Myopathology of Adult and Paediatric Mitochondrial Diseases.
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ABSTRACT:
SUBMITTER: Phadke R
PROVIDER: S-EPMC5532572 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:OBJECTIVE:To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions. METHODS:Muscle DNA samples from patients presenting with undefined encephalomyopathies or myopathies were analysed for mtDNA content by quantitative real-time PCR and for deletions by long-range PCR. Direct sequencing of mtDNA maintenance genes and whole-exome sequencing were used to study the genetic aetiologies of the diseases. Clinical and laboratory findings were collected. RESULTS:Muscle samples were obtained from 104 paediatric patients with neuromuscular diseases. mtDNA depletion was found in three patients with severe early-onset encephalomyopathy or myopathy. Two of these patients presented with novel types of mitochondrial DNA depletion syndromes associated with increased serum creatine kinase (CK) and multiorgan disease without mutations in any of the known mtDNA maintenance genes; one patient had pathologic endoplasmic reticulum (ER) membranes in muscle. The third patient with mtDNA depletion was diagnosed with merosine-deficient muscular dystrophy caused by a homozygous mutation in the LAMA2 gene. Two patients with an early-onset Kearns-Sayre/Pearson-like phenotype harboured a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content. CONCLUSIONS:Novel encephalomyopathic mtDNA depletion syndrome with structural alterations in muscle ER was identified. mtDNA depletion may also refer to secondary mitochondrial changes related to muscular dystrophy. We suggest that a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content associated with Kearns-Sayre/Pearson syndromes may be secondary changes caused by mutations in an unknown nuclear gene.
| S-EPMC4484910 | biostudies-literature
Project description:ObjectivesTo describe the experiences, priorities, and needs of patients with rheumatic disease and their parents during transition from paediatric to adult healthcare.SettingFace-to-face and telephone semistructured interviews were conducted from December 2018 to September 2019 recruited from five hospital centres in Australia.ParticipantsFourteen young people and 16 parents were interviewed. Young people were included if they were English speaking, aged 14-25 years, diagnosed with an inflammatory rheumatic disease (eg, juvenile idiopathic arthritis, juvenile dermatomyositis, systemic lupus erythematosus, panniculitis, familial Mediterranean fever) before 18 years of age. Young people were not included if they were diagnosed in the adult setting.ResultsWe identified four themes with respective subthemes: avoid repeat of past disruption (maintain disease stability, preserve adjusted personal goals, protect social inclusion); encounter a daunting adult environment (serious and sombre mood, discredited and isolated identity, fear of a rigid system); establish therapeutic alliances with adult rheumatology providers (relinquish a trusting relationship, seek person-focused care, redefine personal-professional boundaries, reassurance of alternative medical supports, transferred trust to adult doctor) and negotiate patient autonomy (confidence in formerly gained independence, alleviate burden on patients, mediate parental anxiety).ConclusionsDuring transition, patients want to maintain disease stability, develop a relationship with their adult provider centralised on personal goals and access support networks. Strategies to comprehensively communicate information between providers, support self-management, and negotiate individualised goals for independence during transition planning may improve satisfaction, and health and treatment outcomes.
| S-EPMC7783517 | biostudies-literature
Project description:ObjectiveThere is an urgent need for reliable and universally applicable outcome measures for children with mitochondrial diseases. In this study, we aimed to adapt the currently available Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to the International Paediatric Mitochondrial Disease Scale (IPMDS) during a Delphi-based process with input from international collaborators, patients and caretakers, as well as a pilot reliability study in eight patients. Subsequently, we aimed to test the feasibility, construct validity and reliability of the IPMDS in a multicentre study.MethodsA clinically, biochemically and genetically heterogeneous group of 17 patients (age 1.6-16 years) from five different expert centres from four different continents were evaluated in this study.ResultsThe feasibility of the IPMDS was good, as indicated by a low number of missing items (4 %) and the positive evaluation of patients, parents and users. Principal component analysis of our small sample identified three factors, which explained 57.9 % of the variance. Good construct validity was found using hypothesis testing. The overall interrater reliability was good [median intraclass correlation coefficient for agreement between raters (ICCagreement) 0.85; range 0.23-0.99).ConclusionIn conclusion, we suggest using the IPMDS for assessing natural history in children with mitochondrial diseases. These data should be used to further explore construct validity of the IPMDS and to set age limits. In parallel, responsiveness and the minimal clinically important difference should be studied to facilitate sample size calculations in future clinical trials.
