Diagnostic value of serum biomarkers FGF21 and GDF15 compared to muscle sample in mitochondrial disease

The aim of this study was to compare the value of serum biomarkers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), with histological analysis of muscle in the diagnosis of mitochondrial disease. We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme-labeled immunosorbent assay. Clinical data were collected using a structured questionnaire. Only 39% of patients with genetically verified mitochondrial disease had mitochondrial pathology in their muscle histology. In contrast, biomarkers were elevated in 62% of patients with genetically verified mitochondrial disease. Those with both biomarkers elevated had a muscle manifesting disorder and a defect affecting mitochondrial DNA expression. If at least one of the biomarkers was induced and the patient had a myopathic disease, a mitochondrial DNA expression disease was the cause with 94% probability. Among patients with biomarker analysis and muscle biopsy takenPeer reviewe

Phenotype-genotype correlations in Leigh syndrome : new insights from a multicentre study of 96 patients

Background Leigh syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder. While some genetic defects are associated with well-described phenotypes, phenotype-genotype correlations in Leigh syndrome are not fully explored. Objective We aimed to identify phenotype-genotype correlations in Leigh syndrome in a large cohort of systematically evaluated patients. Methods We studied 96 patients with genetically confirmed Leigh syndrome diagnosed and followed in eight European centres specialising in mitochondrial diseases. Results We found that ataxia, ophthalmoplegia and cardiomyopathy were more prevalent among patients with mitochondrial DNA defects. Patients with mutations in MT-ND and NDUF genes with complex I deficiency shared common phenotypic features, such as early development of central nervous system disease, followed by high occurrence of cardiac and ocular manifestations. The cerebral cortex was affected in patients with NDUF mutations significantly more often than the rest of the cohort. Patients with the m. 8993T> G mutation in MT-ATP6 gene had more severe clinical and radiological manifestations and poorer disease outcome compared with patients with the m. 8993T> C mutation. Conclusion Our study provides new insights into phenotype-genotype correlations in Leigh syndrome and particularly in patients with complex I deficiency and with defects in the mitochondrial ATP synthase.Peer reviewe

Renal Phenotype in Mitochondrial Diseases : A Multicenter Study

Aims: This study aimed to investigate associations between renal and extrarenal manifestations of mitochondrial diseases and their natural history as well as predictors of renal disease severity and overall disease outcome. The secondary aim was to generate a protocol of presymptomatic assessment and monitoring of renal function in patients with a defined mitochondrial disease. Methods: A multicenter, retrospective cohort study was performed by the Mitochondrial Clinical and Research Network (MCRN). Patients of any age with renal manifestations associated with a genetically verified mitochondrial disease were included from 8 expert European centers specializing in mitochondrial diseases: Gothenburg, Oulu, Copenhagen, Bergen, Helsinki, Stockholm, Rotterdam, and Barcelona. Results: Of the 36 patients included, two-thirds had mitochondrial DNA-associated disease. Renal manifestations were the first sign of mitochondrial disease in 19%, and renal involvement was first identified by laboratory tests in 57% of patients. Acute kidney injury occurred in 19% of patients and was the first sign of renal disease in the majority of these. The most common renal manifestation was chronic kidney disease (75% with stage 2 or greater), followed by tubulopathy (44.4%), the latter seen mostly among patients with single large-scale mitochondrial DNA deletions. Acute kidney injury and tubulopathy correlated with worse survival outcome. The most common findings on renal imaging were increased echogenicity and renal dysplasia/hypoplasia. Renal histology revealed focal segmental glomerulosclerosis, nephrocalcinosis, and nephronophthisis. Conclusion: Acute kidney injury is a distinct renal phenotype in patients with mitochondrial disease. Our results highlight the importance to recognize renal disease as a sign of an underlying mitochondrial disease. Acute kidney injury and tubulopathy are 2 distinct indicators of poor survival in patients with mitochondrial diseases.Peer reviewe

