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Journal of Cardiovascular Magnetic... May 2015Mitochondrial myopathies (MM) are a heterogeneous group of inherited conditions resulting from a primary defect in the mitochondrial respiratory chain with consecutively... (Comparative Study)
Comparative Study
Characteristic cardiac phenotypes are detected by cardiovascular magnetic resonance in patients with different clinical phenotypes and genotypes of mitochondrial myopathy.
BACKGROUND
Mitochondrial myopathies (MM) are a heterogeneous group of inherited conditions resulting from a primary defect in the mitochondrial respiratory chain with consecutively impaired cellular energy metabolism. Small sized studies using mainly electrocardiography (ECG) and echocardiography have revealed cardiac abnormalities ranging from conduction abnormalities and arrhythmias to hypertrophic or dilated cardiomyopathy in these patients. Recently, characteristic patterns of cardiac involvement were documented by cardiovascular magnetic resonance (CMR) in patients with chronic progressive external ophthalmoplegia (CPEO)/Kearns-Sayre syndrome (KSS) and with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). The present study aimed to characterize the prevalence and pattern of cardiac abnormalities and to test the additional diagnostic value of CMR in this patient population. The hypothesis that different neuromuscular MM syndromes present with different cardiac disease phenotypes was evaluated.
METHODS
Sixty-four MM patients (50 ± 15 years, 44% male) and 25 matched controls (52 ± 14 years, 36% male) prospectively underwent cardiac evaluations including CMR (comprising cine- and late-gadolinium-enhancement (LGE) imaging). Based on the neuromuscular phenotype and genotype, the patients were grouped: (a) CPEO/KSS (N = 33); (b) MELAS/-like (N = 11); c) myoclonic epilepsy with ragged-red fibers (MERRF) (N = 3) and d) other non-specific MM forms (N = 17).
RESULTS
Among the 64 MM patients, 34 (53%) had at least one abnormal CMR finding: 18 (28%) demonstrated an impaired left ventricular ejection-fraction (LV-EF <60%), 14 (22%) had unexplained LV hypertrophy and 21 (33%) were LGE-positive. Compared to controls, MM patients showed significantly higher maximal wall thickness (10 ± 3 vs. 8 ± 2 mm, p = 0.005) and concentricity (LV mass to end-diastolic volume: 0.84 ± 0.27 vs. 0.67 ± 0.11, p < 0.0001) with frequent presence of non-ischemic LGE (30% vs. 0%, p = 0.001). CPEO/KSS showed a predominantly intramural pattern of LGE mostly confined to the basal LV inferolateral wall (8/10; 80%) in addition to a tendency toward concentric remodelling. MELAS/-like patients showed the highest frequency of cardiac disease (in 10/11 (91%)), a mostly concentric LV hypertrophy (6/9; 67%) with or without LV systolic dysfunction and a predominantly focal, patchy LGE equally distributed among LV segments (8/11; 73%). Patients with MERRF and non-specific MM had no particular findings. Pathological CMR findings indicating cardiac involvement were detected significantly more often than pathological ECG results or elevated cardiac serum biomarkers (34 (53%) vs. 18 (28%) vs. 21 (33%); p = 0.008).
CONCLUSION
Cardiac involvement is a frequent finding in MM patients - and particularly present in KSS/CPEO as well as MELAS/-like patients. Despite a high variability in clinical presentation, CPEO/KSS patients typically show an intramural pattern of LGE in the basal inferolateral wall whereas MELAS patients are characterized by overt concentric hypertrophy and a rather unique, focally accentuated and diffusely distributed LGE.
