bims-curels 2023-07-02 papers

Issue of 2023–07–02
six papers selected by
Cure Mito Foundation

Nat Metab. 2023 06;5(6): 955-967

Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.

Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during normative ageing, also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh syndrome. Here we show that another drug that extends lifespan and delays normative ageing in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of inhibition of the mechanistic target of rapamycin. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short-chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression, while depletion of the endogenous microbiome in Ndufs4-/- mice appears to fully recapitulate the effects of acarbose on healthspan and lifespan in these animals. To our knowledge, this study provides the first evidence that alteration of the gut microbiome plays a significant role in severe mitochondrial disease and provides further support for the model that biological ageing and severe mitochondrial disorders share underlying common mechanisms.

DOI: https://doi.org/10.1038/s42255-023-00815-w

Front Genet. 2023 ;14 1191159

Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases.

Asuman Gedikbasi, Guven Toksoy, Meryem Karaca, Cagri Gulec, Mehmet Cihan Balci, Dilek Gunes, Seda Gunes, Ayca Dilruba Aslanger, Gokcen Unverengil, Birsen Karaman, Seher Basaran, Mubeccel Demirkol, Gulden Fatma Gokcay, Zehra Oya Uyguner.

Background: Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed. Methods: Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alterations in five other affected family members and healthy parents. Results: Exome sequencing revealed 14 different pathogenic variants in nine genes encoding mitochondrial function peptides (AARS2, EARS2, ECHS1, FBXL4, MICOS13, NDUFAF6, OXCT1, POLG, and TK2) in 12 patients from nine families and four variants in genes encoding important for muscle structure (CAPN3, DYSF, and TCAP) in six patients from four families. Three probands carried pathogenic mtDNA variations in two genes (MT-ATP6 and MT-TL1). Nine variants in five genes are reported for the first time with disease association: (AARS2: c.277C>T/p.(R93*), c.845C>G/p.(S282C); EARS2: c.319C>T/p.(R107C), c.1283delC/p.(P428Lfs*); ECHS1: c.161G>A/p.(R54His); c.202G>A/p.(E68Lys); NDUFAF6: c.479delA/p.(N162Ifs*27); and OXCT1: c.1370C>T/p.(T457I), c.1173-139G>T/p.(?). Conclusion: Bi-genomic DNA sequencing clarified genetic etiology in 67% (16/24) of the families. Diagnostic utility by mtDNA sequencing in 13% (3/24) and exome sequencing in 54% (13/24) of the families prioritized searching for nuclear genome pathologies for the first-tier test. Weakness and muscle wasting observed in 17% (4/24) of the families underlined that limb-girdle muscular dystrophy, similar to mitochondrial myopathy, is an essential point for differential diagnosis. The correct diagnosis is crucial for comprehensive genetic counseling of families. Also, it contributes to making treatment-helpful referrals, such as ensuring early access to medication for patients with mutations in the TK2 gene.

Keywords: bi-genomic sequencing; differential diagnosis; exome sequencing; mitochondrial diseases; mtDNA

DOI: https://doi.org/10.3389/fgene.2023.1191159

Clin Hypertens. 2023 Jul 01. 29(1): 18

Arterial hypertension in Leigh syndrome due to m.13513G > A is multicausal, requiring an extensive search to identify its pathphysiology.

Josef Finsterer.

Keywords: Arterial hypertension; Brain; Cardiac; Catecholamines; Leigh syndrome; mtDNA

DOI: https://doi.org/10.1186/s40885-023-00247-4

J Patient Exp. 2023 ;10 23743735231183677

Patient-Partners as Educators: Vulnerability Related to Sharing of Lived Experience.

Kateryna Metersky, Rezwana Rahman, Jennifer Boyle.

Patient-partners are invaluable in health professions' education. Sharing their lived experiences with prospective and current healthcare providers can provide an opportunity for these participants to hone their patient-centric skills. However, sharing stories publicly is a vulnerable role and may feel emotionally risky for patient-partners. Using reflective dialogue, this manuscript outlines recommendations through the Sender-Receiver Model of Communication for Patient-Partners encounters when working with patient-partners in health professions' education. These recommendations include recognizing that: Patient-partners need to consider if they are ready to share their story. Some stories are wounds requiring further healing; other stories are scars fully processed by patient-partners and ready to be shared publicly.The audience should differentiate between questions that can promote critical thinking versus feel like a "personal attack." Audiences should recognize vulnerability patient-partners may experience in sharing their stories and engage accordingly.Pre-session and post-session debriefs are important. Shared stories may elicit intense emotions from patient-partners and audiences. Both groups should be given an opportunity to process and work through emotions.

Keywords: interprofessional education; patient engagement; patient expectations; patient feedback; patient perspectives/narratives; patient satisfaction; patient/relationship centered skills

DOI: https://doi.org/10.1177/23743735231183677

Stud Health Technol Inform. 2023 Jun 29. 305 139-140

Context-Sensitive Common Data Models for Genetic Rare Diseases - A Concept.

Najia Ahmadi, Michele Zoch, Brita Sedlmayr, Katharina Schuler, Waldemar Hahn, Martin Sedlmayr, Markus Wolfien.

Current challenges of rare diseases need to involve patients, physicians, and the research community to generate new insights on comprehensive patient cohorts. Interestingly, the integration of patient context has been insufficiently considered, but might tremendously improve the accuracy of predictive models for individual patients. Here, we conceptualized an extension of the European Platform for Rare Disease Registration data model with contextual factors. This extended model can serve as an enhanced baseline and is well-suited for analyses using artificial intelligence models for improved predictions. The study is an initial result that will develop context-sensitive common data models for genetic rare diseases.

Keywords: Common Data Model; Context-Sensitive; Rare Disease

DOI: https://doi.org/10.3233/SHTI230443

J Am Acad Orthop Surg. 2023 Jun 23.

The Use of Patient-Reported Outcome Measures in Clinical Practice and Clinical Decision Making.

Eric C Makhni, Mary E Hennekes.

Patient-reported outcome measures (PROMs) are highly effective measures of quality of care and outcomes that matter to patients regarding their physical, mental, and social health. While PROMs have played a notable role in research and registry reporting, they are also useful as clinical tools. Real-time PROM collection can be integrated into routine clinical care with immediate access to scores within the electronic health record. This can be integral when discussing treatment options and using decision aids. PROM scores can also be useful for postoperative monitoring. Various approaches to quantifying clinical efficacy have been developed, including the minimal clinically important difference, the substantial clinical benefit, and the patient acceptable symptom state (PASS). As the patient experience and patient-reported outcome measurement of health-related outcomes become increasingly emphasized in patient-centered, high value care, so too will the importance of methods to gauge clinical benefit using these instruments for improved clinical decision-making.

DOI: https://doi.org/10.5435/JAAOS-D-23-00040