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Asian Journal of Surgery Aug 2020
Topics: Connective Tissue Diseases; Dermatologic Surgical Procedures; Humans; Laparoscopy; Lipomatosis, Multiple Symmetrical; MERRF Syndrome; Male; Middle Aged; Subcutaneous Tissue; Surgery, Plastic
PubMed: 32456962
DOI: 10.1016/j.asjsur.2020.04.012 -
Neurology India 2020Neurological diseases can be due to direct diseases of the central nervous system (CNS) or peripheral nervous system (PNS) or be a bystander syndrome of systemic...
INTRODUCTION
Neurological diseases can be due to direct diseases of the central nervous system (CNS) or peripheral nervous system (PNS) or be a bystander syndrome of systemic diseases. Treatment options depend on the cause. Toxic, metabolic and nutritional, and immune-mediated consequences of clinically occult neoplasms produce a spectrum of neurological diseases, recognition of which has therapeutic and prognostic importance.
PATIENTS AND METHODS
Children, as well as adults who presented to the authors in the last 5 years with neurological diseases and later their diseases could be diagnosed or attributed to neoplasms which were occult, were included for the study.
OBSERVATION
28 patients were seen by the authors in the last 5 years with neurological manifestation and hidden tumor. Maximum incidence was in the age of above 60 years followed by the age group of 21-40 years. The commonest neurological presentation was muscle and nerve in adults and seizure in children.
DISCUSSION
Short duration, rapid progression, severe weight loss, and poor response to treatment given for nontumor associated neurological syndrome are the red flags which point to the diagnosis.
CONCLUSION
Seizures and psychosis formed the commonest features in children, muscle and nerve in adults. Short duration, rapid progression, and resistance to treatment are the markers for possible underlying neoplasm.
Topics: Adenoma; Adolescent; Adult; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Ataxia; Carcinoma; Child; Dementia; Diagnosis, Differential; Diagnostic Errors; Female; Ganglioneuroma; Humans; Hypokalemic Periodic Paralysis; Lipoma; Lymphoma, Non-Hodgkin; MERRF Syndrome; Male; Middle Aged; Myoclonic Epilepsy, Juvenile; Neoplasms; Nervous System Diseases; Neuroblastoma; Opsoclonus-Myoclonus Syndrome; Ovarian Neoplasms; POEMS Syndrome; Pancreatic Neoplasms; Paraneoplastic Syndromes, Nervous System; Parathyroid Neoplasms; Parkinsonian Disorders; Plasmacytoma; Polymyositis; Stomach Neoplasms; Subacute Combined Degeneration; Teratoma; Thymus Neoplasms; Young Adult
PubMed: 32415012
DOI: 10.4103/0028-3886.280647 -
The FEBS Journal Sep 2020Various pathogenic variants in both mitochondrial tRNA and Phenylalanyl-tRNA synthetase mitochondrial protein coding gene (FARS2) gene encoding for the human...
Various pathogenic variants in both mitochondrial tRNA and Phenylalanyl-tRNA synthetase mitochondrial protein coding gene (FARS2) gene encoding for the human mitochondrial PheRS have been identified and associated with neurological and/or muscle-related pathologies. An important Guanine-34 (G34)A anticodon mutation associated with myoclonic epilepsy with ragged red fibers (MERRF) syndrome has been reported in hmit-tRNA . The majority of G34 contacts in available aaRSs-tRNAs complexes specifically use that base as an important tRNA identity element. The network of intermolecular interactions providing its specific recognition also largely conserved. However, their conservation depends also on the invariance of the residues in the anticodon binding domain (ABD) of human mitochondrial Phenylalanyl-tRNA synthetase (hmit-PheRS). A defect in recognition of the anticodon of tRNA may happen not only because of G34A mutation, but also due to mutations in the ABD. Indeed, a pathogenic mutation in FARS2 has been recently reported in a 9-year-old female patient harboring a p.Asp364Gly mutation. Asp364 is hydrogen bonded (HB) to G34 in WT hmit-PheRS. Thus, there are two pathogenic variants disrupting HB between G34 and Asp364: one is associated with G34A mutation, and the other with Asp364Gly mutation. We have measured the rates of tRNA aminoacylation catalyzed by WT hmit-PheRS and mutant enzymes. These data ranked the residues making a HB with G34 according to their contribution to activity and the signal transduction pathway in the hmit-PheRS-tRNA complex. Furthermore, we carried out extensive MD simulations to reveal the interdomain contact topology on the dynamic trajectories of the complex, and gaining insight into the structural and dynamic integrity effects of hmit-PheRS complexed with tRNA . DATABASE: Structural data are available in PDB database under the accession number(s): 3CMQ, 3TUP, 5MGH, 5MGV.