Topics: Adult; Aged; Cardiomyopathies; Case-Control Studies; Female; Genetic Predisposition to Disease; Germany; Humans; Hypertrophy, Left Ventricular; Kearns-Sayre Syndrome; MELAS Syndrome; MERRF Syndrome; Magnetic Resonance Imaging; Male; Middle Aged; Mitochondrial Myopathies; Myocardium; Ophthalmoplegia, Chronic Progressive External; Phenotype; Predictive Value of Tests; Prevalence; Prospective Studies; Stroke Volume; Ventricular Function, Left; Ventricular Remodeling
PubMed: 26001801
DOI: 10.1186/s12968-015-0145-x -
Case Reports in Neurological Medicine 2018Mitochondrial (mt) tRNA (MTT) gene mutations are an important cause of mitochondrial diseases and are associated with a wide range of clinical presentations. Most...
Mitochondrial (mt) tRNA (MTT) gene mutations are an important cause of mitochondrial diseases and are associated with a wide range of clinical presentations. Most mutations fall into three mitochondrial tRNAs (tRNAIle, tRNALeu (UUR), and tRNALys) and are responsible for half of the mitochondrial diseasees associated with tRNA mutation, with MERRF, MELAS, mitochondrial myopathy, and Leigh syndrome being the most frequent phenotypes. More than 100 tRNA pathogenetic mutations are described, showing little correlation between the observed clinical phenotype and a specific mitochondrial tRNA mutation. Furthermore different mutation can manifest with similar clinical phenotypes, making the genotype-phenotype correlation difficult. Here we report the case of an Italian 53-year-old woman presenting with a proximal myopathy and the m.5835G>A mutation in MT-TY gene coding for the mitochondrial tRNA Tyrosine gene.
PubMed: 30643656
DOI: 10.1155/2018/8406712 -
Stem Cell Research Nov 2016Human iPSC line iMERRF-C7 was generated from PBMCs of a patient with mitochondrial disorder MERRF. Using Sendai virus, the reprogramming factors Oct3/4, Sox2, Klf4, and...
Human iPSC line iMERRF-C7 was generated from PBMCs of a patient with mitochondrial disorder MERRF. Using Sendai virus, the reprogramming factors Oct3/4, Sox2, Klf4, and cMyc were delivered non-integratively. The resulting iPSCs expressed pluripotency markers, could differentiate into the three germ layers in vivo, had normal genomic structure, and retained the disease-causing m.8344 mutation with similar heteroplasmic level.
Topics: Animals; Base Sequence; Cell Line; Cellular Reprogramming; Female; Genetic Loci; Genetic Vectors; Humans; Induced Pluripotent Stem Cells; Karyotype; Kruppel-Like Factor 4; Leukocytes, Mononuclear; MERRF Syndrome; Mice; Mice, Inbred NOD; Mice, SCID; Microscopy, Fluorescence; Polymorphism, Single Nucleotide; Sendai virus; Sequence Analysis, DNA; Teratoma; Transcription Factors
PubMed: 27934592
DOI: 10.1016/j.scr.2016.11.008 -
Biochimica Et Biophysica Acta Sep 2016The Coq protein complex assembled from several Coq proteins is critical for coenzyme Q6 (CoQ6) biosynthesis in yeast. Secondary CoQ10 deficiency is associated with...
Disruption of the human COQ5-containing protein complex is associated with diminished coenzyme Q10 levels under two different conditions of mitochondrial energy deficiency.
BACKGROUND
The Coq protein complex assembled from several Coq proteins is critical for coenzyme Q6 (CoQ6) biosynthesis in yeast. Secondary CoQ10 deficiency is associated with mitochondrial DNA (mtDNA) mutations in patients. We previously demonstrated that carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) suppressed CoQ10 levels and COQ5 protein maturation in human 143B cells.
METHODS
This study explored the putative COQ protein complex in human cells through two-dimensional blue native-polyacrylamide gel electrophoresis and Western blotting to investigate its status in 143B cells after FCCP treatment and in cybrids harboring the mtDNA mutation that caused myoclonic epilepsy with ragged-red fibers (MERRF) syndrome. Ubiquinol-10 and ubiquinone-10 levels were detected by high-performance liquid chromatography. Mitochondrial energy status, mRNA levels of various PDSS and COQ genes, and protein levels of COQ5 and COQ9 in cybrids were examined.
