs and healthcare resource use data.
Diversities in Leigh Syndrome Associated with MT-ATP6 Gene Variants.
Determining Commonalities in the Experiences of Patients with Rare Diseases: A Qualitative Analysis of US Food and Drug Administration Patient Engagement Sessions.
Co-creation of the Global Patient Experience Data Navigator: a multi-stakeholder initiative to ensure the patient voice is represented in health decision-making.
Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey.
Encouraging diversity in family engagement in research: Reflections on the development of knowledge translation tools.
Seizure phenomenology in MELAS.
H - 17 Neuropsychological Assessment in Rare Pediatric Neurogenetic Disorders: Considerations for Clinical Research.
THE ROLE OF GENETICS IN DISEASE DIAGNOSIS AND TREATMENT MITOCHONDRIAL RESPIRATORY CHAIN DYSREGULATION IN GENOMIC MEDICINE.
Involving patients in healthcare research is well documented but can it work in lab-based research?
The First Reported Case of a Child with Two Different Rare Metabolic Disorders: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency and Encephalomyopathic Mitochondrial DNA Depletion Syndrome 13.

Orphanet J Rare Dis. 2023 Oct 11. 18(1): 320

The burden of mitochondrial disease with associated seizures: systematic literature reviews of health-related quality of life, utilities, costs and healthcare resource use data.

Enrico Bertini, Emily Gregg, Chris Bartlett, Vij Senthilnathan, Mick Arber, Deborah Watkins, Sara Graziadio, Ioannis Tomazos.

  BACKGROUND: Mitochondrial disease is a degenerative, progressive, heterogeneous group of genetic disorders affecting children and adults. Mitochondrial disease is associated with morbidity and mortality, with predominantly neurological and neuromuscular symptoms including dystonia, weakness, encephalopathy, developmental delay and seizures. Seizures are one of the most common and severe manifestations of mitochondrial disease. These seizures are typically refractory to common anti-seizure therapies. There are no approved disease-modifying treatments for mitochondrial disease. Our objective was to conduct two systematic literature reviews to identify health-related quality of life (HRQoL), utilities, costs and healthcare resource use data in mitochondrial disease with associated seizures.METHODS: A range of databases and information sources were searched up to July 2022 to identify eligible studies. Search strategies included a range of variant terms for mitochondrial disease and HRQoL, utilities, cost and healthcare resource use outcomes. Two reviewers independently assessed articles against the eligibility criteria; studies were extracted by one reviewer and checked by a second. Risk of bias was assessed for studies reporting HRQoL data. Results were narratively assessed.
RESULTS: Seven studies were eligible for the HRQoL and utilities review. The studies used different tools to report data, and despite the variability in methods, HRQoL scores across the studies showed moderate/severe disease in patients with mitochondrial disease with associated seizures. Parents of patients with mitochondrial disease with associated seizures were characterised by high total parenting stress. No studies reported utilities data. Two case reports and one retrospective review of medical records of children who died in hospital were eligible for the costs and resource use review. These provided limited information on the duration of hospital stay, in an intensive care unit (ICU), on mechanical ventilation. No studies reported costs data.
CONCLUSION: These reviews highlight the limited HRQoL, utilities, costs and resource use data and the variability of instruments used in mitochondrial disease with associated seizures. However, the data available indicate that mitochondrial disease with associated seizures affects patients' and caregivers' HRQoL alike. No robust conclusion can be drawn on the impact of mitochondrial disease with associated seizures on hospital or ICU length of stay. Trial registration PROSPERO: CRD42022345005.

Keywords:  Costs; Disease burden; Epilepsy; Health state utility values; Health-related quality of life; Healthcare resource use; Mitochondrial diseases; Seizures; Systematic literature reviews; Utilities

DOI:  https://doi.org/10.1186/s13023-023-02945-6
Endocr Metab Immune Disord Drug Targets. 2023 Oct 04.

Diversities in Leigh Syndrome Associated with MT-ATP6 Gene Variants.

Sara Martins, Maria João Santos, Marta Simões, Sandra Jacinto, Cristina Martins Halpern, Juliette Dupont, Luísa Diogo, Manuela Grazina.

