bims-curels 2024-12-15 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–12–15
eleven papers selected by
Cure Mito Foundation

Identification of a novel pathogenic gene, NDUFA3, in Leigh Syndrome through whole exome sequencing.
Clinical features and treatment of stroke-like episodes in mitochondrial disease: a cohort-based study.
Cryopreserved PBMCs can be used for the analysis of mitochondrial respiration and serve as a diagnostic tool for mitochondrial diseases.
Optimizing rare disorder trials: a phase 1a/1b randomized study of KL1333 in adults with mitochondrial disease.
Health-related quality of life in patients with diverse rare diseases: An online survey.
Lived Experience of Patients and Caregivers in Rare Genetic Neurological Gene Therapy Clinical Trials in Children.
[A case of neonatal Mitochondrial DNA depletion syndrome type 13 caused by FBXL4 gene mutation].
Parental attitudes and experiences in pursuing genetic testing for their child's motor speech disorder.
Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.
Mitochondria-targeted nanotherapeutics: A new Frontier in neurodegenerative disease treatment.
Educational needs in diagnosing rare diseases: A multinational, multispecialty clinician survey.

Neurogenetics. 2024 Nov 28. 26(1): 13

Identification of a novel pathogenic gene, NDUFA3, in Leigh Syndrome through whole exome sequencing.

Bao-Guang Li, Wen-Juan Wu, Li-Hui Wang, Xin Wang, Chong Liu, Ya-Kun Du, Bao-Chi Li, Jin-Tong Hu, Su-Zhen Sun.

   BACKGROUND: Leigh syndrome is a common mitochondrial disorder caused by gene mutations in the nucleus and mitochondria. When building mitochondrial complex I, the main subunit ND1 combines with the Q module to form a 273 kDa complex, which then adds Ndufa3, Ndufa8, and Ndufa13 to create an intermediate product of about 283 kDa called Q/Pp-a. Although Ndufa8 and Ndufa13 have been linked to mitochondrial diseases, the role of Ndufa3 in disease development is still not fully understood.
METHODS: A family suspected of having Leigh syndrome was examined. Subjects (two brothers and a sister) underwent brain imaging, and their clinical symptoms were evaluated. Also, whole exome sequencing and minigene testing were performed by examining peripheral blood samples (2 ml) collected from the proband, his parents, and brothers.
RESULTS: Three affected children showed early-onset symptoms, including abnormalities in muscle tone and delayed motor and language development. Symptoms were relatively mild. The second child of the second pregnancy experienced worsened muscle tone abnormalities after injury, slow wound healing, and sustained increased muscle tone up to a year after wound closure. His brain scans revealed lesions in the basal ganglia and brainstem, consistent with Leigh syndrome diagnosis. Genetic analysis identified compound heterozygous mutations in the Ndufa3 gene in all affected family members.
CONCLUSION: This is the first report of a family affected by Leigh syndrome associated with mutations in the Ndufa3 gene. Our analyses of clinical symptoms, radiological scans, and genetic investigations broaden our understanding of Ndufa3 gene mutations and their role in the development of Leigh syndrome.

Keywords:   Ndufa3 ; Leigh syndrome; Mitochondrial disease

DOI:  https://doi.org/10.1007/s10048-024-00782-8
J Neurol. 2024 Dec 12. 272(1): 47

Clinical features and treatment of stroke-like episodes in mitochondrial disease: a cohort-based study.

Nora Mickelsson, Jussi Hirvonen, Mika H Martikainen.