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Project description:The evidence so far suggests that the paediatric inflammatory diseases encountered in rheumatology practice may be largely genetic in origin, where common single nucleotide polymorphisms (SNPs) in multiple genes contribute to risk, with real but variable environmental components. As far as genetic susceptibility to common paediatric rheumatic diseases is concerned, only juvenile idiopathic arthritis (JIA) has been investigated in any substantial way so far. This article discusses susceptibility for different types of JIA, the different methods used and their advantages and disadvantages. The genetic code is also modifiable by epigenetic mechanisms and examples of these in immunity and rheumatoid arthritis are given to indicate another area of research in the elucidation of the genetics of paediatric rheumatic diseases.
| S-EPMC2994185 | biostudies-literature
Project description:Differences in CD8+ T-cell expression have previously been reported to correlate with disease outcome in adult patients diagnosed with Inflammatory Bowel Diseases (IBD). In addition, T-cell exhaustion was found to be associated with a milder disease course in adults. The purpose of this study was to test the prognostic value of the reported adult T-cell expression and exhaustion signatures in a cohort of children newly diagnosed with Crohn's disease (CD) and ulcerative colitis (UC). We also investigated the possibility of a paediatric specific prognostic expression signature.
2019-09-01 | E-MTAB-7923 | biostudies-arrayexpress
Project description:BackgroundWhether decreased physical functioning of patients with mitochondrial disease (MD) is related to altered body composition or low protein intake needs clarification at the background of the nutrition state.MethodsIn this 2-site cross-sectional study, MD patients were age-, body mass index (BMI)-, and gender-matched to controls. Body composition was assessed by dual-energy x-ray absorptiometry. Physical functioning was measured by handgrip strength, 6-minute walking test, 30-second sit-to-stand test (30SCT), and 6-minute mastication test. Total daily protein intake was calculated by 3-day food records. Malnutrition was assessed by Patient-Generated Subjective Global Assessment and the Global Leadership Initiative on Malnutrition (GLIM) criteria and sarcopenia by the 2018 consensus. Data were analyzed using independent samples t-tests, Fisher exact test, and Spearman and Pearson correlation coefficients.ResultsThirty-seven MD patients (42 ± 12 years, BMI: 23 ± 4 kg/m2 , 59% females) and 37 matched controls were included. Handgrip strength was moderate, inversely related to fat mass index in both MD patients and controls, whereas it correlated with fat-free mass index in controls solely. Protein intake was associated with muscle strength (handgrip strength and 30SCT) in MD patients but not in controls. Twenty-seven MD patients (73%) were malnourished, and 5 (14%) were classified as sarcopenic.ConclusionsMuscle strength is related to body composition and protein intake in MD patients. This, in combination with the high incidence of both malnutrition and sarcopenia, warrants individual nutrition assessment in MD patients.
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Project description:As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes in morphology, components and functions in response to various environmental stresses and cellular demands. Previous studies of mitochondria research have gradually evolved, from focusing on morphological change analysis to systematic multiomics, thereby revealing the mitochondrial variation between cells or within the mitochondrial population within a single cell. The phenomenon of mitochondrial variation features is defined as mitochondrial heterogeneity. Moreover, mitochondrial heterogeneity has been reported to influence a variety of physiological processes, including tissue homeostasis, tissue repair, immunoregulation, and tumor progression. Here, we comprehensively review the mitochondrial heterogeneity in different tissues under pathological states, involving variant features of mitochondrial DNA, RNA, protein and lipid components. Then, the mechanisms that contribute to mitochondrial heterogeneity are also summarized, such as the mutation of the mitochondrial genome and the import of mitochondrial proteins that result in the heterogeneity of mitochondrial DNA and protein components. Additionally, multiple perspectives are investigated to better comprehend the mysteries of mitochondrial heterogeneity between cells. Finally, we summarize the prospective mitochondrial heterogeneity-targeting therapies in terms of alleviating mitochondrial oxidative damage, reducing mitochondrial carbon stress and enhancing mitochondrial biogenesis to relieve various pathological conditions. The possibility of recent technological advances in targeted mitochondrial gene editing is also discussed.