  INTRODUCTION: Leigh syndrome (LS) is clinically and genetically heterogeneous and presents defective mitochondrial bioenergetics. Patients present neurological symptoms and imagiological features that may result in early death [1]. The LS has been associated with mitochondrial DNA (mtDNA) variants, e.g., m.8993T>G (L156R) and m.8993T>C (L156P), in the MT-ATP6 gene. They lead to the substitution of a highly conserved amino acid in subunit 6 of ATP synthase, affecting the F0 domain and ATP synthesis [1-3]. We present five cases with m.8993T>G and a family harbouring m.8993T>C+m.1555A>G (proband and four relatives).METHODS: Our laboratory received 48 samples from LS-suspected patients. The samples (various tissues) were assessed for bioenergetics (activity of mitochondrial respiratory chain (MRC) complexes, ubiquinone content) and genetic analyses (mtDNA copy number, Sequencing and PCR-RFLP) by established protocols.
RESULTS/CASE REPORT: Bioenergetics were assessed in 5 patients (various tissues) with varying levels of MRC/ATP synthase impairment. Six cases had a mtDNA pathogenic variant in the 8993 nucleotide associated with LS. Five cases presented the m.8993T>G variant, one of which (P5) possibly de novo. This variant was homoplasmy (P1-3) or very high heteroplasmy (P4/5, 90-95%). Of the four patients with bioenergetics assessment, three (P1/3/4) had deficiencies of MRC complexes, and P5 had small deficits. The other case (familial, proband and 4 relatives) presented a combination of m.1555A>G (homoplasmy) and m.8993T>C (heteroplasmy) variants. The proband presents m.8993T>C in 95% heteroplasmy and 85-35% in three relatives. All have m.1555A>G in homoplasmy, including the fourth relative without m.8993T>C. A deficiency (31%) was found in complex V activity in muscle for proband.
CONCLUSION: We present a case series of patients harbouring pathogenic variants in the 8993 nucleotide of mtDNA, which have been associated with LS and impairment of MRC's complex V. These cases highlight the variability in clinical symptoms and their severity, as well as genetic heterogeneity within LS. Many patients will not present a classic pathogenic variant and there are many cases of asymptomatic relatives (carriers). It is important to get a broader view of the cases - classical methods and multiple tissue analysis are still valuable tools for the comprehensive characterization of patients.

Keywords:  Leigh syndrome; disease heterogeneity; methodology; mitochondrial cytopathies; mtDNA; pathogenic sequence variants

DOI:  https://doi.org/10.2174/0118715303273271230928060000
Patient. 2023 Oct 13.

Determining Commonalities in the Experiences of Patients with Rare Diseases: A Qualitative Analysis of US Food and Drug Administration Patient Engagement Sessions.

Catherine Mease, Lewis J Fermaglich, Karen Jackler, Shawn Shermer, Kathleen L Miller.

BACKGROUND: Rare diseases are estimated to affect more than one in ten Americans. However, most patients with a rare disease face significant emotional, physical, and social challenges. To better understand the burden of disease and unmet needs, the US Food and Drug Administration (FDA) conducts and supports multiple patient engagement platforms. We analyzed summaries from these discussions to identify commonalities among patients with disparate rare diseases, the results of which could inform priorities for cross-disease policies and medical product development.METHODS: We conducted a qualitative analysis of patient engagement session summaries to investigate shared experiences across rare diseases. Cross-disease similarities were identified within four dimensions: product development/regulatory, clinical/physical, social/psychological, and economic/financial. Summaries from 29 rare diseases were included in our analyses.
RESULTS: Within the product development/regulatory dimension, we observed that patients and caregivers across rare diseases shared the desire for development of medical products that cured their disease or improved their overall quality of life. In the clinical/physical dimension, we found that patients had numerous common symptoms, including pain and fatigue. In the social/psychological dimension, we observed significant negative impact on mental health. Within the economic/financial dimension, patients and caregivers shared that disease burden caused significant financial hardships.
CONCLUSION: We found remarkable similarities among patients with rare diseases across all four dimensions. Our results indicate that, even among rare diseases with diverse etiologies, patients share numerous commonalties due to their diseases: a lack of effective treatment options, certain physical symptoms, mental health challenges, and financial concerns.

