bims-curels Biomed News
on Leigh syndrome
Issue of 2024–05–19
seven papers selected by
Cure Mito Foundation
  1. Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.
  2. The Blood-Brain Barrier Is Unaffected in the Ndufs4-/- Mouse Model of Leigh Syndrome.
  3. Mitochondrial cardiomyopathy: a puzzle for the final diagnosis.
  4. Mitochondrial Biomarkers in the Omics Era: A Clinical-Pathophysiological Perspective.
  5. A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies.
  6. Exploring the role of digital tools in rare disease management: An interview-based study.
  7. Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A.
  1. J Neuromuscul Dis. 2024 May 13.
    Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.
    Catarina Olimpio, Ida Paramonov, Leslie Matalonga, Steven Laurie, Katherine Schon, Kiran Polavarapu, Janbernd Kirschner, Ulrike Schara-Schmidt, Hanns Lochmüller, Patrick F Chinnery, Rita Horvath.
       Background: The genetic diagnosis of mitochondrial disorders is complicated by its genetic and phenotypic complexity. Next generation sequencing techniques have much improved the diagnostic yield for these conditions. A cohort of individuals with multiple respiratory chain deficiencies, reported in the literature 10 years ago, had a diagnostic rate of 60% by whole exome sequencing (WES) but 40% remained undiagnosed.
    Objective: We aimed to identify a genetic diagnosis by reanalysis of the WES data for the undiagnosed arm of this 10-year-old cohort of patients with suspected mitochondrial disorders.
    Methods: The WES data was transferred and processed by the RD-Connect Genome-Phenome Analysis Platform (GPAP) using their standardized pipeline. Variant prioritisation was carried out on the RD-Connect GPAP.
    Results: Singleton WES data from 14 individuals was reanalysed. We identified a possible or likely genetic diagnosis in 8 patients (8/14, 57%). The variants identified were in a combination of mitochondrial DNA (n = 1, MT-TN), nuclear encoded mitochondrial genes (n = 2, PDHA1, and SUCLA2) and nuclear genes associated with nonmitochondrial disorders (n = 5, PNPLA2, CDC40, NBAS and SLC7A7). Variants in both the NBAS and CDC40 genes were established as disease causing after the original cohort was published. We increased the diagnostic yield for the original cohort by 15% without generating any further genomic data.
    CONCLUSIONS: In the era of multiomics we highlight that reanalysis of existing WES data is a valid tool for generating additional diagnosis in patients with suspected mitochondrial disease, particularly when more time has passed to allow for new bioinformatic pipelines to emerge, for the development of new tools in variant interpretation aiding in reclassification of variants and the expansion of scientific knowledge on additional genes.
    Keywords:  Mitochondrial diseases; mitochondrial genes; next generation sequencing; respiratory chain deficiencies
    DOI:  https://doi.org/10.3233/JND-240020
  2. Int J Mol Sci. 2024 Apr 29. pii: 4828. [Epub ahead of print]25(9):
    The Blood-Brain Barrier Is Unaffected in the Ndufs4-/- Mouse Model of Leigh Syndrome.
    Robin Reynaud-Dulaurier, Romain Clément, Sara Yjjou, Cassandra Cresson, Yasmina Saoudi, Mathilde Faideau, Michael Decressac.
      Mitochondrial dysfunction plays a major role in physiological aging and in many pathological conditions. Yet, no study has explored the consequence of primary mitochondrial deficiency on the blood-brain barrier (BBB) structure and function. Addressing this question has major implications for pharmacological and genetic strategies aimed at ameliorating the neurological symptoms that are often predominant in patients suffering from these conditions. In this study, we examined the permeability of the BBB in the Ndufs4-/- mouse model of Leigh syndrome (LS). Our results indicated that the structural and functional integrity of the BBB was preserved in this severe model of mitochondrial disease. Our findings suggests that pharmacological or gene therapy strategies targeting the central nervous system in this mouse model and possibly other models of mitochondrial dysfunction require the use of specific tools to bypass the BBB. In addition, they raise the need for testing the integrity of the BBB in complementary in vivo models.