Topics: Amino Acid Substitution; Anticodon; Aspartic Acid; Child; Consanguinity; DNA, Mitochondrial; Disease Progression; Female; Genetic Pleiotropy; Guanine; Humans; Hydrogen Bonding; MERRF Syndrome; Mitochondrial Proteins; Models, Molecular; Molecular Dynamics Simulation; Motion; Mutation, Missense; Paraparesis, Spastic; Phenotype; Phenylalanine-tRNA Ligase; Point Mutation; Protein Conformation; Protein Domains; RNA, Transfer, Phe
PubMed: 32115907
DOI: 10.1111/febs.15268 -
European Annals of Otorhinolaryngology,... May 2020
Topics: Genotype; Humans; MERRF Syndrome; Phenotype
PubMed: 32063498
DOI: 10.1016/j.anorl.2018.12.003 -
Biochimica Et Biophysica Acta.... Jun 2020Mitochondrial diseases are considered rare genetic disorders characterized by defects in oxidative phosphorylation (OXPHOS). They can be provoked by mutations in nuclear...
Mitochondrial diseases are considered rare genetic disorders characterized by defects in oxidative phosphorylation (OXPHOS). They can be provoked by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most frequent mitochondrial diseases, principally caused by the m.8344A>G mutation in mtDNA, which affects the translation of all mtDNA-encoded proteins and therefore impairs mitochondrial function. In the present work, we evaluated autophagy and mitophagy flux in transmitochondrial cybrids and fibroblasts derived from a MERRF patient, reporting that Parkin-mediated mitophagy is increased in MERRF cell cultures. Our results suggest that supplementation with coenzyme Q (CoQ), a component of the electron transport chain (ETC) and lipid antioxidant, prevents Parkin translocation to the mitochondria. In addition, CoQ acts as an enhancer of autophagy and mitophagy flux, which partially improves cell pathophysiology. The significance of Parkin-mediated mitophagy in cell survival was evaluated by silencing the expression of Parkin in MERRF cybrids. Our results show that mitophagy acts as a cell survival mechanism in mutant cells. To confirm these results in one of the main affected cell types in MERRF syndrome, mutant induced neurons (iNs) were generated by direct reprogramming of patients-derived skin fibroblasts. The treatment of MERRF iNs with Guttaquinon CoQ (GuttaQ), a water-soluble derivative of CoQ, revealed a significant improvement in cell bioenergetics. These results indicate that iNs, along with fibroblasts and cybrids, can be utilized as reliable cellular models to shed light on disease pathomechanisms as well as for drug screening.
Topics: Autophagy; Cells, Cultured; DNA, Mitochondrial; Energy Metabolism; Fibroblasts; Humans; Lipid Peroxidation; MERRF Syndrome; Membrane Potential, Mitochondrial; Mitochondria; Mitophagy; Oxidative Phosphorylation; Protein Transport; Ubiquinone; Ubiquitin-Protein Ligases
PubMed: 32061767
DOI: 10.1016/j.bbadis.2020.165726 -
European Annals of Otorhinolaryngology,... May 2020
Topics: Humans; Lipomatosis; MERRF Syndrome
PubMed: 32061576
DOI: 10.1016/j.anorl.2020.01.016 -
Polish Journal of Pathology : Official... 2019
Topics: Humans; MERRF Syndrome; Mutation
PubMed: 31556566
DOI: 10.5114/pjp.2019.87106 -
Neurology. Genetics Aug 2019Our goal was to perform a systematic review of the literature to demonstrate the prevalence of cardiac abnormalities identified using cardiac investigations in patients...