DOI: https://doi.org/10.1007/s40271-023-00648-5
Res Involv Engagem. 2023 Oct 12. 9(1): 92

Co-creation of the Global Patient Experience Data Navigator: a multi-stakeholder initiative to ensure the patient voice is represented in health decision-making.

Tom Willgoss, Omar A Escontrias, Carole Scrafton, Elisabeth Oehrlein, Victoria Livingstone, Fiona C Chaplin, Maddalena Benivento, Hayley Chapman, Nicholas Brooke.

  BACKGROUND: Putting patients' needs and priorities at the forefront of healthcare initiatives and medical product development is critical to achieve outcomes that matter most to patients. This relies on the integration of early, meaningful patient engagement (PE) to learn what is important to patients, and collection of representative patient experience data (PXD). The increased number of PE/PXD efforts across global regulatory, health technology assessment, and healthcare systems is an important step forward to deliver improved health outcomes for patients. However, these initiatives are fragmented and lack integration, which is necessary to maximize efforts and reduce burden on patients. To overcome these challenges, the Global Patient Experience Data Navigator has been co-created by Patient Focused Medicines Development to provide practical resources that can facilitate and optimize PXD generation, collection, analysis, and dissemination for patient benefit and aims to be applicable across all therapeutic areas for all stakeholders.METHODS: Co-creation of the Navigator took place through an iterative process of validation and formalization driven by a diverse, multi-stakeholder working group with individuals who have varying knowledge/experience in PE/PXD.
RESULTS: A series of workshops took place to conduct a gap analysis, develop a taxonomy model, and integrate existing frameworks. The collective insights led to the development of the Navigator consisting of four specific tools in the form of downloadable templates, which can be used to: (1) prioritize outcomes that matter most to patients and their caregivers; (2) select appropriate measurement methods for these outcomes; (3) identify when and why PXD is used throughout the product development cycle for each stakeholder; (4) identify when and why PXD is used throughout the healthcare process for each stakeholder. A public consultation was carried out to collect user feedback before the Navigator was made publicly available in December 2022.
CONCLUSION: To our knowledge, the Global Patient Experience Data Navigator is the only publicly available toolkit developed with a multi-stakeholder and disease-agnostic approach providing taxonomically grouped resources to optimize the collection and collation of PXD for patient benefit. Future work will aim to further engage patients by adding a PE dimension to the Navigator.

Keywords:  Healthcare; Medical, pharmaceutical, and technology development; Patient engagement; Patient experience data; Patient-centered care; Patient-generated data; Patient-preference studies; Patient-reported outcomes; Public and patient involvement

DOI:  https://doi.org/10.1186/s40900-023-00503-9
J Neurol. 2023 Oct 13.

Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey.

Michelangelo Mancuso, Piervito Lopriore, Costanza Lamperti, Thomas Klopstock, Shamima Rahman, Laura Licchetta, Cornelia Kornblum, Saskia B Wortmann, Hélène Dollfus, Maria T Papadopoulou, Alexis Arzimanoglou, Maurizio Scarpa, Holm Graessner, Teresinha Evangelista.

  BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey.METHODS: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe.
RESULTS: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases.
CONCLUSIONS: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities.

Keywords:  Europe; European Reference Networks; Mitochondrial diseases; Rare diseases; Survey

DOI:  https://doi.org/10.1007/s00415-023-12017-1
Res Involv Engagem. 2023 Oct 13. 9(1): 94

Encouraging diversity in family engagement in research: Reflections on the development of knowledge translation tools.

Janet W T Mah, Katie Nickerson.

