COVID-19-Related Outcomes in Primary Mitochondrial Diseases: An International Study

OBJECTIVES: To identify factors associated with severe COVID-19, defined by hospitalization status, in patients with primary mitochondrial diseases (PMDs), thereby enabling future risk stratification and informed management decisions. METHODS: We undertook a cross-sectional, international, registry-based study. Data was extracted from the "International Neuromuscular COVID-19 Database" and collected between 1st May 2020 and 31st May 2021. The database included subjects with: 1) PMD diagnosis (any age), clinically/histopathologically suspected and/or genetically confirmed; and (2) COVID-19 diagnosis classified as "confirmed", "probable", or "suspected" based on World Health Organization definitions. The primary outcome was hospitalization due to COVID-19. We collected demographic information, smoking status, coexisting comorbidities, outcome following COVID-19 infection, and PMD genotype-phenotype. Baseline status was assessed using the modified Rankin scale (mRS) and the Newcastle Mitochondrial Disease Adult Scale (NMDAS). RESULTS: Seventy-nine subjects with PMDs from 10 countries were included (mean age 41.5±18 years): 25 (32%) were hospitalized; 48 (61%) recovered fully; 28 (35%) improved with sequelae; and three (4%) died. Statistically significant differences in hospitalization status were observed in: baseline status, including NMDAS score (p=0.003) and mRS (p=0.001); presence of respiratory dysfunction (p<0.001), neurologic involvement (p=0.003); and more than four comorbidities (p=0.002). In multivariable analysis, respiratory dysfunction was independently associated with COVID-19 hospitalization (OR, 7.66; 95%CI, 2 to 28; p=0.002). DISCUSSION: Respiratory dysfunction is an independent risk factor for severe COVID-19 in PMDs, while high disease burden and coexisting comorbidities contribute towards COVID-19 related hospitalization. These findings will enable risk stratification and informed management decisions for this vulnerable population

Critical Early Roles for col27a1a and col27a1b in Zebrafish Notochord Morphogenesis, Vertebral Mineralization and Post-embryonic Axial Growth

Fibrillar collagens are well known for their links to human diseases, with which all have been associated except for the two most recently identified fibrillar collagens, type XXIV collagen and type XXVII collagen. To assess functions and potential disease phenotypes of type XXVII collagen, we examined its roles in zebrafish embryonic and post-embryonic development.We identified two type XXVII collagen genes in zebrafish, col27a1a and col27a1b. Both col27a1a and col27a1b were expressed in notochord and cartilage in the embryo and early larva. To determine sites of type XXVII collagen function, col27a1a and col27a1b were knocked down using morpholino antisense oligonucleotides. Knockdown of col27a1a singly or in conjunction with col27a1b resulted in curvature of the notochord at early stages and formation of scoliotic curves as well as dysmorphic vertebrae at later stages. These defects were accompanied by abnormal distributions of cells and protein localization in the notochord, as visualized by transmission electron microscopy, as well as delayed vertebral mineralization as detected histologically.Together, our findings indicate a key role for type XXVII collagen in notochord morphogenesis and axial skeletogenesis and suggest a possible human disease phenotype

Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics.

Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B are an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mitochondrial DNA deletions in adults, following POLG [polymerase (DNA directed), gamma] and PEO1 (now called C10ORF2, encoding the Twinkle helicase) mutations. However, the clinico-pathological and molecular features of adults with RRM2B-related disease have not been clearly defined. In this multicentre study of 26 adult patients from 22 independent families, including five additional cases published in the literature, we show that extra-ocular neurological complications are common in adults with genetically confirmed RRM2B mutations. We also demonstrate a clear correlation between the clinical phenotype and the underlying genetic defect. Myopathy was a prominent manifestation, followed by bulbar dysfunction and fatigue. Sensorineural hearing loss and gastrointestinal disturbance were also important findings. Severe multisystem neurological disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype with a later mean age of disease onset at 46 years. Skeletal muscle biopsies revealed subsarcolemmal accumulation of mitochondria and/or cytochrome c oxidase-deficient fibres. Multiple mitochondrial DNA deletions were universally present in patients who underwent a muscle biopsy. We identified 18 different heterozygous RRM2B mutations within our cohort of patients, including five novel mutations that have not previously been reported. Despite marked clinical overlap between the mitochondrial maintenance genes, key clinical features such as bulbar dysfunction, hearing loss and gastrointestinal disturbance should help prioritize genetic testing towards RRM2B analysis, and sequencing of the gene may preclude performance of a muscle biopsy

Outcomes after urgent thyroidectomy following rapid control of thyrotoxicosis in Graves’ disease are similar to those after elective surgery in well-controlled disease

