bims-curels 2025-01-12 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–01–12
ten papers selected by
Cure Mito Foundation

Diagnosis and Management of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome.
Mitochondrial diseases: from molecular mechanisms to therapeutic advances.
Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.
Liberalism and mitochondrial replacement technique.
[Study of the feasibility of polar body transfer combined with preimplantation genetic testing for blocking the intergenerational transmission of mitochondrial genetic diseases].
Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.
COA5 has an essential role in the early stage of mitochondrial complex IV assembly.
Radiologic Findings in a Patient With Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes Syndrome: A Case Report.
Challenges Faced by Newborns with Inherited Metabolic Disorders and Their Mothers During Antepartum, Intrapartum, and Postpartum Periods.
Caregiver-Reported Economic Impacts of Pediatric Rare Diseases-A Scoping Review.

Biomolecules. 2024 Nov 28. pii: 1524. [Epub ahead of print]14(12):

Diagnosis and Management of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome.

Ji-Hoon Na, Young-Mock Lee.

  Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a complex mitochondrial disorder characterized by a wide range of systemic manifestations. Key clinical features include recurrent stroke-like episodes, seizures, lactic acidosis, muscle weakness, exercise intolerance, sensorineural hearing loss, diabetes, and progressive neurological decline. MELAS is most commonly associated with mutations in mitochondrial DNA, particularly the m.3243A>G mutation in the MT-TL1 gene, which encodes tRNALeu (CUR). These mutations impair mitochondrial protein synthesis, leading to defective oxidative phosphorylation and energy failure at the cellular level. The clinical presentation and severity vary widely among patients, but the syndrome often results in significant morbidity and reduced life expectancy because of progressive neurological deterioration. Current management is largely focused on conservative care, including anti-seizure medications, arginine or citrulline supplementation, high-dose taurine, and dietary therapies. However, these therapies do not address the underlying genetic mutations, leaving many patients with substantial disease burden. Emerging experimental treatments, such as gene therapy and mitochondrial replacement techniques, aim to correct the underlying genetic defects and offer potential curative strategies. Further research is essential to understand the pathophysiology of MELAS, optimize current therapies, and develop novel treatments that may significantly improve patient outcomes and extend survival.

Keywords:  MELAS; MT-TL1; mitochondrial disease; mitochondrial encephalopathy lactic acidosis and stroke-like episodes; stroke-like episode

DOI:  https://doi.org/10.3390/biom14121524
Signal Transduct Target Ther. 2025 Jan 10. 10(1): 9

Mitochondrial diseases: from molecular mechanisms to therapeutic advances.

Haipeng Wen, Hui Deng, Bingyan Li, Junyu Chen, Junye Zhu, Xian Zhang, Shigeo Yoshida, Yedi Zhou.

Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism and signaling. They possess various metabolic and quality control mechanisms crucial for maintaining normal cellular activities. Mitochondrial genetic disorders can arise from a wide range of mutations in either mitochondrial or nuclear DNA, which encode mitochondrial proteins or other contents. These genetic defects can lead to a breakdown of mitochondrial function and metabolism, such as the collapse of oxidative phosphorylation, one of the mitochondria's most critical functions. Mitochondrial diseases, a common group of genetic disorders, are characterized by significant phenotypic and genetic heterogeneity. Clinical symptoms can manifest in various systems and organs throughout the body, with differing degrees and forms of severity. The complexity of the relationship between mitochondria and mitochondrial diseases results in an inadequate understanding of the genotype-phenotype correlation of these diseases, historically making diagnosis and treatment challenging and often leading to unsatisfactory clinical outcomes. However, recent advancements in research and technology have significantly improved our understanding and management of these conditions. Clinical translations of mitochondria-related therapies are actively progressing. This review focuses on the physiological mechanisms of mitochondria, the pathogenesis of mitochondrial diseases, and potential diagnostic and therapeutic applications. Additionally, this review discusses future perspectives on mitochondrial genetic diseases.

DOI: https://doi.org/10.1038/s41392-024-02044-3
Commun Biol. 2025 Jan 09. 8(1): 24

Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.

Julie Faitg, Tracey Davey, Ross Laws, Conor Lawless, Helen Tuppen, Eric Fitton, Doug Turnbull, Amy E Vincent.

