bims-curels 2023-03-26 papers

Issue of 2023–03–26
six papers selected by
Cure Mito Foundation

J Stroke Cerebrovasc Dis. 2023 Mar 15. pii: S1052-3057(23)00104-0. [Epub ahead of print]32(5): 107080

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes diagnosed after metformin-triggered stroke-like episodes.

Keishu Murakami, Ken Sakamoto, Hiroshi Ishiguchi, Hidefumi Ito.

A 40-year-old man with sensorineural hearing loss and diabetes mellitus was hospitalized with acute-onset impaired consciousness and clumsiness in his left hand. He had been taking metformin for 4 months. A neurological examination revealed confusion and weakness in the left upper limb. Increased lactate levels were detected in the serum and cerebrospinal fluid. Magnetic resonance imaging revealed lesions in the right parietal and bilateral temporal lobes with a lactate peak in magnetic resonance spectroscopy. Finally, we made a genetic diagnosis of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes based on the detection of m.3243A>G. It is well-known that metformin should not be administered in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes because metformin inhibits mitochondrial function and triggers stroke-like episodes. However, our patient was diagnosed with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes after metformin administration. Thus, we encourage physicians to exercise caution in the prescription of metformin in patients with short stature, sensorineural hearing loss, or young-onset diabetes mellitus because these patients may have undiagnosed mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes.

Keywords: MELAS; Metformin; Mitochondrial diseases; Stroke-like episodes

DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2023.107080

Zhongguo Dang Dai Er Ke Za Zhi. 2023 Mar 15. pii: 1008-8830(2023)03-0308-07. [Epub ahead of print]25(3): 308-314

[Clinical diagnostic techniques for rare genetic diseases in children: current status, advances, and thoughts].

Jin-Yue Huang, Bi-Li Zhang, Wei Liu.

Rare diseases refer to a group of single diseases with low incidence rates, complex pathogeneses, severe disease conditions, and rapid progression. Most rare diseases have a genetic background and may occur in childhood. Paying attention to the rare genetic diseases in children and performing early diagnosis and treatment can effectively delay the course of disease and improve the quality of life of children. Many rare diseases can be diagnosed with the help of various experimental techniques, but the diagnosis of rare diseases is still not widely understood. This article summarizes the laboratory diagnostic techniques currently used for rare genetic diseases in children, so as to provide clues for the diagnosis and treatment of such diseases and help to enhance the theoretical understanding and precise medical treatment of rare genetic diseases in children.

Keywords: Child; Diagnostic technique; Genetics; Rare disease

DOI: https://doi.org/10.7499/j.issn.1008-8830.2211010

Cardiol Young. 2023 Mar 23. 1-3

Hypertrophic cardiomyopathy as the initial presentation of mitochondrial disease in an infant born to a diabetic mother.

Jun Chul Byun, Hee Joung Choi.

In contrast to hypertrophic cardiomyopathy caused by maternal diabetes, neonatal mitochondrial cardiomyopathy is rare and has a poor prognosis. We report an infant born to a mother with maternal diabetes with persistent ventricular hypertrophy, who was diagnosed with mitochondrial disease associated with m.3243A>G mutation in a mitochondrial tRNA leucine 1 gene. The hypertrophic cardiomyopathy was his initial and only clinical presentation.

Keywords: Hypertrophic cardiomyopathy; MT-TL1 mutation; infant of a diabetic mother; mitochondrial cardiomyopathy

DOI: https://doi.org/10.1017/S1047951123000392

Anal Biochem. 2023 Mar 20. pii: S0003-2697(23)00087-8. [Epub ahead of print] 115122

Research development and the prospect of animal models of mitochondrial DNA-related mitochondrial diseases.

Xiaolei Wang, Hedong Lu, Min Li, Zhiguo Zhang, Zhaolian Wei, Ping Zhou, Yunxia Cao, Dongmei Ji, Weiwei Zou.

Mitochondrial diseases (MDs) are genetic and clinical heterogeneous diseases caused by mitochondrial oxidative phosphorylation defects. It is not only one of the most common genetic diseases, but also the only genetic disease involving two different genomes in humans. As a result of the complicated genetic condition, the pathogenesis of MDs is not entirely elucidated at present, and there is a lack of effective treatment in the clinic. Establishing the ideal animal models is the critical preclinical platform to explore the pathogenesis of MDs and to verify new therapeutic strategies. However, the development of animal modeling of mitochondrial DNA (mtDNA)-related MDs is time-consuming due to the limitations of physiological structure and technology. A small number of animal models of mtDNA mutations have been constructed using cell hybridization and other methods. However, the diversity of mtDNA mutation sites and clinical phenotypes make establishing relevant animal models tricky. The development of gene editing technology has become a new hope for establishing animal models of mtDNA-related mitochondrial diseases.

