bims-curels 2024-05-12 papers

Issue of 2024–05–12
seven papers selected by
Cure Mito Foundation

J Hum Genet. 2024 May 10.

A novel pathogenic mitochondrial DNA variant m.4344T>C in tRNAGln causes developmental delay.

Xiaojie Yin, Qiyu Dong, Shuanglong Fan, Lina Yang, Hao Li, Yijun Jin, Mahlatsi Refiloe Laurentinah, Xiandan Chen, Aliaksei Sysa, Hezhi Fang, Jianxin Lyu, Yongguo Yu, Ya Wang.

Mitochondrial diseases are a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA. However, the genetic spectrum of this disease is not yet complete. In this study, we identified a novel variant m.4344T>C in mitochondrial tRNAGln from a patient with developmental delay. The mutant loads of m.4344T>C were 95% and 89% in the patient's blood and oral epithelial cells, respectively. Multialignment analysis showed high evolutionary conservation of this nucleotide. TrRosettaRNA predicted that m.4344T>C variant would introduce an additional hydrogen bond and alter the conformation of the T-loop. The transmitochondrial cybrid-based study demonstrated that m.4344T>C variant impaired the steady-state level of mitochondrial tRNAGln and decreased the contents of mitochondrial OXPHOS complexes I, III, and IV, resulting in defective mitochondrial respiration, elevated mitochondrial ROS production, reduced mitochondrial membrane potential and decreased mitochondrial ATP levels. Altogether, this is the first report in patient carrying the m.4344T>C variant. Our data uncover the pathogenesis of the m.4344T>C variant and expand the genetic mutation spectrum of mitochondrial diseases, thus contributing to the clinical diagnosis of mitochondrial tRNAGln gene variants-associated mitochondrial diseases.

DOI: https://doi.org/10.1038/s10038-024-01254-5

Nat Metab. 2024 May 08.

Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.

Andrew Y Sung, Rachel M Guerra, Laura H Steenberge, Charlotte L Alston, Kei Murayama, Yasushi Okazaki, Masaru Shimura, Holger Prokisch, Daniele Ghezzi, Alessandra Torraco, Rosalba Carrozzo, Agnès Rötig, Robert W Taylor, James L Keck, David J Pagliarini.

Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding interpretation of potential disease-causing genetic variants. To address these challenges, we devised a deep mutational scanning approach to systematically assess the function of thousands of NDUFAF6 genetic variants. Guided by these data, biochemical analyses and cross-linking mass spectrometry, we discovered that the CIAF NDUFAF6 facilitates incorporation of NDUFS8 into CI and reveal that NDUFS8 overexpression rectifies NDUFAF6 deficiency. Our data further provide experimental support of pathogenicity for seven novel NDUFAF6 variants associated with human pathology and introduce functional evidence for over 5,000 additional variants. Overall, our work defines the molecular function of NDUFAF6 and provides a clinical resource for aiding diagnosis of NDUFAF6-related diseases.

DOI: https://doi.org/10.1038/s42255-024-01039-2

Ann Clin Transl Neurol. 2024 May 04.

Primary mitochondrial disorders and mimics: Insights from a large French cohort.

MitoDiag's Network Collaborators

OBJECTIVE: The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear-encoded genes.
METHODS: Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear-encoded genes.
RESULTS: The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases.
INTERPRETATION: We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with "possible" PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy.

DOI: https://doi.org/10.1002/acn3.52062

Int J Pharm. 2024 May 02. pii: S0378-5173(24)00428-9. [Epub ahead of print] 124194

Mitochondrial transplantation: A promising therapy for mitochondrial disorders.

Qiangqiang Jiao, Li Xiang, Yuping Chen.