   BACKGROUND: Stroke-like episode (SLE) is a subacute evolving brain syndrome in patients with primary mitochondrial diseases. Despite previous research, the understanding of the clinical spectrum, treatment, and outcomes of mitochondrial SLEs is far from complete. In this single centre study, we report the clinical symptoms and radiological findings as well as the medical treatment and outcomes of SLEs in patients with mitochondrial disease.
METHODS: This retrospective, observational study during years 2000-2023 was based on a cohort of patients diagnosed with mitochondrial disease at Turku University Hospital (TUH; Turku, Finland) in the region of Southwest Finland. Data were obtained from the hospital electronic medical record system.
RESULTS: The investigated cohort consisted of 76 patients (37 men, 39 women) with a diagnosis of mitochondrial disease. Among these, 12 patients had a history of at least one SLE; the total number of SLEs was 20. The most common genetic aetiology among patients with SLEs was m.3243A > G (N = 7). The mean age at first SLE was 40 years (range: 5-66 years), and the mean interval between episodes was 4.8 years (range: 4 months-10 years). The duration of episodes varied between 1 and 193 days (median 14 days, mean 37 days); 10 patients needed intensive care unit (ICU) treatment. The mean survival time between the first SLE and death was 3.6 years (range: 0-16 years).
CONCLUSION: Our study highlights the importance of early recognition and prompt management of SLE symptoms, especially epileptic seizures, in this life-threatening entity.

Keywords:  Epilepsy; Genetics; Mitochondrial DNA; Mitochondrial diseases; Stroke-like episode

DOI:  https://doi.org/10.1007/s00415-024-12745-y
Anal Biochem. 2024 Dec 05. pii: S0003-2697(24)00289-6. [Epub ahead of print] 115745

Cryopreserved PBMCs can be used for the analysis of mitochondrial respiration and serve as a diagnostic tool for mitochondrial diseases.

Zuzana Korandová, Petr Pecina, Alena Pecinová, Eliška Koňaříková, Markéta Tesařová, Josef Houštěk, Hana Hansíková, Hana Ptáčková, Jiří Zeman, Tomáš Honzík, Tomáš Mráček.

  Mitochondrial diseases are severe, inherited metabolic disorders that affect the paediatric population. They affect the functioning of mitochondrial oxidative phosphorylation (OXPHOS) apparatus either directly or indirectly. Since mutations in mtDNA are responsible for only 25% of paediatric cases and next-generation sequencing does not always provide a conclusive diagnosis, the biochemical approach still represents a valuable tool in diagnostics. Mitochondrial defects can be identified in tissue biopsies (muscle or skin). However, they also often manifest in peripheral blood cells. We developed a protocol for isolation and cryopreservation of peripheral blood mononuclear cells (PBMCs) from 5 ml of children's blood using Ficoll centrifugation which can be utilised for subsequent functional measurements on thawed samples. Furthermore, we evaluated the diagnostic utility of the optimised high-resolution oxygraphy protocol using digitonin-permeabilized cryopreserved PBMCs on 47 samples from patients with confirmed or suspected mitochondrial disease. Overall, the diagnosis was confirmed in 72% of cases, while the analysis of cryopreserved PBMCs provided a false negative outcome in 13% of cases. Our study demonstrates a sensitive, fast, and non-invasive approach for the diagnostics of various types of mitochondrial disorders, especially those of nuclear genetic origin manifesting in paediatric patients.

Keywords:  OXPHOS; PBMC; cryopreservation; diagnostics; glycolysis; mitochondrial diseases; oxidative phosphorylation; peripheral blood mononuclear cells; respirometry

DOI:  https://doi.org/10.1016/j.ab.2024.115745
Brain. 2024 Dec 09. pii: awae308. [Epub ahead of print]

Optimizing rare disorder trials: a phase 1a/1b randomized study of KL1333 in adults with mitochondrial disease.

Chiara Pizzamiglio, Renae J Stefanetti, Robert McFarland, Naomi Thomas, George Ransley, Matilda Hugerth, Alvar Grönberg, Sonia Simon Serrano, Eskil Elmér, Michael G Hanna, Magnus J Hansson, Gráinne S Gorman, Robert D S Pitceathly.