Mitochondria play a crucial role in maintaining cellular health. It is interesting that the shape of mitochondria can vary depending on the type of cell, mitochondrial function, and other cellular conditions. However, there are limited studies that link functional assessment with mitochondrial morphology evaluation at high magnification, even fewer that do so in situ and none in human muscle biopsies. Therefore, we have developed a method which combines functional assessment of mitochondria through Cytochrome c Oxidase (COX) histochemistry, with a 3D electron microscopy (EM) technique, serial block-face scanning electron microscopy (SBFSEM). Here we apply COX-SBFSEM to muscle samples from patients with single, large-scale mtDNA deletions, a cause of mitochondrial disease. These deletions cause oxidative phosphorylation deficiency, which can be observed through changes in COX activity. One of the main advantages of combining 3D-EM with the COX reaction is the ability to look at how per-mitochondrion oxidative phosphorylation status is spatially distributed within muscle fibres. Here we show a robust spatial pattern in COX-positive and intermediate-fibres and that the spatial pattern is less clear in COX-deficient fibres.

DOI: https://doi.org/10.1038/s42003-024-07389-7
J Med Ethics. 2025 Jan 09. pii: jme-2024-110373. [Epub ahead of print]

Liberalism and mitochondrial replacement technique.

Marco Tang.

  How should defenders of liberalism think about access to reproductive technologies? Mitochondrial replacement technique (MRT) enables women with pathogenic variations of mitochondrial disease to have children without the fear of transmission. This technology can also allow lesbians, or partners with female-assigned physiology (PFP), to have genetically related offspring. Cavaliere and Palacios-Gonzalez argue that lesbians should be able to access MRT on autonomy grounds. They argue MRT should not be restricted to those with mitochondrial disease because it is non-therapeutic and invokes the Millian harm principle. Yet, Baylis argues that a desire for genetically related offspring is not sufficient to access MRT because it contributes to harmful social narratives about adopted families. I strengthen Cavaliere and Palacios-Gonzalez's liberal defence by bringing another liberal commitment-equality. Ultimately, I argue that the liberal state must allow PFPs to use MRT. I first show that the use of MRT by PFPs is permissible even if MRT is therapeutic by comparing MRT with cosmetic surgery-that is, social uses of therapeutic interventions are permitted if we are interested in doing so. Borrowing from Dillard, a possible interest is self-replication. Next, I outline and respond to a possible criticism by Baylis-MRT is necessary but not sufficient for self-replication. Ultimately, I show that the liberal state must permit MRT because (a) it provides PFPs with an equal opportunity to experience having genetically related offspring with their partner and (b) contributing to harmful social narratives is insufficient for limiting autonomy.

Keywords:  Ethics- Medical; Gene Transfer Techniques; Paternalism; Personal Autonomy; Reproductive Medicine

DOI:  https://doi.org/10.1136/jme-2024-110373
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025 Jan 10. 42(1): 18-25

[Study of the feasibility of polar body transfer combined with preimplantation genetic testing for blocking the intergenerational transmission of mitochondrial genetic diseases].

Dongmei Ji, Zhikang Zhang, Weiwei Zou, Ning Zhang, Kai Zong, Yinan Du, Xun Su, Xin Wang, Dawei Chen, Chunmei Liang, Zhiguo Zhang, Yunxia Cao.

