Patient care standards for primary mitochondrial disease in Australia: an Australian adaptation of the Mitochondrial Medicine Society recommendations.

This document provides consensus-based recommendations for general physicians and primary care physicians who diagnose and manage patients with mitochondrial diseases (MD). It builds on previous international guidelines, with particular emphasis on clinical management in the Australian setting. This statement was prepared by a working group of medical practitioners, nurses and allied health professionals with clinical expertise and experience in managing Australian patients with MD. As new treatments and management plans emerge, these consensus-based recommendations will continue to evolve, but current standards of care are summarised in this document.

Clinical drivers of hospitalisation in patients with mitochondrial diseases.

Background: Mitochondrial diseases in adults are generally chronic conditions with a wide spectrum of severity contributing to disease burden and healthcare resource utilisation. Data on healthcare resource utilisation in mitochondrial diseases are limited. Objectives: We performed a retrospective longitudinal study to investigate the clinical drivers of hospitalisation in adult patients with mitochondrial diseases to better understand healthcare resource utilisation. Methods: We recruited participants from our specialised Mitochondrial Disease Clinic in Sydney, Australia between September 2018 and December 2021. We performed a retrospective chart review for the period 2013-2022 considering emergency department (ED) and/or hospital admission notes, as well as discharge summaries. We used multiple linear regression models to examine the association between the type of presenting symptom(s) and duration of hospital stay and frequency of admissions, while adjusting for relevant covariates. Results: Of the 99 patients considered, the duration of hospitalisation ranged from 0 to 116 days per participant and the number of admissions ranged from 0 to 21 per participant. Participants with one or more mitochondrial disease-associated admissions constituted 52% of the study cohort. 13% of the participants presented to the ED without requiring an admission and 35% never attended the ED or required a hospital admission during this period. Neurological (p<0.0001), gastroenterological (p=0.01) and symptoms categorised as 'other' (p<0.0001) were the main presentations driving the total number of days admitted to hospital. A statistically significant association was evident for the number of admissions and all types of presenting symptoms (p<0.0001). Conclusion: There are variable reasons for hospitalisation in adults with mitochondrial diseases, with neurological and gastroenterological presentations being associated with prolonged and complex hospitalisation. A better understanding of clinical drivers such as these allows for better informed and well-coordinated management aimed at optimising healthcare resource utilisation.

Healthcare resource utilization of patients with mitochondrial disease in an outpatient hospital setting.

BACKGROUND AND OBJECTIVES: Mitochondrial diseases present as multi-system disorders requiring a comprehensive multidisciplinary approach. The data on healthcare resource utilization associated with mitochondrial diseases and the clinical drivers of these costs are limited including for the out-patient setting where the majority of the clinical care for mitochondrial disease patients occurs. We performed a cross-sectional retrospective study of out-patient healthcare resource utilization and costs for patients with a confirmed diagnosis of mitochondrial disease. METHODS: We recruited participants from the Mitochondrial Disease Clinic in Sydney and stratified them into three groups: those with mitochondrial DNA (mtDNA) mutations (Group 1), those with nuclear DNA (nDNA) mutations and the predominant phenotype of chronic progressive external ophthalmoplegia (CPEO) or optic atrophy (Group 2) and those without a confirmed genetic diagnosis but clinical criteria and muscle biopsy findings supportive of a diagnosis of mitochondrial disease (Group 3). Data was collected through retrospective chart review and out-patient costs were calculated using the Medicare Benefits Schedule. RESULTS: We analyzed the data from 91 participants and found that Group 1 had the greatest average out-patient costs per person per annum ($838.02; SD 809.72). Neurological investigations were the largest driver of outpatient healthcare costs in all groups (average costs per person per annum:-Group 1: $364.11; SD 340.93, Group 2: $247.83; SD 113.86 and Group 3: $239.57; SD 145.69) consistent with the high frequency (94.5%) of neurological symptoms. Gastroenterological and cardiac-related out-patient costs were also major contributors to out-patient healthcare resource utilization in Groups 1 and 3. In Group 2, ophthalmology was the second-most resource intensive specialty ($136.85; SD 173.35). The Group 3 had the greatest average healthcare resource utilization per person over the entire duration of out-patient clinic care ($5815.86; SD 3520.40) most likely due to the lack of a molecular diagnosis and a less customized management approach. CONCLUSION: The drivers of healthcare resource utilization are dependent on the phenotype-genotype characteristics. Neurological, cardiac, and gastroenterological costs were the top three drivers in the out-patient clinics unless the patient had nDNA mutations with predominant phenotype of CPEO and/or optic atrophy wherein ophthalmological-related costs were the second most resource intensive driver.

The DASH complex and Klp5/Klp6 kinesin coordinate bipolar chromosome attachment in fission yeast.

We identified a truncated allele of dam1 as a multicopy suppressor of the sensitivity of cdc13-117 (cyclin B) and mal3-1 (EB-1) cells to thiabendazole, a microtubule poison. We find that Dam1 binds to the plus end of spindle microtubules and kinetochores as cells enter mitosis and this is dependent on other components of the fission yeast DASH complex, including Ask1, Duo1, Spc34 and Dad1. By contrast, Dad1 remains bound to kinetochores throughout the cell cycle and its association is dependent on the Mis6 and Mal2, but not Mis12, Nuf2 or Cnp1, kinetochore proteins. In cells lacking Dam1, or other components of the DASH complex, anaphase is delayed due to activation of the spindle assembly checkpoint and lagging sister chromatids are frequently observed and occasionally sister chromatid pairs segregate to the same spindle pole. We find that the mitotic centromere-associated Klp5/Klp6 kinesin complex is essential in cells lacking components of the DASH complex. Cells lacking both Dam1 and Klp5 undergo a first cell cycle arrest in mitosis due to a failure to establish bipolar chromosome attachment.