As a vital energy source for cellular metabolism and tissue survival, the mitochondrion can undergo morphological or positional change and even shuttle between cells in response to various stimuli and energy demands. Multiple human diseases are originated from mitochondrial dysfunction, but the curative succusses by traditional treatments are limited. Mitochondrial transplantation therapy (MTT) is an innovative therapeutic approach that is to deliver the healthy mitochondria either derived from normal cells or reassembled through synthetic biology into the cells and tissues suffering from mitochondrial damages and finally replace their defective mitochondria and restore their function. MTT has already been under investigation in clinical trial for cardiac ischemia-reperfusion injury and given an encouraging performance in animal models of numerous fatal critical diseases including central nervous system disorders, cardiovascular diseases, inflammatory conditions, cancer, renal injury, and pulmonary damage. This review article summarizes the mechanisms and strategies of mitochondrial transfer and the MTT application for types of mitochondrial diseases, and discusses the potential challenge in MTT clinical application, aiming to exhibit the good therapeutic prospects of MTTs in clinics.

Keywords: Artificial mitochondria; Clinical trials; Mitochondrial medicine; Mitochondrial transplantation

DOI: https://doi.org/10.1016/j.ijpharm.2024.124194

Eur J Ophthalmol. 2024 May 07. 11206721241254408

Autosomal recessive leber hereditary optic neuropathy in a choroideremia carrier. A case report.

Eva Roomets, Laura Mauring.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is an inherited progressive optic neuropathy usually caused by mitochondrial DNA mutations. Recently, autosomal recessive (arLHON), which is caused by biallelic mutations in the DNAJC30 gene (usually c.152A > G), has been described. The onset of LHON before the age of 12 is uncommon and it is typically associated with a more variable clinical course and a more favorable visual prognosis than adult-onset LHON.
MATERIALS AND METHODS: Detailed clinical findings of a female child with vision loss due to arLHON together with choroideremia (CHM) carrier state are presented.
RESULTS: Genetic testing for the three most common mitochondrial LHON pathogenic variants was negative. On suspicion of arLHON, genetic testing was continued with the next-generation sequencing (NGS) of the nuclear DNA, identifying a homozygous pathogenic variant in DNAJC3°c.152A > G, p.(Tyr51Cys), but no alterations in the CHM gene. Idebenone treatment was started 4.5 months after the first evaluation. Clinical diagnosis of the CHM carrier state was confirmed by multiplex ligation-dependent probe amplification (MLPA) assay, which revealed a heterozygous deletion of all exons of the CHM.
CONCLUSIONS: In children with acute or subacute, simultaneous, or sequential vision loss that is unresponsive to immunomodulatory treatment, LHON should be considered as a possible diagnosis. Our case emphasizes the diagnostic advantage of sequencing DNAJC30 in parallel with the mitochondrial DNA, especially in Eastern European descent patients. Genomic rearrangement testing should be considered for patients with a CHM carrier phenotype who have negative results on sequencing tests.

Keywords: Autosomal recessive LHON; CHM; DNAJC30 gene; Leber hereditary optic neuropathy; arLHON p.(Tyr51Cys) variant.; choroideremia carrier

DOI: https://doi.org/10.1177/11206721241254408

Orphanet J Rare Dis. 2024 May 06. 19(1): 187

Scoping review of the recommendations and guidance for improving the quality of rare disease registries.

J E Tarride, A Okoh, K Aryal, C Prada, Deborah Milinkovic, A Keepanasseril, A Iorio.

BACKGROUND: Rare disease registries (RDRs) are valuable tools for improving clinical care and advancing research. However, they often vary qualitatively, structurally, and operationally in ways that can determine their potential utility as a source of evidence to support decision-making regarding the approval and funding of new treatments for rare diseases.
OBJECTIVES: The goal of this research project was to review the literature on rare disease registries and identify best practices to improve the quality of RDRs.
METHODS: In this scoping review, we searched MEDLINE and EMBASE as well as the websites of regulatory bodies and health technology assessment agencies from 2010 to April 2023 for literature offering guidance or recommendations to ensure, improve, or maintain quality RDRs.
RESULTS: The search yielded 1,175 unique references, of which 64 met the inclusion criteria. The characteristics of RDRs deemed to be relevant to their quality align with three main domains and several sub-domains considered to be best practices for quality RDRs: (1) governance (registry purpose and description; governance structure; stakeholder engagement; sustainability; ethics/legal/privacy; data governance; documentation; and training and support); (2) data (standardized disease classification; common data elements; data dictionary; data collection; data quality and assurance; and data analysis and reporting); and (3) information technology (IT) infrastructure (physical and virtual infrastructure; and software infrastructure guided by FAIR principles (Findability; Accessibility; Interoperability; and Reusability).
CONCLUSIONS: Although RDRs face numerous challenges due to their small and dispersed populations, RDRs can generate quality data to support healthcare decision-making through the use of standards and principles on strong governance, quality data practices, and IT infrastructure.