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Project description:In those who survive tuberculous meningitis (TBM), the long-term outcome is uncertain; individuals may suffer neurocognitive, functional and psychiatric impairment, which may significantly affect their ability to lead their lives as they did prior to their diagnosis of TBM. In children who survive, severe illness has occurred at a crucial timepoint in their development, which can lead to behavioural and cognitive delay. The extent and nature of this impairment is poorly understood, particularly in adults. This is in part due to a lack of observational studies in this area but also inconsistent inclusion of outcome measures which can quantify these deficits in clinical studies. This leads to a paucity of appropriate rehabilitative therapies available for these individuals and their caregivers, as well as burden at a socioeconomic level. In this review, we discuss what is known about neurocognitive impairment in TBM, draw on lessons learnt from other neurological infections and discuss currently available and emerging tools to evaluate function and cognition and their value in TBM. We make recommendations on which measures should be used at what timepoints to assess for impairment, with a view to optimising and standardising assessment of neurocognitive and functional impairment in TBM research.
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Project description:Mucopolysaccharidoses (MPS) are rare disorders associated with enzyme deficiencies, resulting in glycosaminoglycan (GAG) accumulation in multiple organ systems. As patients increasingly survive to adulthood, the need for a smooth transition into adult care is essential. Using case studies, we outline strategies and highlight the challenges of transition, illustrating practical solutions that may be used to optimise the transition process for patients with MPS disorders. Seven MPS case studies were provided by four European inherited metabolic disease centres; six of these patients transferred to an adult care setting and the final patient remained under paediatric care. Of the patients who transferred, age at the start of transition ranged between 14 and 18 years (age at transfer ranged from 16 to 19 years). While there were some shared features of transition strategies, they varied in duration, the healthcare professionals involved and the management of adult patients with MPS. Challenges included complex symptoms, patients' unwillingness to attend appointments with unfamiliar team members and attachment to paediatricians. Challenges were resolved by starting transition at an early age, educating patients and families, and providing regular communication with and reassurance to the patient and family. Sufficient time should be provided to allow patients to understand their responsibilities in the adult care setting while feeling assured of continued support from healthcare professionals. The involvement of a coordinated multidisciplinary team with expertise in MPS is also key. Overall, transition strategies must be comprehensive and individualised to patients' needs.
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Project description:The mitochondrial genome encodes core catalytic peptides that affect major metabolic processes within a cell. Here, we investigated the association between mitochondrial DNA (mtDNA) variants and allergic diseases, including atopic dermatitis (AD) and asthma, alongside heteroplasmy within the mtDNA in subjects with allergic sensitization. We collected genotype data from 973 subjects with allergic sensitization, consisting of 632 children with AD, 498 children with asthma, and 481 healthy controls by extracting DNA from their blood samples. Fisher's exact test was used to investigate mtDNA and nuclear DNA variants related to mitochondrial function (MT-nDNA) to identify their association with allergic diseases. Among the 69 mtDNA variants, rs28357671 located on the MT-ND6 gene displayed statistically significant associations with allergic diseases (Bonferroni-corrected P < 7.25E-4), while 6, 4, and 2 genes were associated with allergic sensitization, AD, and asthma, respectively (P < 0.0002), including NLRX1, OCA2, and CHCHD3 among the MT-nDNA genes. Heteroplasmy of mitochondrial DNA associated with allergic sensitization was evaluated in a separate cohort of patients consisting of 59 subjects with allergic sensitization and 52 controls. Heteroplasmy was verified when a patient carried both alleles of a mitochondrial single-nucleotide polymorphism (SNP) when clustered. One of the 134 mitochondrial SNPs showed heteroplasmy at a level of 0.4313 when clustering was applied. The probe sequence located at mitochondrial position 16217 and within the D-loop, which acts as a major control site for mtDNA expression. This is the first study to evaluate the association between mitochondrial DNA variants and allergic diseases. A harmonized effect of genes related to mitochondrial function may contribute to the risk of allergic diseases.
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