bims-symami 2023-06-04 papers

Issue of 2023‒06‒04
six papers selected by
The Lily Foundation

Orphanet J Rare Dis. 2023 05 29. 18(1): 129

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

Sameen Haque, Karen Crawley, Rupendra Shrestha, Deborah Schofield, Carolyn M Sue.

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.

Keywords: Health care costs; Health resources; Health services; Mitochondrial diseases; Mitochondrial disorders; Outpatients

DOI: https://doi.org/10.1186/s13023-023-02746-x

Ann Neurol. 2023 May 31.

Expert panel curation of 113 primary mitochondrial disease genes for the Leigh syndrome spectrum.

NICHD ClinGen U24 Mitochondrial Disease Gene Curation Expert Panel

OBJECTIVE: Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present in adults. A major challenge for accurate diagnosis of LSS in the genomic medicine era is establishing gene-disease relationships (GDRs) for this syndrome with >100 monogenic causes across both nuclear and mitochondrial genomes.METHODS: The Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP), comprising 40 international PMD experts, met monthly for 4 years to review GDRs for LSS. The GCEP standardized gene curation for LSS by refining the phenotypic definition, modifying the ClinGen Gene-Disease Clinical Validity Curation Framework to improve interpretation for LSS, and establishing a scoring rubric for LSS.
RESULTS: The GDR with LSS across the nuclear and mitochondrial genomes was classified as definitive for 31/114 gene-disease relationships curated (27%); moderate for 38 (33%); limited for 43 (38%); and 2 as disputed (2%). Ninety genes were associated with autosomal recessive inheritance, 16 were maternally inherited, 5 autosomal dominant, and 3 X-linked.
INTERPRETATION: GDRs for LSS were established for genes across both nuclear and mitochondrial genomes. Establishing these GDRs will allow accurate variant interpretation, expedite genetic diagnosis of LSS, and facilitate precision medicine, multi-system organ surveillance, recurrence risk counselling, reproductive choice, natural history studies and eligibility for interventional clinical trials. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ana.26716

Acta Neuropathol Commun. 2023 May 31. 11(1): 86

Astrocytic pathology in Alpers' syndrome.

Laura A Smith, Chun Chen, Nichola Z Lax, Robert W Taylor, Daniel Erskine, Robert McFarland.

Refractory epilepsy is the main neurological manifestation of Alpers' syndrome, a severe childhood-onset mitochondrial disease caused by bi-allelic pathogenic variants in the mitochondrial DNA (mtDNA) polymerase gamma gene (POLG). The pathophysiological mechanisms underpinning neuronal hyperexcitabilty leading to seizures in Alpers' syndrome remain unknown. However, pathological changes to reactive astrocytes are hypothesised to exacerbate neural dysfunction and seizure-associated cortical activity in POLG-related disease. Therefore, we sought to phenotypically characterise astrocytic pathology in Alpers' syndrome. We performed a detailed quantitative investigation of reactive astrocytes in post-mortem neocortical tissues from thirteen patients with Alpers' syndrome, eight neurologically normal controls and five sudden unexpected death in epilepsy (SUDEP) patients, to control for generalised epilepsy-associated astrocytic pathology. Immunohistochemistry to identify glial fibrillary acidic protein (GFAP)-reactive astrocytes revealed striking reactive astrogliosis localised to the primary visual cortex of Alpers' syndrome tissues, characterised by abnormal-appearing hypertrophic astrocytes. Phenotypic characterisation of individual GFAP-reactive astrocytes demonstrated decreased abundance of mitochondrial oxidative phosphorylation (OXPHOS) proteins and altered expression of key astrocytic proteins including Kir4.1 (subunit of the inwardly rectifying K+ ion channel), AQP4 (astrocytic water channel) and glutamine synthetase (enzyme that metabolises glutamate). These phenotypic astrocytic changes were typically different from the pathology observed in SUDEP tissues, suggesting alternative mechanisms of astrocytic dysfunction between these epilepsies. Crucially, our findings provide further evidence of occipital lobe involvement in Alpers' syndrome and support the involvement of reactive astrocytes in the pathogenesis of POLG-related disease.

Keywords: Alpers’ syndrome; Aquaporin 4 (AQP4); GFAP; Glutamine synthetase (GS); Kir4.1; Mitochondrial Epilepsy; POLG; Reactive astrogliosis

DOI: https://doi.org/10.1186/s40478-023-01579-w

Neurology. 2023 Jun 02. pii: 10.1212/WNL.0000000000207402. [Epub ahead of print]

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.