RESULTS
A high-molecular-weight protein complex containing COQ5, but not COQ9, in the mitochondria was identified and its level was suppressed by FCCP and in cybrids with MERRF mutation. That was associated with decreased mitochondrial membrane potential and mitochondrial ATP production. Total CoQ10 levels were decreased under both conditions, but the ubiquinol-10:ubiquinone-10 ratio was increased in mutant cybrids. The expression of COQ5 was increased but COQ5 protein maturation was suppressed in the mutant cybrids.
CONCLUSIONS
A novel COQ5-containing protein complex was discovered in human cells. Its destabilization was associated with reduced CoQ10 levels and mitochondrial energy deficiency in human cells treated with FCCP or exhibiting MERRF mutation.
GENERAL SIGNIFICANCE
The findings elucidate a possible mechanism for mitochondrial dysfunction-induced CoQ10 deficiency in human cells.
Topics: Ataxia; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cell Line; DNA, Mitochondrial; Humans; MERRF Syndrome; Membrane Potential, Mitochondrial; Methyltransferases; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; RNA, Messenger; Ubiquinone
PubMed: 27155576
DOI: 10.1016/j.bbagen.2016.05.005 -
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 -
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 -
Journal of Neurology Mar 2016
Topics: Aged; Electroencephalography; Female; Humans; Lactose; MERRF Syndrome; Myoclonus; Pancreatitis
PubMed: 26810726
DOI: 10.1007/s00415-016-8028-0 -
Clinical Neurology and Neurosurgery Jan 2018Studies exploring the outcome of epilepsy in patients with mitochondrial disorders are limited. This study examined the outcome of epilepsy in patients with...
OBJECTIVES
Studies exploring the outcome of epilepsy in patients with mitochondrial disorders are limited. This study examined the outcome of epilepsy in patients with mitochondrial disorders and its relation with the clinical phenotype, genotype and magnetic resonance imaging findings.
PATIENTS AND METHODS
The cohort was derived from the database of 67 patients with definite genetic diagnosis of mitochondrial disorders evaluated over a period of 11years (2006-2016). Among this, 27 had epilepsy and were included in final analysis. Data were analyzed with special reference to clinical phenotypes, genotypes, epilepsy characteristics, EEG findings, anti epileptic drugs used, therapeutic response, and magnetic resonance imaging findings. Patients were divided into three groups according to the seizure frequency at the time of last follow up: Group I- Seizure free; Group II- Infrequent seizures; Group III- uncontrolled seizures. For each group the clinical phenotype, genotype, magnetic resonance imaging and duration of epilepsy were compared.
RESULTS
The phenotypes & genotypes included Mitochondrial Encephalopathy Lactic Acidosis and Stroke like episodes (MELAS) & m.3243A>G mutation (n = 10), Myoclonic Epilepsy Ragged Red Fiber syndrome (MERRF) & m.8344A>G mutation (n = 4), Chronic Progressive External Ophthalmoplegia plus &POLG1 mutation (CPEO, n = 6), episodic neuroregression due to nuclear mutations (n = 6; NDUFV1 (n = 3), NDUFA1, NDUFS2, MPV17-1 one each), and one patient with infantile basal ganglia stroke syndrome, mineralizing angiopathy &MT-ND5 mutations. Seven patients (25.9%) were seizure free; seven had infrequent seizures (25.9%), while thirteen (48.1%) had frequent uncontrolled seizures. Majority of the subjects in seizure free group had episodic neuroregression & leukoencephalopathy due to nuclear mutations (85.7%). Patients in group II with infrequent seizures had CPEO, POLG1 mutation and a normal MRI (71%) while 62% of the subjects in group III had MELAS, m.3243A>G mutation and stroke like lesions on MRI.
CONCLUSIONS
A fair correlation exists between the outcome of epilepsy, clinical phenotypes, genotypes and magnetic resonance imaging findings in patients with mitochondrial disorders. The recognition of these patterns is important clinically because of the therapeutic and prognostic implications.