  BACKGROUND: Family engagement in research is crucial to generating relevant, impactful, and meaningful priorities and outcomes. Although there has been increased awareness and value for patient-oriented research, most patient partners in North America are from Western, educated, industrialized, rich and democratic societies. Encouraging underserviced and marginalized populations to join the partnerships is important. This project demonstrates the development of two knowledge translation tools created to encourage diversity in patient-family and researcher partnerships.CASE STUDY: Our diverse cross-Canadian team embodies the family-researcher partnership as it consists of two research personnel from non-Western origins with immigrant experiences, a parent with lived experience, and a project director. All group members have experience in the field of mental health and neurodevelopmental conditions. Four infographics were created: 3 patient-oriented ones (in English, Chinese, and Farsi) and 1 researcher-targeted one. Content for the infographics were generated to address common barriers to patient engagement identified from literature reviews, as well as key concepts discussed during the McMaster University Continuing Education Family Engagement in Research Certificate Course sponsored by CanChild & Kids Brain Health Network. Peer consultations helped to improve the infographics to be more culturally sensitive and appealing. The patient-oriented infographic presents concise bullet points about 5 main topics: (1) what is research, (2) reasons to join, (3) your role, (4) talking to researchers, and (5) how to join. The researcher-targeted infographic presents concise bullet points about 4 topics: 1) why team up with diverse patient partners, (2) ways to partner, (3) how to connect, and (4) talking to diverse partners.
CONCLUSION: Infographics were co-designed to encourage diversity in family engagement in research. Lessons learned throughout the project include barriers encountered (e.g., team collaboration considerations, design limitations) and strategies that facilitated the project (e.g., online collaboration platforms). Future directions include translations into other languages, increased dissemination across agencies, and evaluating the effectiveness of the infographic tools.

Keywords:  Diversity; Family engagement; Partnerships; Patient-oriented research

DOI:  https://doi.org/10.1186/s40900-023-00486-7
Seizure. 2023 Oct;pii: S1059-1311(23)00062-6. [Epub ahead of print]111 223-224

Seizure phenomenology in MELAS.

Josef Finsterer, Sounira Mehri.



Keywords:  Heteroplasmy; MELAS; Respiratory chain; Seizures; Stroke-like episode; mtDNA

DOI:  https://doi.org/10.1016/j.seizure.2023.03.001
Arch Clin Neuropsychol. 2023 Oct 08. pii: acad067.335. [Epub ahead of print]

H - 17 Neuropsychological Assessment in Rare Pediatric Neurogenetic Disorders: Considerations for Clinical Research.

Karen A Dorsman, Beatriz MacDonald, Souad Messahel, Daniel Horton, Veronica Bordes Edgar.

OBJECTIVE: Approximately 80% of rare diseases in childhood have a genetic cause. Neuropsychological assessments offer a greater understanding of the clinical presentation and trajectory of neurogenetic disorders. Given the rarity of the conditions, the limited funding allocated to study psychosocial factors, the diversity within the patient populations (e.g., country of origin, clinical phenotypes), and the limitations of our tools, there are no clear guidelines for evaluations. We aim to present a systematic approach to create assessment protocols that track disease progression and/or efficacy of therapeutic interventions.METHOD: Our gene therapy program has created nine assessment protocols to evaluate conditions ranging from epileptic encephalopathies, lysosomal storage, neuromuscular, and mitochondrial diseases. Through review of past protocols, we created a neuropsychological assessment selection checklist (NASC) and standard operating procedure (SOP) checklist.
RESULTS: The NASC systematizes updated multidisciplinary disease knowledge and relevant desirable outcomes (e.g., cognitive, motor, quality of life). Cultural elements (e.g., beliefs around health, disease, testing) and necessary accommodations (e.g., interpreters, sensory impairments) must be considered. Additional sociocultural and socioeconomic information of the sample is germane not only to contextualize results but also to help narrow possible tools. The SOP aims to increase standardization (e.g., starting points) and maximize use of the data collected (e.g., deferment reasons.).
CONCLUSIONS: Neuropsychological assessments offer a wealth of cognitive, behavioral, emotional, and adaptive functioning data that is crucial to better understand the progression and treatment of rare neurogenetic diseases. Cultural considerations and in-depth clinical and assessment skills are essential to creating evaluation protocols that are valid, useful, and comprehensive.

DOI: https://doi.org/10.1093/arclin/acad067.335
Georgian Med News. 2023 Jul-Aug;(340-341): 217-226

THE ROLE OF GENETICS IN DISEASE DIAGNOSIS AND TREATMENT MITOCHONDRIAL RESPIRATORY CHAIN DYSREGULATION IN GENOMIC MEDICINE.

G Patel M, B Varshini, A Mandal, D Krishna, V Rastogi, M Varma.