MMPOWER-3 Trial Investigators

BACKGROUND AND OBJECTIVES: Primary Mitochondrial Myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely impacting physical function, exercise capacity, and quality of life (QoL). Current PMM standards-of-care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically-confirmed PMM.METHODS: Following screening, eligible participants were randomized 1:1 to receive either 24weeks of elamipretide 40mg/day or placebo subcutaneously. Primary efficacy endpoints included change from baseline to Week 24 on the distance walked on the 6-minute Walk Test (6MWT), and Total Fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included Most Bothersome Symptom Score on the PMMSA, NeuroQoL Fatigue Short Form scores, and the Patient- and Clinician-Global Impression of PMM Symptoms.
RESULTS: Participants (N=218) were randomized (n=109 elamipretide; n=109 placebo). Mean age was 45.6 year (64% women; 94% white). The majority of participants (n=162 [74%]) had mitochondrial DNA (mtDNA) mutations, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, mean distance walked on the 6MWT was 336.7±81.2 meters, mean score for Total Fatigue on the PMMSA was 10.6±2.5, and mean T-score for the Neuro-QoL Fatigue Short Form was 54.7±7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA Total Fatigue Score (TFS). Between the participants receiving elamipretide versus placebo, the difference in the Least Squares Mean (SE) from baseline to Week 24 on distance walked on the 6MWT was -3.2 (95% confidence interval,-18.7,12.3; p=0.69) meters and on the PMMSA Total Fatigue Score was -0.07 (95% confidence interval,-0.10,0.26; p=0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity.
DISCUSSION: Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated.
TRIAL REGISTRATION INFORMATION: Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017;first patient enrolled October 9, 2017. https://clinicaltrials.gov/ct2/show/NCT03323749?term=elamipretide&draw=2&rank=9 CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that elamipretide does not improve the 6 minute walk test or fatigue at 24 weeks compared to placebo in patients with primary mitochondrial myopathy.

Keywords: elamipretide; exercise intolerance; myopathy; primary mitochondrial disease; primary mitochondrial myopathy

DOI: https://doi.org/10.1212/WNL.0000000000207402

HGG Adv. 2023 Jul 13. 4(3): 100202

The genetic and phenotypic correlates of mtDNA copy number in a multi-ancestry cohort.

Penn Medicine BioBank

Mitochondrial DNA copy number (mtCN) is often treated as a proxy for mitochondrial (dys-) function and disease risk. Pathological changes in mtCN are common symptoms of rare mitochondrial disorders, but reported associations between mtCN and common diseases vary across studies. To understand the biology of mtCN, we carried out genome- and phenome-wide association studies of mtCN in 30,666 individuals from the Penn Medicine BioBank (PMBB)-a diverse cohort of largely African and European ancestry. We estimated mtCN in peripheral blood using exome sequence data, taking cell composition into account. We replicated known genetic associations of mtCN in the PMBB and found that their effects are highly correlated between individuals of European and African ancestry. However, the heritability of mtCN was much higher among individuals of largely African ancestry (h2=0.3) compared with European ancestry individuals(h2=0.1). Admixture mapping suggests that there are undiscovered variants underlying mtCN that are differentiated in frequency between individuals with African and European ancestry. We show that mtCN is associated with many health-related phenotypes. We discovered robust associations between mtDNA copy number and diseases of metabolically active tissues, such as cardiovascular disease and liver damage, that were consistent across African and European ancestry individuals. Other associations, such as epilepsy and prostate cancer, were only discovered in either individuals with European or African ancestry but not both. We show that mtCN-phenotype associations can be sensitive to blood cell composition and environmental modifiers, explaining why such associations are inconsistent across studies. Thus, mtCN-phenotype associations must be interpreted with care.

Keywords: GWAS; Mitochondrial DNA; Penn Medicine Biobank; PheWAS; heritability; mtDNA copy number; multi-ancestry

DOI: https://doi.org/10.1016/j.xhgg.2023.100202

J Diabetes Investig. 2023 May 29.

Fibroblast growth factor 21 as a candidate of a novel serum biomarker for mitochondrial diabetes.

Yuji Komorita, Akiyo Shiroozu, Hidetoshi Nakamura.

Serum fibroblast growth factor 21 levels in patients with mitochondrial diabetes might be much higher than in those with other diabetes types. The results of this study could lead to the establishment of a simple method for screening mitochondrial diabetes using peripheral blood serum.

DOI: https://doi.org/10.1111/jdi.14030