bims-curels Biomed News
on Leigh syndrome
Issue of 2023–12–24
eleven papers selected by
Cure Mito Foundation
  1. Comment on "Reflections on patient engagement by patient partners: How it can go wrong".
  2. Patient Engagement in Research: Considerations in Creating a Registry for Adults with Congenital Heart Disease.
  3. The West of Scotland Cohort of Mitochondrial Individuals with the m.3243A>G Variant: Variations in Phenotypes and Predictors of Disease Severity.
  4. Challenges in Genetic Diagnosis of Mitochondrial Diseases: What Can Functional Genomics' Studies Do?
  5. The power of language: how to bridge the gap between healthcare research and patients: a scoping review.
  6. Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals.
  7. Pre-implantation Genetic Testing in Inherited Metabolic Diseases? Stateof- the-art and current challenges.
  8. Caregiving experiences of caregivers of children with rare diseases: A qualitative meta-synthesis.
  9. A rare cause of anejaculation: mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome: case report.
  10. A Case Report of SYNE1 Deficiency-Mimicking Mitochondrial Disease and the Value of Pangenomic Investigations.
  11. A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies.
  1. Res Involv Engagem. 2023 Dec 22. 9(1): 122
    Comment on "Reflections on patient engagement by patient partners: How it can go wrong".
    Paola Zaratin, Usman Khan, Guendalina Graffigna.
      As patient-advocacy, public policy and clinical researchers with special knowledge on Responsible Research Innovation (RRI) governance and the public health and psychology underlying patient engagement, we read with interest the comment contribution by Richards et al., "Reflections on patient engagement by patient partners: How it can go wrong" (Richards et al. in Res Involv Engagem 9:41, 2023. https://doi.org/10.1186/s40900-023-00454-13 ). As a way to help meet the "take-away actions for readers" included by the authors at the end of the article, we would like to further stimulate discussion with relevant stakeholder communities about the need to rethink the use of "expert patient". Based on our experience, the lack of a governance model engaging patients who are representative of the target patient community, as opposed to expert patients, is at the root of the tokenistic approach, the "patient partner as a checkmark statement" and the "lack of recognizing the vulnerability of patient partners", which results in "patient engagement going wrong". According to our experience, the Responsible Research Innovation (RRI) MULTI-ACT model has the potential to help meet these challenges.
    Keywords:  Participatory governance model; Patient engagement, tokenism; Responsible research innovation
    DOI:  https://doi.org/10.1186/s40900-023-00534-2
  2. Curr Cardiol Rep. 2023 Dec 22.
    Patient Engagement in Research: Considerations in Creating a Registry for Adults with Congenital Heart Disease.
    Ruth Phillippi, Scott Leezer, Mindi Messmer, Danielle Hile, Anitha S John.
       PURPOSE OF REVIEW: Patient engagement is defined as the meaningful involvement and active partnership of patients and key partners throughout the entire research project. This article reviews the importance of developing a patient engagement plan to promote better alignment of research with patients' and clinicians' real-world needs and concerns.
    RECENT FINDINGS: The Congenital Heart Initiative (CHI) launched in 2020 is an entirely web-based longitudinal registry designed in close coordination with the adult congenital heart disease (ACHD) community it is intended to serve. Successful community engagement has resulted in real-world data being collected in large scale in a rare disease population. Establishing patient engagement plans is critical to conducting patient-centered outcomes research. Continued improvement of community engagement strategies is needed to ensure the entire ACHD population is represented to facilitate future research and improved clinical care.
    Keywords:  Congenital heart disease; Patient engagement; Registry
    DOI:  https://doi.org/10.1007/s11886-023-02013-2
  3. J Neuromuscul Dis. 2023 Dec 13.
    The West of Scotland Cohort of Mitochondrial Individuals with the m.3243A>G Variant: Variations in Phenotypes and Predictors of Disease Severity.
    Charlie Saunders, Cheryl Longman, Grainne Gorman, Kelly James, Agata Oliwa, Richard Petty, Lesley Snadden, Maria Elena Farrugia.
       BACKGROUND: The m.3243A>G variant is the commonest mitochondrial (mt) DNA pathogenic variant and a frequent cause of mitochondrial disease. Individuals present with a variety of clinical manifestations from diabetes to neurological events resembling strokes. Due to this, patients are commonly cared for by a multidisciplinary team.