Although mitochondrial DNA respiration circuit abnormalities are among the most common metabolic diseases to manifest in children, identification can be difficult due to their medical variability. Given the multisystem nature of the condition and its diverse and generalized manifestations, making a final diagnosis often takes a long time. Within this summary, they give an in-depth account of the physical signs of adolescent Mitochondrial Respiratory Chain Disorders (MRCDs),analyze the available diagnostics and treatment possibilities, and emphasize current developments in this field of study. During the discovery of fresh biomarkers and the development of next generation sequencing (NGS) technology, extensive research over the years has considerably enhanced the regularity that precise diagnoses are produced. Given the intricate nature of mitochondrial DNA biology and its double genomic investments, Sequencing has made significant progress in identifying the genetic basis of Mitochondrial Respiratory Chain Disorders (MRCDs). Research studies have been created employing a variety of various methods of therapy in an effort to shift the goal on therapy that is mainly curative to possibly having a positive impact on the natural course of the trouble. That's because there is gained a greater awareness of the underlying causes of this category of ailments.
Res Involv Engagem. 2023 Oct 12. 9(1): 90

Involving patients in healthcare research is well documented but can it work in lab-based research?

Adele E Connor, Claire Hughes, Lea Schäfer, Lorraine McNally, Deirdre O' Raw, Katayoun Bahramian, Bridget Carr, Ingrid Halligan Dunne, Joanne Lysaght, Sharon A O' Toole, Jeremy C Simpson, Antoinette S Perry.

  Public and Patient Involvement in research is becoming a requirement on most research funding applications; this includes both healthcare and lab-based research. Whilst case studies and practical guides have been developed and are well documented for PPI in healthcare research, there is very little guidance available for PPI in lab-based research. In this piece we discuss our experience of how we have successfully involved patients in our translational cancer research, which is focused on developing personalised treatment for high-grade serous ovarian cancer. We discuss the benefits it has made to both our research and to us as researchers. The patients involved write about their experience, what they enjoyed, and the benefits they felt. Although PPI is quite topical and is being widely discussed, there is hesitancy among researchers, especially those in lab-based research about getting started because of a lack of practical guidance about how to implement it. Here, we have shared our experience, hopefully providing a practical example of how PPI can be incorporated into a lab-based research project.

Keywords:  Ovarian cancer; PPI; Precision medicine; Translational research

DOI:  https://doi.org/10.1186/s40900-023-00500-y
Glob Med Genet. 2023 Dec;10(4): 278-281

The First Reported Case of a Child with Two Different Rare Metabolic Disorders: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency and Encephalomyopathic Mitochondrial DNA Depletion Syndrome 13.

Maha Alotaibi, Amal Alqasmi, Faisal Albassam, Turki Alkahtani, Muath Alqahtany, Mohammed Alkhaldi.

  One of the most common inborn errors in fatty acid β oxidation (FAO) is a very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency. It is autosomal recessive. The enzyme used in the first phase of FAO is VLCAD. The enzyme is responsible for β oxidation spiral pathway's initial step, the dehydrogenation process of long-chain fatty acyl-CoA. The phenotypes include hypoglycemia, hepatomegaly, cardiomyopathy, and occasionally abrupt mortality. Most VLCAD deficiencies in newborns are now detected during the neonatal period due to the development of newborn screening programs. Mitochondrial DNA depletion syndromes (MTDPS) are one of the rarest metabolic disorders. It is an autosomal recessive disease caused by defects in genes necessary for the maintenance of mitochondrial DNA (mtDNA). One of these FBXL4 (F-box and leucine-rich repeat protein 4) variants causes encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), which presents as a failure to thrive, severe global developmental delay, hypotonia, early infantile onset of encephalopathy, and lactic acidosis. We report here the case of a Saudi infant born to consanguineous parents who presented to us with severe failure to thrive, profound neurodevelopmental delays, and facial dysmorphic features. Whole-exome sequencing (WES) showed the infants had MTDPS13. The FBXL4 variant c.1698A > G p. (Ile566Met) has previously been described as a disease that causes developmental delay and lactic acidosis, and another variant has also been detected in the patient. The ACADVL variant c.134C > A p. (Ser45*) has previously been described to cause VLCAD deficiency. A comprehensive literature review showed our patient to be the first case of MTDPS13 and VLCAD reported to date worldwide.

Keywords:  FBXL4; hypoglycemia; mitochondrial DNA; mitochondrial diseases; pediatric genetics; very long-chain acyl-CoA dehydrogenase deficiency

DOI:  https://doi.org/10.1055/s-0043-1775979