    Keywords:  AAV vector; Leigh syndrome; blood–brain barrier; mitochondrial diseases
    DOI:  https://doi.org/10.3390/ijms25094828
  3. Cardiol Young. 2024 May 16. 1-4
    Mitochondrial cardiomyopathy: a puzzle for the final diagnosis.
    Andreia Duarte Constante, Susana Martins Abreu, Conceição Trigo.
      Hypertrophic cardiomyopathy in children has diverse causes. Mitochondrial diseases, a rare aetiology leading to cardiomyopathy in 20-40% of affected children, predominantly present as hypertrophic cardiomyopathy. Diagnosis is challenging due to inconsistent genotype-phenotype correlation, resulting in various clinical presentations. We present a case of a one-month-old infant with severe hypertrophic cardiomyopathy and cardiac tamponade. Genetic diagnosis revealed a Valyl-tRNA synthetase 2 (VARS2) gene mutation, linking it to mitochondrial encephalopathy-cardiomyopathy. This case highlights novel variants and expands the understanding of hypertrophic cardiomyopathy aetiology in infants.
    Keywords:  VARS2; hypertrophic cardiomyopathy; mitochondrial diseases
    DOI:  https://doi.org/10.1017/S1047951124025095
  4. Int J Mol Sci. 2024 Apr 29. pii: 4855. [Epub ahead of print]25(9):
    Mitochondrial Biomarkers in the Omics Era: A Clinical-Pathophysiological Perspective.
    Jacopo Gervasoni, Aniello Primiano, Michela Cicchinelli, Lavinia Santucci, Serenella Servidei, Andrea Urbani, Guido Primiano, Federica Iavarone.
      Mitochondrial diseases (MDs) affect 4300 individuals, with different ages of presentation and manifestation in any organ. How defects in mitochondria can cause such a diverse range of human diseases remains poorly understood. In recent years, several published research articles regarding the metabolic and protein profiles of these neurogenetic disorders have helped shed light on the pathogenetic mechanisms. By investigating different pathways in MDs, often with the aim of identifying disease biomarkers, it is possible to identify molecular processes underlying the disease. In this perspective, omics technologies such as proteomics and metabolomics considered in this review, can support unresolved mitochondrial questions, helping to improve outcomes for patients.
    Keywords:  FTIR; LC-MS; biomarkers; metabolomics; mitochondrial diseases; personalized medicine; proteomics
    DOI:  https://doi.org/10.3390/ijms25094855
  5. Orphanet J Rare Dis. 2024 May 16. 19(1): 200
    A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies.
    Daniele Sala, Silvia Marchet, Lorenzo Nanetti, Andrea Legati, Caterina Mariotti, Eleonora Lamantea, Daniele Ghezzi, Alessia Catania, Costanza Lamperti.
       BACKGROUND: MT-ATP6 is a mitochondrial gene which encodes for the intramembrane subunit 6 (or A) of the mitochondrial ATP synthase, also known asl complex V, which is involved in the last step of oxidative phosphorylation to produce cellular ATP through aerobic metabolism. Although classically associated with the NARP syndrome, recent evidence highlights an important role of MT-ATP6 pathogenic variants in complicated adult-onset ataxias.
    METHODS: We describe two unrelated patients with adult-onset cerebellar ataxia associated with severe optic atrophy and mild cognitive impairment. Whole mitochondrial DNA sequencing was performed in both patients. We employed patients' primary fibroblasts and cytoplasmic hybrids (cybrids), generated from patients-derived cells, to assess the activity of respiratory chain complexes, oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential.