A multicenter study on Leigh syndrome: Disease course and predictors of survival

Background: Leigh syndrome is a progressive neurodegenerative disorder, associated with primary or secondary dysfunction of the mitochondrial oxidative phosphorylation. Despite the fact that Leigh syndrome is the most common phenotype of mitochondrial disorders in children, longitudinal natural history data is missing. This study was undertaken to assess the phenotypic and genotypic spectrum of patients with Leigh syndrome, characterise the clinical course and identify predictors of survival in a large cohort of patients. Methods. This is a retrospective study of patients with Leigh syndrome that have been followed at eight centers specialising in mitochondrial diseases in Europe; Gothenburg, Rotterdam, Helsinki, Copenhagen, Stockholm, Brussels, Bergen and Oulu. Results: A total of 130 patients were included (78 males; 52 females), of whom 77 patients had identified pathogenic mutations. The median age of disease onset was 7 months, w

A multicenter study on Leigh syndrome : disease course and predictors of survival

Peer reviewe

Mitochondrial encephalopathies in early childhood

Early-onset mitochondrial encephalopathies comprise a challenging group of neurodegenerative disorders. This is due to their progressive nature, often leading to major disability and premature death, as well as their diagnostic complexity and lack of customized treatments. The overall aim of the research presented in this thesis was to explore the phenotypic and genotypic spectrum of childhood-onset mitochondrial diseases with central nervous system involvement. The present thesis focuses on early-onset mitochondrial encephalopathies with particular emphasis on Alpers and Leigh syndromes. We studied 19 patients with Alpers syndrome and showed specific genotype-phenotype correlations depending on the presence or not of POLG1 mutations. We have further identified, with the help of whole exome sequencing, mutations in NARS2 and PARS2 in two of our patients with Alpers syndrome not associated to POLG1, being the first to link mutations in these genes to human disease and to Alpers syndrome. We also present the natural history data on a unique cohort of 130 patients with Leigh syndrome, along with predictors of long-term outcomes. Disease onset before six months of age, failure to thrive, brainstem lesions on neuroimaging and intensive care treatment were associated with poorer survival. Based on the findings from this study, we suggest revised diagnostic criteria for Leigh syndrome. We also studied the brain MRIs of 66 patients with mitochondrial disorders with central nervous system involvement. We describe the optimal use of brain neuroimaging in the diagnostic work-up of suspected mitochondrial disorders, as well as its role in the differential diagnosis among mitochondrial encephalopathies and from other diseases with similar features. This thesis advances our knowledge of the phenotypic and genotypic spectrum of early-onset mitochondrial encephalopathies and discusses the applicable diagnostic methods, from the diagnostic criteria used to define clinical syndromes, to the role of the traditional and modern methodologies in the diagnostic work-up of these complex disorders. The study of patients with Leigh syndrome is the first joint research work between eight centers from six European countries specializing in mitochondrial diseases, creating a strong platform for ongoing collaboration on mitochondrial research projects

Isolation, structure elucidation and use of components from the plant Dittrichia Viscosa against the bee parasite Varroa Destructor