Keywords: Animal models; Mitochondrial DNA; Mitochondrial diseases; MtDNA mutation

DOI: https://doi.org/10.1016/j.ab.2023.115122

Hum Reprod. 2023 Mar 23. pii: dead052. [Epub ahead of print]

A shared pattern of altered gene expression in human embryos affected by mitochondrial diseases.

Kalliopi Chatzovoulou, Anne Mayeur, Nicolas Cagnard, Mohammed Zarhrate, Christine Bole, Patrick Nitschke, Fabienne Jabot-Hanin, Agnès Rötig, Sophie Monnot, Arnold Munnich, Nelly Frydman, Julie Steffann.

STUDY QUESTION: Does mitochondrial deficiency affect human embryonic preimplantation development?
SUMMARY ANSWER: The presence of a pathogenic mitochondrial variant triggers changes in the gene expression of preimplantation human embryos, compromising their development, cell differentiation, and survival.
WHAT IS KNOWN ALREADY: Quantitative and qualitative anomalies of mitochondrial DNA (mtDNA) are reportedly associated with impaired human embryonic development, but the underlying mechanisms remain unexplained.
STUDY DESIGN, SIZE, DURATION: Taking advantage of the preimplantation genetic testing for mitochondrial disorders in at-risk couples, we have compared gene expression of 9 human embryos carrying pathogenic variants in either mtDNA genes or nuclear genes encoding mitochondrial protein to 33 age-matched control embryos.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Single-embryo transcriptomic analysis was performed on whole human blastocyst embryos donated to research.
MAIN RESULTS AND THE ROLE OF CHANCE: Specific pathogenic mitochondrial variants downregulate gene expression in preimplantation human embryos [566 genes in oxidative phosphorylation (OXPHOS)-deficient embryos], impacting transcriptional regulators, differentiation factors, and nuclear genes encoding mitochondrial proteins. These changes in gene expression primarily alter OXPHOS and cell survival pathways.
LIMITATIONS, REASONS FOR CAUTION: The number of OXPHOS-deficient embryos available for the study was limited owing to the rarity of this material. However, the molecular signature shared by all these embryos supports the relevance of the findings.
WIDER IMPLICATIONS OF THE FINDINGS: While identification of reliable markers of normal embryonic development is urgently needed in ART, our study prompts us to consider under-expression of the targeted genes reported here, as predictive biomarkers of mitochondrial dysfunction during preimplantation development.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the 'Association Française contre les Myopathies (AFM-Téléthon)' and the 'La Fondation Maladies Rares'. No competing interests to declare.
TRIAL REGISTRATION NUMBER: N/A.

Keywords: RNA sequencing; differential gene expression; human embryo development; mitochondrial metabolism; mitochondrial mutation; transcriptome

DOI: https://doi.org/10.1093/humrep/dead052

Genet Med. 2023 Mar 22. pii: S1098-3600(23)00845-6. [Epub ahead of print] 100832

Individualized Interventions for Rare Genetic Conditions and the Research-Treatment Spectrum: Stakeholder Perspectives.

Sandra Soo-Jin Lee, Mikaella Caruncho, Wendy K Chung, Josephine Johnston, Kathryn Tabb, Paul S Appelbaum.

PURPOSE: Advances in the study of ultra-rare genetic conditions are leading to the development of targeted interventions developed for single or very small numbers of patients. Due to the experimental but also highly individualized nature of these interventions, they are difficult to classify cleanly as either research or clinical care. Our goal was to understand how parents, IRB members, and clinical geneticists familiar with individualized genetic interventions conceptualize these activities and their implications for the relationship between research and clinical care.
METHODS: We conducted qualitative, semi-structured interviews with 28 parents, IRB members, and clinical geneticists, and derived themes from those interviews through content analysis.
RESULTS: Individuals described individualized interventions as blurring the lines between research and clinical care and focused on hopes for therapeutic benefit and expectations for generalizability of knowledge and benefit to future patients.
CONCLUSION: Individualized interventions aimed at one or few patients reveal the limitations of a binary framing of research and clinical care. As a hybrid set of activities, individualized interventions suggest the need for flexibility and new frameworks that acknowledge these activities across the spectrum of research and clinical care.

Keywords: funding; gene therapy; pediatrics; rare genetic disease; regulatory governance; research and clinical care

DOI: https://doi.org/10.1016/j.gim.2023.100832