    OBJECTIVES: This project aimed to identify patients with confirmed mt.3243A>G-related mitochondrial disease attending the Muscle Clinic at Queen Elizabeth University Hospital in Glasgow. We explored potential correlates between clinical phenotypes and mtDNA heteroplasmy levels, HbA1c levels, body mass index, and specific clinical manifestations. We investigated if there were discrepancies between non-neurological speciality labelling in clinical records and individuals' phenotypes.
    METHODS: Data were gathered from the West of Scotland electronic records. Phenotypes were ascertained by a clinician with expertise in mitochondrial disorders. Statistical analyses were applied to study relationships between tissue heteroplasmy, HbA1c and clinical phenotypes including body mass index (BMI).
    RESULTS: Forty-six individuals were identified from 31 unrelated pedigrees. Maternally inherited diabetes and deafness was the prominent syndromic phenotype (48%). A significant association was found between overall number of symptoms and bowel dysmotility (p <  0.01). HbA1c was investigated as a predictor of severity with potential association seen. Although used widely as a prognosticator, neither corrected blood nor urine mtDNA heteroplasmy levels were associated with increased number of symptoms. In 74.1% of records, syndromic phenotypes were incorrectly used by non-neurological specialities.
    CONCLUSIONS: This m.3243 A >  G patient cohort present with marked clinical heterogeneity. Urine and blood heteroplasmy levels are not reliable predictors of disease severity. HbA1c may be a novel predictor of disease severity with further research required to investigate this association. We infer that prognosis may be worse in patients with low BMIs and in those with bowel dysmotility. These results underscore a multidisciplinary approach and highlight a problem with inaccurate use of the existing nomenclature.
    Keywords:  Epidemiology; m.3243A>G; mitochondrial DNA; mitochondrial conditions; multidisciplinary team
    DOI:  https://doi.org/10.3233/JND-230166
  4. Endocr Metab Immune Disord Drug Targets. 2023 Dec 18.
    Challenges in Genetic Diagnosis of Mitochondrial Diseases: What Can Functional Genomics' Studies Do?
    Marta Simões, Maria João Santos, Sara Martins, Maria do Carmo Macário, João Durães, Luísa Diogo, João Paulo Oliveira, José Carlos Ferreira, Manuela Grazina.
       INTRODUCTION: Mitochondrial oxidative phosphorylation (OXPHOS) diseases are challenging both from clinical and therapeutic perspectives. The advent of next-generation sequencing (NGS) boosted the discovery of new genetic defects affecting OXPHOS, with pathogenic variants identified in >350 genes to date [1]. However, in many patients, novel variants of unknown clinical significance are found. Subsequent functional studies may clarify its pathogenic consequences and modify the variant's classification, establishing a genetic diagnosis [2, 3].
    METHODS: Analysis of data obtained from patients (P1-P5) with novel genetic causes and functional genomics' studies performed, namely OXPHOS respiratory/glycolytic rates (Seahorse XF), enzymatic activity and assembly (BN-page), protein levels (SDS-WB), single muscle fiber assay, NGS and bioinformatics.
    RESULTS/CASE REPORT: P1-Leigh syndrome (40y, male); Complex IV activity deficiency (full assembly absent), homozygous deletion (c.-11_13del, SURF1), not detected by NGS[2]. P2- Epileptic encephalopathy (8y, male); homozygous c.882-1G>A, FASTKD2; OXPHOS decrease; reduced FASTKD2 expression and abnormal respiratory/glycolytic rates. P3-Cardiomyopathy/ nephropathy (39y, male); c.29G>C, FASTKD2; OXPHOS decrease; reduced FASTKD2 levels. P4-CPEO (62y, female); multiple OXPHOS deficiency; mtDNA alterations (m.7486G>A, MTTS1; 4,977bp del); higher levels of mutant mtDNA alterations in COX-deficient fibers [3]. P5- Polyneuropathy (15y, female); heterozygous c.1437C>A, POLG; combined def. or normal OXPHOS activity/respiratory capacity (tissue variable), raised CI assembly; normal POLG levels. Also, proteins' expression levels were reduced (P1-4), confirming pathogenicity. In P5, data do not support pathogenicity.