Στην παρούσα ερευνητική εργασία πραγματοποιήθηκε η απομόνωση του πλέον δραστικού συστατικού από το φυτό Dittrichia viscosa, το οποίο χρησιμοποιείται για την καταπολέμηση του παρασίτου Varroa destructor της μέλισσας Apis mellifera, με σκοπό την παρασκευή σχετικού σκευάσματος. Παρουσιάζονται τα φασματοσκοπικά αποτελέσματα της μελέτης της δομής του συστατικού αυτού, το οποίο ταυτοποιήθηκε ως το costic acid. Σειρά πειραμάτων απέδειξε ότι το costic acid δρα κατά του παρασίτου χωρίς να έχει τοξικές επιπτώσεις στη μέλισσα. Επίσης, τα πειράματα πεδίου φανέρωσαν ότι το costic acid δεν έχει καμία τοξική επίδραση ούτε στην κυψέλη και κατά συνέπεια ούτε στο μέλι. Εκμεταλλευόμενοι τις ιδιότητες αυτές, μπορούμε να προχωρήσουμε στην βιομηχανική παρασκευή ενός οικολογικού, ασφαλούς, οικονομικού και εύκολου στη χρήση προϊόντος για τους μελισσοκόμους με σκοπό την καταπολέμηση της βαρρόωσης, μία από τις σοβαρότερες ασθένειες των μελισσών. Επίσης παρουσιάζεται η ανάλυση των συστατικών του αιθέριου ελαίου της Dittrichia viscosa και τα αποτελέσματα συγκρίνονται με αντίστοιχα βιβλιογραφικά δεδομένα.This thesis includes results on the isolation and identification of the active component from the extract of the leaves of Dittrichia viscosa, a shrub growing in the area of Crete, Greece. The plant is traditionally used by bee keepers as a means of controlling the parasite known as Varroa destructor, that causes varroosis, a serious disease of the common bee, Apis mellifera. The spectral study leading to the identification of the active component as a terpenoid known with the name of costic acid is presented, as well as data clarifying discrepancies on the NMR data of the compound that appear in the literature. In vivo assays indicated that costic acid acts against the parasite with high efficacy without any toxic effects on the common bee. Moreover, preliminary field tests indicated that no toxic effects were found in the bee hives after the experiments meaning that the honey produced by the bees is free of costic acid. The above results strongly suggest that costic acid may be used as the basic component for the formulation of an environmentally safe product that can be used against varoosis. The analysis of the components of the essential oil of Dittrichia viscosa is also presented in the thesis, and the data are compared to those of related studies reported in the scientific literature

Use of costic acid, a natural extract from Dittrichia viscosa, for the control of Varroa destructor, a parasite of the European honey bee

Costic acid has been isolated from the plant Dittrichia viscosa and its efficacy against Varroa destructor, a parasite of Apis mellifera, the European honey bee, has been studied. Costic acid exhibited potent in vivo acaricidal activity against the parasite. Initial experiments showed that the compound is not toxic for human umbilical vein endothelial cells (HUVEC) at concentrations of up to 230 micromolar (μM), indicating that costic acid could be used as a safe, low-cost and efficient agent for controlling varroosis in honey bee colonies

Novel imaging findings in pyruvate dehydrogenase complex (PDHc) deficiency—Results from a nationwide population-based study

The vast clinical and radiological spectrum of pyruvate dehydrogenase complex (PDHc) deficiency continues to pose challenges both in diagnostics and disease monitoring. Prompt diagnosis is important to enable early initiation of ketogenic diet. The patients were recruited from an ongoing population-based study in Sweden. All patients with a genetically confirmed diagnosis who had been investigated with an MRI of the brain were included. Repeated investigations were assessed to study the evolution of the MRI changes. Sixty-two MRI investigations had been performed in 34 patients (23 females). The genetic cause was mutations in PDHA1 in 29, PDHX and DLAT in 2 each, and PDHB in 1. The lesions were prenatal developmental in 16, prenatal clastic in 18, and postnatal clastic in 15 individuals. Leigh-like lesions with predominant involvement of globus pallidus were present in 12, while leukoencephalopathy was present in 6 and stroke-like lesions in 3 individuals. A combination of prenatal developmental and clastic lesions was present in 15 individuals. In addition, one male with PDHA1 also had postnatal clastic lesions. The most common lesions found in our study were agenesis or hypoplasia of corpus callosum, ventriculomegaly, or Leigh-like lesions. Furthermore, we describe a broad spectrum of other MRI changes that include leukoencephalopathy and stroke-like lesions. We argue that a novel important clue, suggesting the possibility of PDHc deficiency on MRI scans, is the simultaneous presence of multiple lesions on MRI that have occurred during different phases of brain development