  Over the past two decades there has been increased interest in orphan drug development for rare diseases. However, hurdles to clinical trial design for these disorders remain. This phase 1a/1b study addressed several challenges, while evaluating the safety and tolerability of the novel oral molecule KL1333 in healthy volunteers and subjects with primary mitochondrial disease. KL1333 aims to normalize the NAD+:NADH ratio that is critical for ATP production. The trial incorporated innovative design elements with potential translatability to other rare diseases including patient involvement, adaptive design and exploratory objectives, all of which have subsequently informed the protocol of an ongoing phase 2, pivotal efficacy study of KL1333. Results indicate KL1333 is safe and well tolerated, with dose-dependent gastrointestinal side effects, and validate potential novel outcome measures in primary mitochondrial disease including the 30-s Sit to Stand, and the patient-reported fatigue scales. Importantly, the data from the trial support efficacy of KL1333 based on improvements in fatigue and functional strength and endurance. Furthermore, the study highlights the value in using phase 1 studies to capture data that helps optimize later phase efficacy trial design.

Keywords:  KL1333; clinical trial; phase 1 trial; primary mitochondrial disease; rare diseases

DOI:  https://doi.org/10.1093/brain/awae308
Genet Med Open. 2024 ;2 101889

Health-related quality of life in patients with diverse rare diseases: An online survey.

Anoushka Rao, Megan Yabumoto, Eliana Ward-Lev, Emily G Miller, Hetanshi Naik, Meghan C Halley.

   Purpose: Rare diseases substantially contribute to population morbidity and mortality. Understanding rare disease health-related quality of life (HRQL) is essential for evaluating platform-based interventions that aim to tackle multiple rare diseases at a time. However, most HRQL studies focus on single or select group of rare diseases, often in a single country. Our study aimed to identify patient- and disease-specific correlates of HRQL across diverse rare diseases.
Methods: We conducted an international online survey of rare disease patients and caregiver proxies affected by a systematically identified sample of rare diseases. We calculated EQ-5D scores and conducted multivariate linear regression to examine sociodemographic and disease predictors of EQ-5D-5L visual analog scale (VAS) and utility scores (United States only).
Results: A total of 1053 individuals affected by 103 different rare diseases participated, including 660 patients and 393 caregiver proxies. Disability status and disease prevalence correlated with poorer HRQL across models (P < .05). Increased pain and decreased ability to perform usual activities also correlated with lower VAS for both adult patients and caregiver proxies (P < .05). Being unemployed approached significance as a correlate of both lower caregiver proxy VAS and lower patient utility scores.
Conclusion: Our results suggest that across rare diseases, lower HRQL is associated with a reduced rare disease prevalence and disability status, among other predictors. Understanding the key correlates of HRQL is essential for developing interventions for improving health care delivery and quality of life for rare disease patients and families.

Keywords:  EQ-5D; Genetic diseases; Health related quality of life; Rare diseases; Utility score

DOI:  https://doi.org/10.1016/j.gimo.2024.101889
Pediatr Neurol. 2024 Nov 09. pii: S0887-8994(24)00379-5. [Epub ahead of print]163 46-49

Lived Experience of Patients and Caregivers in Rare Genetic Neurological Gene Therapy Clinical Trials in Children.

Alison Bateman-House, Kirsten Cowley, Vivian Fernandez, Michelle Gilmor, Cara Hunt, Marie-Laure Nevoret, Erin Ward, Lesha D Shah, Jared B Smith.

  To date, sparse attention has been paid to the importance of the "lived experience" of participants and their caregivers in pediatric gene therapy (GT) trials for rare genetic neurological disorders. Pediatric GT studies differ meaningfully from adult GT studies as the decision to participate involves a dyad: the child participant and their caregiver(s). As a multistakeholder group of authors, we are a diverse group with expert perspectives on the social, emotional, physical, and logistical burdens/benefits of trial participation and the myriad ways they affect pediatric GT research. For both pragmatic and ethical reasons, it is essential to prioritize addressing child participant and adult caregiver needs and concerns when designing and conducting GT clinical trials in pediatric populations with rare genetic neurological disorders. We use the term "lived experience" in reference to how people think about and make decisions regarding participation in research studies and how they articulate the emotional, social, ethical, and equity tradeoffs that impact their lives and illness experience. In this article, we describe why accounting for child participants' and adult caregivers' lived experience and addressing pertinent equity issues are essential when designing and conducting pediatric GT trials for rare genetic neurological diseases.