    RESULTS: In both patients, we identified the same novel m.8777 T > C variant in MT-ATP6 with variable heteroplasmy level in different tissues. We identifed an additional heteroplasmic novel variant in MT-ATP6, m.8879G > T, in the patients with the most severe phenotype. A significant reduction in complex V activity, OCR and ATP production was observed in cybrid clones homoplasmic for the m.8777 T > C variant, while no functional defect was detected in m.8879G > T homoplasmic clones. In addition, fibroblasts with high heteroplasmic levelsof m.8777 T > C variant showed hyperpolarization of mitochondrial membranes.
    CONCLUSIONS: We describe a novel pathogenic mtDNA variant in MT-ATP6 associated with adult-onset ataxia, reinforcing the value of mtDNA screening within the diagnostic workflow of selected patients with late onset ataxias.
    Keywords:   MT-ATP6 ; ATP synthase; Ataxia; Complex V; Cybrids; Mitochondria; OXPHOS; Oxygen consumption
    DOI:  https://doi.org/10.1186/s13023-024-03212-y
  6. J Genet Couns. 2024 May 13.
    Exploring the role of digital tools in rare disease management: An interview-based study.
    Andrea Chang, Sarah D Huang, Daniel J Benjamin, Johanna L Schmidt, Christina G S Palmer, Nanibaa' A Garrison.
      While digital tools, such as the Internet, smartphones, and social media, are an important part of modern society, little is known about the specific role they play in the healthcare management of individuals and caregivers affected by rare disease. Collectively, rare diseases directly affect up to 10% of the global population, suggesting that a significant number of individuals might benefit from the use of digital tools. The purpose of this qualitative interview-based study was to explore: (a) the ways in which digital tools help the rare disease community; (b) the healthcare gaps not addressed by current digital tools; and (c) recommended digital tool features. Individuals and caregivers affected by rare disease who were comfortable using a smartphone and at least 18 years old were eligible to participate. We recruited from rare disease organizations using purposive sampling in order to achieve a diverse and information rich sample. Interviews took place over Zoom and reflexive thematic analysis was utilized to conceptualize themes. Eight semistructured interviews took place with four individuals and four caregivers. Three themes were conceptualized which elucidated key aspects of how digital tools were utilized in disease management: (1) digital tools should lessen the burden of managing a rare disease condition; (2) digital tools should foster community building and promote trust; and (3) digital tools should provide trusted and personalized information to understand the condition and what the future may hold. These results suggest that digital tools play a central role in the lives of individuals with rare disease and their caregivers. Digital tools that centralize trustworthy information, and that bring the relevant community together to interact and promote trust are needed. Genetic counselors can consider these ideal attributes of digital tools when providing resources to individuals and caretakers of rare disease.
    Keywords:  caregivers; complex disease; digital tools; disability; parents; rare disease
    DOI:  https://doi.org/10.1002/jgc4.1908
  7. Am J Ophthalmol Case Rep. 2024 Jun;34 102070
    Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A.
    Cansu de Muijnck, Mary J van Schooneveld, Astrid S Plomp, Richard J Rodenburg, Maria M van Genderen, Camiel J F Boon.
       Purpose: To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of MT-ATP6 gene variant m.8969G > A.
    Observations: A 20-year-old patient with a history of mild developmental delay, mild cognitive impairment, and positional tremor presented with subacute painless visual loss over a few weeks. Mitochondrial genome sequencing revealed a variant in MT-ATP6, m.8969G > A (p.Ser148Asn). This variant was previously reported in association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) and with nephropathy, followed by brain atrophy, muscle weakness and arrhythmias, but not with optic atrophy.
    Conclusions and importance: Rare variants in MT-ATP6 can also cause LHON like optic atrophy. It is important to perform further genetic analysis of mitochondrial DNA in genetically unsolved cases suspected of Leber's hereditary optic neuropathy to confirm the clinical diagnosis.
    Keywords:  Leber's hereditary optic neuropathy; MT-ATP6; Optic atrophy
    DOI:  https://doi.org/10.1016/j.ajoc.2024.102070
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