OBJECTIVE
Our goal was to perform a systematic review of the literature to demonstrate the prevalence of cardiac abnormalities identified using cardiac investigations in patients with mitochondrial myopathy (MM).
METHODS
This systematic review surveys the available evidence for cardiac investigations in MM from a total of 21 studies including 825 participants. Data were stratified by genetic mutation and clinical syndrome.
RESULTS
We identified echocardiogram and ECG as the principal screening modalities that identify cardiac structural (29%) and conduction abnormalities (39%) in various MM syndromes. ECG abnormalities were more prevalent in patients with m.3243A>G mutations than other gene defects, and patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) had a higher prevalence of ECG abnormalities than patients with other clinical syndromes. Echocardiogram abnormalities were significantly more prevalent in patients with m.3243A>G or m.8344A>G mutations compared with other genetic mutations. Similarly, MELAS and MERRF had a higher prevalence compared with other syndromes. We observed a descriptive finding of an increased prevalence of ECG abnormalities in pediatric patients compared with adults.
CONCLUSIONS
This analysis supports the presence of a more severe cardiac phenotype in MELAS and myoclonic epilepsy with ragged red fibres syndromes and with their commonly associated genetic mutations (m.3243A>G and m.8344A>G). This provides the first evidence basis on which to provide more intensive cardiac screening for patients with certain clinical syndromes and genetic mutations. However, the data are based on a small number of studies. We recommend further studies of natural history, therapeutic response, pediatric participants, and cardiac MRI as areas for future investigation.
PubMed: 31403078
DOI: 10.1212/NXG.0000000000000339 -
Chinese Medical Journal Jul 2019
Topics: Adult; DNA, Mitochondrial; Epilepsies, Myoclonic; Humans; MERRF Syndrome; Male; Mutation
PubMed: 31268906
DOI: 10.1097/CM9.0000000000000337 -
Neuropathology : Official Journal of... Jun 2019We present an autopsied case with A8344G-mutated myoclonus epilepsy with ragged red fibers (MERRF)/mitochondrial encephalomyopathy with lactic acidosis and stroke-like...
We present an autopsied case with A8344G-mutated myoclonus epilepsy with ragged red fibers (MERRF)/mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) overlap syndrome accompanied by stroke-like episodes localized to the precentral gyrus. A 16-year-old Japanese woman suddenly experienced repetitive consciousness disturbances with increased serum lactate and creatine kinase levels. Magnetic resonance imaging showed abnormal intensity of bilateral precentral gyrus. She was clinically diagnosed as having a mitochondrial disorder and the A8344G mutation was detected in mitochondrial DNA. At 17 years of age, she died from congestive heart failure secondary to a third episode of lactic acidosis. Neuropatho-logically, multifocal laminar necrosis, which is responsible for stroke-like episodes in MELAS, was seen in the frontal cortex including the precentral gyrus, but there was no neuronal loss and gliosis in the basal ganglia, cerebellum, and brainstem, which were compatible with MERRF. Hypertrophy of the vascular smooth muscle and choroidal epithelium were seen, and were strongly visualized by an anti-mitochondrial antibody. Skeletal muscles showed uneven muscular diameters, increased central nuclei, and ragged red fibers (RRFs). Decreased cytochrome c oxidase (COX) activity and strongly succinate dehydrogenase (SDH)-reactive blood vessels were also noted. Stroke-like episodes in MERRF/MELAS overlap syndrome are thought to be rare in the frontal cortex including the precentral gyrus. Only two cases of MERRF/MELAS overlap syndrome with A8344G mutation, including this case, have shown stroke-like episodes in the frontal lobes. Other than the A8344G mutation and frontal lobe involvement, they had a high degree of similarity in terms of presence of RRFs, gastrointestinal dysfunction, and lack of typical MERRF neuropathology. In conclusion, this is an important case describing the clinical spectrum associated with A8344G-mutated MERRF/MELAS overlap syndrome.
Topics: Adolescent; Autopsy; Female; Frontal Lobe; Humans; MELAS Syndrome; MERRF Syndrome; Stroke
PubMed: 30972844
DOI: 10.1111/neup.12551