Keywords:  AAV; Clinical trial; Gene therapy; Lived experience; Pediatric; Rare genetic neurological disorder; Viral vector

DOI:  https://doi.org/10.1016/j.pediatrneurol.2024.11.001
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2024 Dec 10. 41(12): 1463-1468

[A case of neonatal Mitochondrial DNA depletion syndrome type 13 caused by FBXL4 gene mutation].

Yuanyuan Zhu, Chenhong Wang, Junjin Chen, Xiaohong Wang, Xiaolu Ma.

OBJECTIVE: To explore the clinical phenotypes and genetic variant in a neonatal case of Mitochondrial DNA depletion syndrome type 13 (MTDPS13).
METHODS: Clinical data and results of genetic testing of a neonate admitted to the Children's Hospital of Zhejiang University School of Medicine in January 2023 was retrospectively analyzed. The study was approved by the Medical Ethics Committee of the Children's Hospital of Zhejiang University.
RESULTS: The male infant was admitted to the NICU due to tachypnea and persistent lactic acidosis 6 hours after birth. At admission, distinctive facial features were noted. Laboratory tests showed elevated lactic acid (< 30 mmol/L). Whole-exome sequencing revealed that he has harbored homozygous c.141del frameshift mutation of FBXL4 gene, which was unreported previously. The mutation was inherited from both of his parents and classified as likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).
CONCLUSION: The clinical phenotypes of this case of MTDPS13 is characterized by lactic acidosis, distinctive facial features, growth retardation and developmental delay, for which the homozygous c.141del variant of the FBXL4 gene may be accountable.

DOI: https://doi.org/10.3760/cma.j.cn511374-20240630-00360
Eur J Hum Genet. 2024 Dec 09.

Parental attitudes and experiences in pursuing genetic testing for their child's motor speech disorder.

Christy Atkinson, Yong Quan Lee, Mariana L Lauretta, Anna Jarmolowicz, David J Amor, Angela T Morgan.

Rare and typically severe motor speech disorders such as childhood apraxia of speech (CAS) and dysarthria affect about 1 in 1000 children. The genetic basis of these speech disorders is well-documented, with approximately 30% of children who undergo genomic testing receiving an explanatory genetic diagnosis. As more children with speech disorders are offered genetic testing, understanding parental views and experiences around genetic testing for their child is critical in providing effective pre- and post-test genetic counselling. This research explored parental attitudes, experiences, and perceived implications of pursuing genetic testing for their child with motor speech disorder. Semi-structured interviews were conducted with 20 parents of children with CAS or dysarthria who had undergone exome sequencing. Eight parents had received a genetic diagnosis for their child and 12 received uninformative genetic test results. Interviews were transcribed verbatim, co-coded, and analysed using reflexive thematic analysis. Parents were highly motivated to pursue genetic testing for their child's speech disorder due to the perceived personal, clinical, social, and financial utility in obtaining a genetic diagnosis. Regardless of testing outcome, parents experienced complex emotional responses in receiving their child's genetic test results. Parents whose child received a genetic diagnosis reported improved access to funding and clinical care; however, they also hoped for ongoing informational, clinical, and peer support in navigating the uncertainty surrounding their child's rare diagnosis. Conversely, parents who received uninformative genetic test results reported finding meaning in this test outcome, and used emotional-focused and problem-focused strategies to cope with their child's continued diagnostic odyssey.