    CONCLUSION: If specific functional results are similar to controls, one might inquire about the pathogenicity of the studied variant and more genetic or bioinformatics analyses and family investigations are needed. There are also limitations of NGS in mutation detection that Sanger sequencing can overcome (P1). When performed first, the OXPHOS activity may guide to genetic screening or interpretation, concordant to later assembly results. All cases were solved and data may be crucial for genetic counseling.
    Keywords:  OXPHOS; functional genomics; laboratorial diagnosis; methodology; mitochondrial cytopathies; rare diseases
    DOI:  https://doi.org/10.2174/0118715303273290231211062420
  5. Curr Med Res Opin. 2023 Dec 22. 1-25
    The power of language: how to bridge the gap between healthcare research and patients: a scoping review.
    Sally-Anne Dews, Rachel Daley, Akhil Bansal, Jennifer Preston, Natalie Bohm.
      Objective: The value of patient involvement to the design, conduct, and outcomes of healthcare research is increasingly being recognized. Patient involvement also provides greater patient accessibility and contribution to research. However, the use of inaccessible and technical language when communicating with patients is a barrier to effective patient involvement.Methods: We analyzed peer-reviewed and gray literature on how language is used in communication between healthcare researchers and patients. We used this analysis to generate a set of recommendations for healthcare researchers about using more inclusive and accessible language when involving patients in research. This scoping review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for Scoping Review (PRISMA-ScR) checklist.Results: Four major themes about the use of language were developed from the literature analysis and were used to develop the set of recommendations. These recommendations include guidance on using standardized terminology and plain language when involving patients in healthcare research. They also discuss the implementation of co-development practices, patient support initiatives, and researcher training, as well as ways to improve emotional awareness and the need for greater equality, diversity, and inclusion.Discussion and Conclusion: The use of inclusive, empathetic, and clear language can encourage patients to be involved in research and, once they are involved, make them feel like equal, empowered, and valued partners. Working toward developing processes and guidelines for the use of language that enables an equal partnership between researchers and patients is critical.
    Keywords:  Patient involvement; language; patient engagement
    DOI:  https://doi.org/10.1080/03007995.2023.2295984
  6. Front Neurol. 2023 ;14 1292320
    Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals.
    Toby Charles Major, Eszter Sara Arany, Katherine Schon, Magdolna Simo, Veronika Karcagi, Jelle van den Ameele, Patrick Yu Wai Man, Patrick F Chinnery, Catarina Olimpio, Rita Horvath.
       Background: Leber Hereditary Optic Neuropathy (LHON) is the most common inherited mitochondrial disease characterized by bilateral, painless, subacute visual loss with a peak age of onset in the second to third decade. Historically, LHON was thought to be exclusively maternally inherited due to mutations in mitochondrial DNA (mtDNA); however, recent studies have identified an autosomal recessive form of LHON (arLHON) caused by point mutations in the nuclear gene, DNAJC30.
    Case Presentations: In this study, we report the cases of three Eastern European individuals presenting with bilateral painless visual loss, one of whom was also exhibiting motor symptoms. After a several-year-long diagnostic journey, all three patients were found to carry the homozygous c.152A>G (p.Tyr51Cys) mutation in DNAJC30. This has been identified as the most common arLHON pathogenic variant and has been shown to exhibit a significant founder effect amongst Eastern European individuals.
    Conclusion: This finding adds to the growing cohort of patients with arLHON and demonstrates the importance of DNAJC30 screening in patients with molecularly undiagnosed LHON, particularly in Eastern European individuals. It is of heightened translational significance as patients diagnosed with arLHON exhibit a better prognosis and response to therapeutic treatment with the co-enzyme Q10 analog idebenone.
    Keywords:  DNA-J heat shock protein family (Hsp40) member C30 (DNAJC30); Leber hereditary optic neuropathy (LHON); autosomal recessive LHON (arLHON); c.152A>G (p.Tyr51Cys); idebenone; mitochondrial LHON (mtLHON); recessive optic neuropathy
    DOI:  https://doi.org/10.3389/fneur.2023.1292320
  7. Endocr Metab Immune Disord Drug Targets. 2023 Dec 18.
    Pre-implantation Genetic Testing in Inherited Metabolic Diseases? Stateof- the-art and current challenges.