Keywords: Guidance; Quality standards; Rare diseases; Registries

DOI: https://doi.org/10.1186/s13023-024-03193-y

Neurobiol Dis. 2024 May 02. pii: S0969-9961(24)00119-0. [Epub ahead of print] 106520

Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis.

Richard E Frye, Nicole Rincon, Patrick J McCarty, Danielle Brister, Adrienne C Scheck, Daniel A Rossignol.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial dysfunction, at least in a subset of individuals. This systematic review and meta-analysis discovered 204 relevant articles which evaluated biomarkers of mitochondrial dysfunction in ASD individuals. Significant elevations (all p < 0.01) in the prevalence of lactate (17%), pyruvate (41%), alanine (15%) and creatine kinase (9%) were found in ASD. Individuals with ASD had significant differences (all p < 0.01) with moderate to large effect sizes (Cohen's d' ≥ 0.6) compared to controls in mean pyruvate, lactate-to-pyruvate ratio, ATP, and creatine kinase. Some studies found abnormal TCA cycle metabolites associated with ASD. Thirteen controlled studies reported mitochondrial DNA (mtDNA) deletions or variations in the ASD group in blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, and brain. Meta-analyses discovered significant differences (p < 0.01) in copy number of mtDNA overall and in ND1, ND4 and CytB genes. Four studies linked specific mtDNA haplogroups to ASD. A series of studies found a subgroup of ASD with elevated mitochondrial respiration which was associated with increased sensitivity of the mitochondria to physiological stressors and neurodevelopmental regression. Lactate, pyruvate, lactate-to-pyruvate ratio, carnitine, and acyl-carnitines were associated with clinical features such as delays in language, social interaction, cognition, motor skills, and with repetitive behaviors and gastrointestinal symptoms, although not all studies found an association. Lactate, carnitine, acyl-carnitines, ATP, CoQ10, as well as mtDNA variants, heteroplasmy, haplogroups and copy number were associated with ASD severity. Variability was found across biomarker studies primarily due to differences in collection and processing techniques as well as the intrinsic heterogeneity of the ASD population. Several studies reported alterations in mitochondrial metabolism in mothers of children with ASD and in neonates who develop ASD. Treatments targeting mitochondria, particularly carnitine and ubiquinol, appear beneficial in ASD. The link between mitochondrial dysfunction in ASD and common physiological abnormalities in individuals with ASD including gastrointestinal disorders, oxidative stress, and immune dysfunction is outlined. Several subtypes of mitochondrial dysfunction in ASD are discussed, including one related to neurodevelopmental regression, another related to alterations in microbiome metabolites, and another related to elevations in acyl-carnitines. Mechanisms linking abnormal mitochondrial function with alterations in prenatal brain development and postnatal brain function are outlined. Given the multisystem complexity of some individuals with ASD, this review presents evidence for the mitochondria being central to ASD by contributing to abnormalities in brain development, cognition, and comorbidities such as immune and gastrointestinal dysfunction as well as neurodevelopmental regression. A diagnostic approach to identify mitochondrial dysfunction in ASD is outlined. From this evidence, it is clear that many individuals with ASD have alterations in mitochondrial function which may need to be addressed in order to achieve optimal clinical outcomes. The fact that alterations in mitochondrial metabolism may be found during pregnancy and early in the life of individuals who eventually develop ASD provides promise for early life predictive biomarkers of ASD. Further studies may improve the understanding of the role of the mitochondria in ASD by better defining subgroups and understanding the molecular mechanisms driving some of the unique changes found in mitochondrial function in those with ASD.

Keywords: Autism Spectrum disorder; Biomarkers; Environmental genetic interactions; Meta-analysis; Mitochondrial DNA; Mitochondrial dysfunction; Mitochondrial respiration; Neurodevelopmental regression

DOI: https://doi.org/10.1016/j.nbd.2024.106520