Background Surgery for Graves’ disease (GD) is usually performed after adequate control with medical treatment. Occasionally, rapid pre-operative optimization is required. The primary objective was to compare the outcomes of patients undergoing elective surgery for well-controlled GD with those undergoing rapid pre-operative treatment. We also propose a formal treatment protocol for future use. Methods A retrospective cohort study in a tertiary referral centre included 247 patients with well-controlled GD undergoing elective surgery and 19 patients with poorly controlled disease undergoing surgery after rapid optimization. The latter group did not respond well to thionamides (carbimazole and/or propylthiouracil) or had intolerance or side effects to thionamides and were treated with a range of non-thionamide drugs, including Lugol’s iodine, cholestyramine, beta blockers and steroids (with or without thionamides), and closely monitored for 1–2 weeks before surgery. Outcome measures included thyroid storm, hypoparathyroidism and recurrent laryngeal nerve palsy. Results In total, 266 patients with male-to-female ratio of 1:6 and median (interquartile range) age of 39 (31–51) were included. Overall, long-term recurrent laryngeal palsy and hypoparathyroidism occurred in 1 (0.38%) and 13 (4.9%) patients, respectively. No patient had thyroid storm. There was no significant difference in hypoparathyroidism (p = 1), vocal cord palsy (p = 0.803) and post-operative bleeding (p = 0.362), between elective surgery and rapid optimization groups. Conclusion Rapid pre-operative treatment is effective, safe and is associated with similar outcomes compared to usual treatment. A rapid pre-operative optimization protocol is proposed

Magnitude of potentially inappropriate prescribing in Germany among older patients with generalized anxiety disorder

<p>Abstract</p> <p>Background</p> <p>Several medications commonly used to treat generalized anxiety disorder (GAD) have been designated "potentially inappropriate" for use in patients aged ≥65 years because their risks may outweigh their potential benefits. The actual extent of use of these agents in clinical practice is unknown, however.</p> <p>Methods</p> <p>Using a database with information from encounters with general practitioners (GP) in Germany, we identified all patients, aged ≥65 years, with any GP office visits or dispensed prescriptions with a diagnosis of GAD (ICD-10 diagnosis code F41.1) between 10/1/2003 and 9/30/2004 ("GAD patients"). Among GAD-related medications (including benzodiazepines, tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors, venlafaxine, hydroxyzine, buspirone, pregabalin, and trifluoperazine), long-acting benzodiazepines, selected short-acting benzodiazepines at relatively high dosages, selected TCAs, and hydroxyzine were designated "potentially inappropriate" for use in patients aged ≥ 65 years, based on published criteria.</p> <p>Results</p> <p>A total of 975 elderly patients with GAD were identified. Mean age was 75 years, and 72% were women; 29% had diagnoses of comorbid depression. Forty percent of study subjects received potentially inappropriate agents – most commonly, bromazepam (10% of all subjects), diazepam (9%), doxepin (7%), amitriptyline (5%), and lorazepam (5%). Twenty-three percent of study subjects received long-acting benzodiazepines, 10% received short-acting benzodiazepines at relatively high doses, and 12% received TCAs designated as potentially inappropriate.</p> <p>Conclusion</p> <p>GPs in Germany often prescribe medications that have been designated as potentially inappropriate to their elderly patients with GAD – especially those with comorbid depressive disorders. Further research is needed to ascertain whether there are specific subgoups of elderly patients with GAD for whom the benefits of these medications outweigh their risks.</p

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

BACKGROUND AND OBJECTIVES: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting 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: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d 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 global impression and clinician global impression of PMM symptoms. RESULTS: Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, 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, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the 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 and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was -3.2 (95% CI -18.7 to 12.3; p = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 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. 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 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy

MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load.

Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5·4months-37years, IQR=17·9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C

Peer-Victimization and Mental Health Problems in Adolescents: Are Parental and School Support Protective?

The aim of this study was to investigate the frequency and effects of peer-victimization on mental health problems among adolescents. Parental and school support were assumed as protective factors that might interact with one another in acting as buffers for adolescents against the risk of peer-victimization. Besides these protective factors, age and gender were additionally considered as moderating factors. The Social and Health Assessment survey was conducted among 986 students aged 11–18 years in order to assess peer-victimization, risk and protective factors and mental health problems. For mental health problems, the Strengths and Difficulties Questionnaire (SDQ) was used. Effects of peer-victimization on mental health problems were additionally compared with normative SDQ data in order to obtain information about clinically relevant psychopathology in our study sample. Results of this study show that peer-victimization carries a serious risk for mental health problems in adolescents. School support is effective in both male and female adolescents by acting as a buffer against the effect of victimization, and school support gains increasing importance in more senior students. Parental support seems to be protective against maladjustment, especially in peer-victimized girls entering secondary school. Since the effect of peer-victimization can be reduced by parental and school support, educational interventions are of great importance in cases of peer-victimization