DOI: https://doi.org/10.1038/s41431-024-01755-z
Brain Commun. 2024 ;6(6): fcae404

Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.

Jacques Bureau, Florence Manero, Olivier Baris, Alexia Bodin, Christophe Verny, Arnaud Chevrollier, Guy Lenaers, Philippe Codron.

  Hereditary optic neuropathies, including dominant optic atrophy and Leber's hereditary optic neuropathy, are genetic disorders characterized by retinal ganglion cell degeneration leading to vision loss, mainly associated with mitochondrial dysfunction. In this study, we analysed mitochondrial distribution and ultrastructure in the retina and longitudinal optic nerve sections of pre-symptomatic hereditary optic neuropathies mouse models with Opa1 and Nd6 deficiency to identify early mitochondrial changes. Our results show significant mitochondrial fragmentation and increased mitophagy in Opa1+/- mice, indicating early mitochondrial changes prior to neuronal loss. Conversely, Nd6P25L mice exhibited mitochondrial hypertrophy, suggesting an adaptive response to compensate for altered energy metabolism. These pre-symptomatic mitochondrial changes were mainly observed in the unmyelinated portion of the retinal ganglion cell axons, where the transmission of the visual information requires high energy expenditure, constituting the specific point of vulnerability in hereditary optic neuropathies. These findings highlight early focal mitochondrial changes prior to neuronal loss in hereditary optic neuropathies and provide insight into pre-symptomatic therapeutic approaches.

Keywords:  Leber hereditary optic neuropathy; Opa1; dominant optic atrophy; hereditary optic neuropathy; mitochondria

DOI:  https://doi.org/10.1093/braincomms/fcae404
Mitochondrion. 2024 Dec 09. pii: S1567-7249(24)00158-2. [Epub ahead of print] 102000

Mitochondria-targeted nanotherapeutics: A new Frontier in neurodegenerative disease treatment.

Nishad Keethedeth, Rajesh Anantha Shenoi.

  Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.

Keywords:  Blood brain barrier; Mitochondria targeting; Nanotherapeutics; Neurodegenerative diseases; Triphenyl Phosphonium

DOI:  https://doi.org/10.1016/j.mito.2024.102000
Genet Med Open. 2023 ;1(1): 100808

Educational needs in diagnosing rare diseases: A multinational, multispecialty clinician survey.

S Christy Rohani-Montez, Jennifer Bomberger, Cong Zhang, Jacob Cohen, Lucy McKay, William R H Evans.

   Purpose: Recognizing rare diseases (RDs) and initiating appropriate investigation and referral is critical for timely diagnosis. Unfortunately, patients with RDs experience significant diagnostic delays, potentially leading to inappropriate or harmful testing or treatment and disease progression.
Methods: A 14-question survey assessing clinician knowledge, experience, and educational needs in RDs was emailed to US and European Union Medscape member clinicians. The survey was available from April 1, 2021, through August 2, 2021.
Results: The respondents included 978 clinicians across 16 specialties. Two-thirds of the respondents considered RDs to be 50 to 500 times rarer than standard European Union or US definitions, and despite a point prevalence of 3.5% to 5.9%, 59% said they never or rarely (1× or 2× per year) see patients with RDs. Although 87% have been involved in an RD diagnosis, only 19% were mostly or very confident in making a diagnosis. In addition, 38% to 44% reported diagnostic barriers such as knowledge of signs/symptoms, time to investigate, guideline availability, test access, and referrals. Highest RD education preferences included a comprehensive online learning platform with current education and resources and case-based, text-based, and short formats (≤15 minutes) taught by world-renowned clinicians.
Conclusion: This research study identified RD knowledge gaps, highlighting the need for education to shorten the diagnostic odyssey, which can enable earlier referral and treatment.

Keywords:  Education; Multinational; Multispecialty; Rare disease; Survey

DOI:  https://doi.org/10.1016/j.gimo.2023.100808