OBJECTIVE: To assess the feasibility of first polar body transfer (PB1T) combined with preimplantation mitochondrial genetic testing for blocking the transmission of a pathogenic mitochondrial DNA 8993T>G mutation.
METHODS: A Chinese family affected with Leigh syndrome which had attended the Reproductive Medicine Centre of the First Affiliated Hospital of Anhui Medical University in September 2021 was selected as the study subject. Controlled ovarian hyperstimulation was carried out for the proband after completing the detection of the mitochondrial DNA 8993T>G mutation load among the pedigree members. Mature MII oocytes were inseminated by intracytoplasmic sperm injection (ICSI), cultured in vitro for 5 to 6 days to the blastocyst stage, and trophoblastocytes were obtained by microbiopsy. Mitochondrial DNA testing (PGT-MT) and chromosomal aneuploidy (PGT-A) analyses were carried out after whole-genome amplification, and the embryos with zero mutation load were selected for transfer. Amniotic fluid and umbilical cord blood samples were collected during middle pregnancy and after birth respectively for mitochondrial DNA testing to verify the reliability of embryo screening. As an attempt, PB1 with good morphology of MII oocytes was selected for transfer into the enucleated oocytoplasm from healthy donors, followed by ICSI fertilization, blastocyst culture and PGT of embryos using the same procedure. This study has been approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 2021zhyx-B12).
RESULTS: An antagonist protocol was used for ovarian stimulation, and a total of 19 oocytes were obtained, of which 14 MII were fertilized by ICSI, and 2 had developed into blastocysts. PGT-MT was carried out on biopsied trophoblastocytes, in which the mitochondrial DNA 8993T>G mutation load was not detected in one embryo, the other was 100% mutated, and the mutation loads of the remaining unfertilized eggs and developmentally arrested embryos ranged from 0% ~ 100%, presenting a clear biased distribution. With fully informed consent, one PGT-MT zero mutation load blastocyst was transferred and clinical pregnancy was achieved. Mitochondrial DNA and chromosomal testing of amniotic fluid cells during middle pregnancy had revealed no abnormalities. The proband had delivered a healthy boy through Caesarean section at 39+5 weeks of gestation, and no mutation was detected in the cord blood sample. Five well-formed PBs from 14 eggs were selected for PB1 transfer, followed by ICSI and culture, and two of the reconstituted embryos had formed blastocysts, with none of the above mutations detected in the biopsied samples.
CONCLUSION: The PGT-MT technology can help families affected with mitochondrial diseases to have healthy offspring. PB1 transfer in combination with ICSI and PGT-MT holds the promise of turning waste into treasure and providing an alternative means of fertility for such families.

DOI: https://doi.org/10.3760/cma.j.cn511374-20240702-00366
medRxiv. 2024 Dec 26. pii: 2024.12.22.24319370. [Epub ahead of print]

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.

Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium

Background: Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is often not specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants.
Methods: Using dedicated pipelines to address the technical challenges posed by the mtDNA - circular genome, variant heteroplasmy, and nuclear misalignment - single nucleotide variants, small indels, and large mtDNA deletions were called from exome and genome sequencing data, in addition to RNA-sequencing when available. A cohort of 6,660 rare disease families were analyzed (5,625 genetically undiagnosed, 84%) from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium as well as other rare disease cohorts.
Results: Diagnostic mtDNA variants were identified in 10 previously genetically undiagnosed families (one large deletion, eight reported pathogenic variants, one novel pathogenic variant). In one additional undiagnosed proband, the detection of >900 heteroplasmic variants provided functional evidence of pathogenicity to a novel de novo variant in the nuclear gene POLG (DNA polymerase gamma), responsible for mtDNA replication and repair.
Conclusion: mtDNA variant calling from data generated by exome and genome sequencing for nuclear variant analysis resulted in a genetic diagnosis or detection of a candidate variant for 0.4% of undiagnosed families affected by a broad range of rare diseases.

DOI: https://doi.org/10.1101/2024.12.22.24319370
Life Sci Alliance. 2025 Mar;pii: e202403013. [Epub ahead of print]8(3):

COA5 has an essential role in the early stage of mitochondrial complex IV assembly.

Jia Xin Tang, Alfredo Cabrera-Orefice, Jana Meisterknecht, Lucie S Taylor, Geoffray Monteuuis, Maria Ekman Stensland, Adam Szczepanek, Karen Stals, James Davison, Langping He, Sila Hopton, Tuula A Nyman, Christopher B Jackson, Angela Pyle, Monika Winter, Ilka Wittig, Robert W Taylor.

Pathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in whom we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with a similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role of COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role in the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.

DOI: https://doi.org/10.26508/lsa.202403013
Cureus. 2024 Dec;16(12): e75268

Radiologic Findings in a Patient With Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes Syndrome: A Case Report.

Sariah Watchalotone, Halley McDonald, Jessica Degolier, Alex Schlangen, Imtiaz Ahmed.

  Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare, genetically inherited mitochondrial disorder that typically manifests in childhood. The most common radiologic features include basal ganglia calcification, atrophy, and stroke-like cortical lesions. We present the case of an 18-year-old female patient with no known medical history who arrived at the emergency department with altered mental status following a suicide attempt. The patient's initial workup, including a computed tomography (CT) scan of the brain, revealed abnormal findings, prompting further investigation into the patient's medical history. It was later discovered that the patient had a previous diagnosis of MELAS syndrome. This diagnosis helped explain both the radiologic abnormalities and her psychiatric symptoms. This case underscores the importance of recognizing radiologic presentations of rare conditions such as MELAS syndrome, which may contribute to the broader spectrum of clinical manifestations associated with the disease.

Keywords:  bilateral basal ganglia calcification; central venous thrombosis; melas syndrome; mitochondrial disorder; rare genetic disorder

DOI:  https://doi.org/10.7759/cureus.75268
Fetal Pediatr Pathol. 2025 Jan 06. 1-10

Challenges Faced by Newborns with Inherited Metabolic Disorders and Their Mothers During Antepartum, Intrapartum, and Postpartum Periods.

Merve Koç Yekedüz, Gözde Nur Yağci, İlknur Sürücü Kara, Merve Evgin, Engin Kose, Fatma Tuba Eminoğlu.

  Inherited metabolic disorders (IMDs) pose various obstetric challenges. In this study investigates the prenatal and perinatal profiles of pregnancies affected by IMDs and examines their obstetric outcomes. The most frequently observed antepartum issues identified among 996 patients with IMDs were intrauterine growth restriction (IUGR), intrauterine microcephaly and oligohydramnios. It was notable that mitochondrial disorders are associated with increased incidence of oligohydramnios (p = 0.010), IUGR (p < 0.001), microcephaly (p < 0.001) and intrauterine cardiac issues (p = 0.002). Furthermore, the incidence of intrauterine and natal facial malformations was significantly elevated in the patient groups with mitochondrial (p < 0.001) and lysosomal/peroxisomal diseases (p = 0.037) when compared to the other IMD groups. The mothers of newborns with mitochondrial diseases developed significantly more complications during previous pregnancies than those with other diagnoses (p = 0.040). Identifying risk factors and complications early on can greatly improve outcomes for both mother and infant by facilitating timely intervention and treatment.

Keywords:  Antepartum; inherited metabolic disorders; intrapartum; obstetric; postpartum; problems

DOI:  https://doi.org/10.1080/15513815.2024.2447082
Healthcare (Basel). 2024 Dec 21. pii: 2578. [Epub ahead of print]12(24):

Caregiver-Reported Economic Impacts of Pediatric Rare Diseases-A Scoping Review.

Niamh Buckle, Orla Doyle, Naonori Kodate, Melissa Kinch, Suja Somanadhan.

  Background/Objectives: Rare diseases are conditions that are individually rare but collectively common. These diseases can incur significant direct and indirect costs with a combination of high medical expenses, loss of income, and additional non-medical costs. Despite this, research into the economic cost for families of children with a rare disease is lacking. This scoping review aimed to document the evidence on the economic impacts of living with a rare disease for children and their families. Methods: Six electronic databases were searched to identify relevant peer-reviewed literature that discussed the family costs (direct medical, direct non-medical, and indirect) of having a child with a rare disease, published between January 1983 and April 2023. The geographical location, type of rare disease, and language were not limited. Data were extracted from the included studies following the screening process and are reported following the PAGER framework for reporting scoping review results. Results: The final analysis included 28 studies. The studies highlighted areas of high costs, including visits to healthcare professionals (n = 36), medication costs (n = 11), presenteeism (n = 17), and informal care (n = 11). However, gaps in the existing research, such as the focus on metabolic or musculoskeletal rare diseases and the lack of a distinction between rare and ultra-rare diseases, were apparent. Conclusions: Having a child with a rare disease can significantly impact a family's financial health, and these costs extend beyond healthcare costs. Understanding the costs experienced by the rare disease population is important to better define and comprehend the economic impact of rare diseases.

Keywords:  economic impact; healthcare cost; indirect cost; non-healthcare cost; pediatric; rare disease

DOI:  https://doi.org/10.3390/healthcare12242578