    Ana Miguel Capela, Ana Cunha, Ana Maria Fortuna, Cláudia Falcão Reis.
       INTRODUCTION: Inborn errors of metabolism (IEM) are genetic diseases involving congenital disorders of enzyme activities. Most follow Mendelian autosomal recessive inheritance and few follow mitochondrial inheritance. In many cases, after the birth of an affected child parents discover that have been the carriers for the condition and worry about the risk of recurrence in future offspring. Preimplantation genetic testing (PGT) can analyze embryos before their transfer to the uterus and prevent the transmission of hereditary conditions to descendants, however this procedure is of limited value in mtDNA conditions.
    METHODS: The list of diseases currently approved for PGT were reviewed. The process for eligibility, was as for the Comissão Nacional Procriação Medicamente Assistida (CNPMA), of Portugal (PT). Review of international practices for Assisted Reproductive Techniques (ART) in IEM was carried out.
    RESULTS: As of 07.2022, 23 IEM diseases associated with deleterious variants in nDNA were approved for PGT in PT. Couples at risk for conditions not included in the list can solicit an evaluation from an expert committee, after a medical genetics consultation. To qualify for approval, diseases must cause significant suffering and/or premature death. Due to a greater number of solicitations many more IEM conditions have been approved for PGT across the world. ART for mtDNA is not available in PT. International expert centers include PGT for specific well documented variants and mitochondrial donation.
    CONCLUSION: PGT is a reliable approach to reduce the risk of transmission of a genetic condition to the offspring. The list of IEM disorders currently accepted for this technique in Portugal are small, but it is expanding, as many more diseases fit the necessary criteria. While appealing in theory, low success rates coupled with limited availability can be discouraging for patients. Genetic counselling is of paramount importance after the diagnosis of IEM diseases. It is important for both clinicians and patients to be made aware of the available reproductive options and their limitations.
    Keywords:  Assisted Reproductive Techniques (ART); Genetic counselling; Inborn errors of metabolism (IEM); Preimplantation genetic testing (PGT); mtDNA
    DOI:  https://doi.org/10.2174/0118715303279986231211090830
  8. J Pediatr Nurs. 2023 Dec 14. pii: S0882-5963(23)00361-5. [Epub ahead of print]75 31-40
    Caregiving experiences of caregivers of children with rare diseases: A qualitative meta-synthesis.
    Chenxi Wu, Xin Chu, Kexin Tang, Dongmei Cheng, Liangjuan Ren.
       PROBLEM: Most rare diseases occur in childhood and are difficult to diagnose and treat. The caregivers are faced with the challenge of providing care to the children afflicted with these rare diseases, resulting in a significant burden of care and an altered family dynamic.
    ELIGIBILITY CRITERIA: A meta-synthesis review was conducted to explore the caregivers' experience of children with rare diseases using eight electronic databases PubMed, Web of Science, the Cochrane Library, EMBASE, VIP database, Wan Fang, Chinese BioMedical Literature Database, and China National Knowledge Infrastructure from each database's inception to October 5, 2023.
    SAMPLE: 4207 records were identified and 20 eligible studies were included.
    RESULTS: Three themes emerged: (1) Life is changed by "rare"; (2) many unmet needs; (3) Strive to adapt and grow.
    CONCLUSIONS: Caregivers of children with rare diseases are full of stress and challenges in the process of caring for them, and their lives have changed greatly due to "rare". Appropriate measures need to be taken to reduce the burden on caregivers.
    IMPLICATIONS: According to the findings, both the medical and health systems, as well as society, should pay attention to the care load and unmet requirements of carers of children with rare diseases, and offer them with practical supportive services. Finally, it can improve the quality of life for caregivers and families of children with rare diseases, as well as stimulate the development of rare diseases.
    Keywords:  Caregiver; Children; Experience; Qualitative meta-synthesis; Rare diseases
    DOI:  https://doi.org/10.1016/j.pedn.2023.12.003
  9. Int J Impot Res. 2023 Dec 21.
    A rare cause of anejaculation: mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome: case report.
    Selman Unal.
      Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is an extremely rare multisystem disorder with autosomal recessive inheritance and impairs mitochondrial DNA replication, which causes myopathy and neurodegeneration. The classical symptoms of this syndrome are progressive gastrointestinal dysmotility and peripheral neuropathy. We are presenting a patient who had MNGIE syndrome and presented with anejaculation for the first time in the literature. A 27-year-old male patient applied to the urology clinic with anejaculation. It was learned that the patient had lifelong anejaculation and had no problems with libido, erection, or orgasm from his sexual history. In the evaluation of the etiology of anejaculation, the patient did not have any known causes of anejaculation. From the patient's medical history, it was learned that he was diagnosed with MNGIE syndrome when he presented to another hospital with gastrointestinal symptoms 5 years ago. Neurodegenerative diseases are the potential cause of anejaculation due to sensorimotor neuropathy and paresthesia. The patient was given genetic counseling and was informed about assisted reproductive techniques and that his partner should be screened for MNGIE syndrome. In conclusion, when evaluating neurodegenerative diseases, it is of great importance to question the patients' sexual problems, which are important for their quality of life, and to provide appropriate counseling.
    DOI:  https://doi.org/10.1038/s41443-023-00813-2
  10. Genes (Basel). 2023 Nov 29. pii: 2154. [Epub ahead of print]14(12):
    A Case Report of SYNE1 Deficiency-Mimicking Mitochondrial Disease and the Value of Pangenomic Investigations.
    Mounir Serag, Morgane Plutino, Perrine Charles, Jean-Philippe Azulay, Annabelle Chaussenot, Véronique Paquis-Flucklinger, Samira Ait-El-Mkadem Saadi, Cécile Rouzier.
      Mitochondrial disorders are characterized by a huge clinical, biochemical, and genetic heterogeneity, which poses significant diagnostic challenges. Several studies report that more than 50% of patients with suspected mitochondrial disease could have a non-mitochondrial disorder. Thus, only the identification of the causative pathogenic variant can confirm the diagnosis. Herein, we describe the diagnostic journey of a family suspected of having a mitochondrial disorder who were referred to our Genetics Department. The proband presented with the association of cerebellar ataxia, COX-negative fibers on muscle histology, and mtDNA deletions. Whole exome sequencing (WES), supplemented by a high-resolution array, comparative genomic hybridization (array-CGH), allowed us to identify two pathogenic variants in the non-mitochondrial SYNE1 gene. The proband and her affected sister were found to be compound heterozygous for a known nonsense variant (c.13258C>T, p.(Arg4420Ter)), and a large intragenic deletion that was predicted to result in a loss of function. To our knowledge, this is the first report of a large intragenic deletion of SYNE1 in patients with cerebellar ataxia (ARCA1). This report highlights the interest in a pangenomic approach to identify the genetic basis in heterogeneous neuromuscular patients with the possible cause of mitochondrial disease. Moreover, even rare copy number variations should be considered in patients with a phenotype suggestive of SYNE1 deficiency.
    Keywords:  SYNE1; WES; array-CGH; mitochondrial disorder
    DOI:  https://doi.org/10.3390/genes14122154
  11. Brain Dev. 2023 Dec 21. pii: S0387-7604(23)00195-X. [Epub ahead of print]
    A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies.
    Sareh Hosseinpour, Ehsan Razmara, Morteza Heidari, Zahra Rezaei, Mahmoud Reza Ashrafi, Ali Zare Dehnavi, Reyhaneh Kameli, Ali Hosseini Bereshneh, Hassan Vahidnezhad, Reza Azizimalamiri, Zahra Zamani, Neda Pak, Maryam Rasulinezhad, Bahram Mohammadi, Homa Ghabeli, Mohammad Ghafouri, Mahmoud Mohammadi, Gholam Reza Zamani, Reza Shervin Badv, Sasan Saket, Bahareh Rabbani, Nejat Mahdieh, Ali Ahani, Masoud Garshasbi, Ali Reza Tavasoli.
       OBJECTIVE: Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies.
    METHODS: This study summarizes the clinical, imaging, and molecular data of these patients for five years.
    RESULTS: The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis.
    CONCLUSIONS: The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).
    Keywords:  Children; Mitochondrial Leukodystrophy; Mutation; OXPHOS; Phenotype
    DOI:  https://doi.org/10.1016/j.braindev.2023.12.003
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