Topics: Adolescent; Adult; Child; Cohort Studies; Electroencephalography; Epilepsy; Female; Genotype; Humans; Magnetic Resonance Imaging; Male; Mitochondrial Diseases; Phenotype; Treatment Outcome; Young Adult
PubMed: 29272804
DOI: 10.1016/j.clineuro.2017.12.010 -
Annales D'endocrinologie Jun 2020While the most frequent mutation responsible for mitochondrial diabetes is the point mutation m.3243 A>G of mitochondrial DNA (mtDNA), few data are available about the...
OBJECTIVE
While the most frequent mutation responsible for mitochondrial diabetes is the point mutation m.3243 A>G of mitochondrial DNA (mtDNA), few data are available about the role of rare mtDNA mutations in the pathophysiology of diabetes. The main objective of our study was to describe the phenotypic characteristics of patients suffering from diabetes linked to rare mtDNA mutations.
RESEARCH DESIGN AND METHODS
We performed a post-hoc analysis of a prospective multicenter cohort of 743 patients with mitochondrial disorder (previously published by the French Network of Mitochondrial Diseases), associated to a literature review of the PubMed database from 1992 to May 2016. We extracted all reported patients with diabetes and identified rare mtDNA mutations and described their clinical and metabolic phenotypes.
RESULTS
The 50 identified patients (10 from the princeps study; 40 from the review of the literature) showed a heterogeneous metabolic phenotype in terms of age, symptoms prior to diagnosis, treatments, and associated clinical and biological signs. However, neurological symptoms were more frequent in case of rare mtDNA mutations compared to the classical m.3243 A>G mutation (P=0.024). In contrast, deafness (65% vs. 95%, P=3.7E-5), macular pattern dystrophy (20% vs. 86%, P=1.6E-10) and nephropathy (8% vs. 28%, P=0.018) were significantly less frequent than in case of the classical m.3243 A>G mutation.
CONCLUSION
Although no specific metabolic phenotype could be identified suggesting or eliminating implication of rare mtDNA mutations in diabetes, clinical phenotypes featured more frequent neurological signs.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cohort Studies; DNA Mutational Analysis; DNA, Mitochondrial; Deafness; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; France; Gene Frequency; Genetic Association Studies; Humans; Infant; Infant, Newborn; MERRF Syndrome; Male; Middle Aged; Mitochondrial Diseases; Mutation; Phenotype; Prospective Studies
PubMed: 32409007
DOI: 10.1016/j.ando.2020.04.007 -
Cureus Aug 2022A myoclonic epilepsy with ragged-red fibers (MERRF) patient who carried the m.8344A>G variant in the homoplasmic form manifested a milder phenotype than his sister who...
A myoclonic epilepsy with ragged-red fibers (MERRF) patient who carried the m.8344A>G variant in the homoplasmic form manifested a milder phenotype than his sister who carried the same variant in the heteroplasmic form, which has not yet been reported. The 27-year-old male, with an uneventful history, presented at age 19 with fatigue and persistent tremor in both hands. When he talked for a long time, his speech would slow down, and he would stutter. Although electroencephalography showed spike-wave complexes in both occipital projections with generalization, no anti-seizure drugs were given. At age 20, the patient suffered a fall due to muscle weakness. From age 21, generalized myocloni occurred. Because the sister had been diagnosed with MERRF-plus syndrome, the patient underwent genetic testing, which revealed the m.8344A>G variant in homoplasmy. L-carnitine was started. At age 27, the patient experienced a first "syncope" after a long walk, which subsequently recurred up to 2-3 times per day. EEG showed low-amplitude spikes, slow-spike waves at the posterior vertex, and generalized slow-spike waves. Clonazepam was recommended but declined by the patient. In conclusion, the m.8344A>G variant may manifest milder and with a later onset in the homoplasmic as compared to the heteroplasmic form. Further, the homoplasmy of the m.8344A>G variant appears to be more beneficial than harmful.
PubMed: 36176839
DOI: 10.7759/cureus.28490