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Stem Cell Research Mar 2018Mitochondrial defects are associated with clinical manifestations from common diseases to rare genetic disorders. Myoclonus epilepsy associated with ragged-red fibers...
Generation of an induced pluripotent stem cell (iPSC) line from a 40-year-old patient with the A8344G mutation of mitochondrial DNA and MERRF (myoclonic epilepsy with ragged red fibers) syndrome.
Mitochondrial defects are associated with clinical manifestations from common diseases to rare genetic disorders. Myoclonus epilepsy associated with ragged-red fibers (MERRF) syndrome results from an A to G transition at nucleotide position 8344 in the tRNA gene of mitochondrial DNA (mtDNA) and is characterized by myoclonus, myopathy and severe neurological symptoms. In this study, Sendai reprogramming method was used to generate an iPS cell line carrying the A8344G mutation of mtDNA from a MERRF patient. This patient-specific iPSC line expressed pluripotent stem cell markers, possessed normal karyotype, and displayed the capability to differentiate into mature cells in three germ layers.
Topics: Adult; Cells, Cultured; DNA, Mitochondrial; Female; Flow Cytometry; Humans; Induced Pluripotent Stem Cells; Karyotyping; MERRF Syndrome; Mutation
PubMed: 29288969
DOI: 10.1016/j.scr.2017.12.013 -
Polish Journal of Pathology : Official... 2019
Topics: Humans; MERRF Syndrome; Mutation
PubMed: 31556566
DOI: 10.5114/pjp.2019.87106 -
Brain : a Journal of Neurology Oct 1989Thirteen patients, including 6 from one family, with the syndrome of myoclonus epilepsy and ragged-red fibres (MERRF) were studied. There was considerable heterogeneity... (Review)
Review
Thirteen patients, including 6 from one family, with the syndrome of myoclonus epilepsy and ragged-red fibres (MERRF) were studied. There was considerable heterogeneity in the age of onset, severity and associated clinical features. Postmortem studies in 3 patients from the one family showed a particular system degeneration. In addition, the youngest and most severely affected family member showed the pathological changes of Leigh's syndrome. Cortical dysfunction is a prominent clinical feature in MERRF, but postmortem examination failed to reveal cortical abnormalities. Positron emission tomographic studies, however, showed decreased cortical metabolic rates for glucose and oxygen utilization, with normal cortical blood flow and cerebral pH. Analyses of kinetic rate constants for uptake and phosphorylation of the glucose analogue, fluorodeoxyglucose showed decreased hexokinase-mediated phosphorylation: normal K1 and k2 values but reduced k3. Phosphorus magnetic resonance spectroscopy studies suggested a normal cerebral intracellular pH. Biochemical studies on muscle homogenates in 6 patients showed partial deficiencies of the activities of certain mitochondrial enzymes in 4 cases, whereas in 2 patients no abnormality was found. Our data, combined with previous reports, show that MERRF is biochemically and genetically heterogeneous. Our experience, and analysis of the literature, suggests that many cases previously described as the Ramsay Hunt syndrome, as well as other hitherto unclassified system degenerations associated with myoclonus epilepsy, are examples of MERRF. These data permit the formulation of a hypothesis to explain the clinical, biochemical and genetic heterogeneity of MERRF, and its overlap with Leigh's syndrome. We suggest that different biochemical defects of the mitochondrial respiratory chain may cause similar cerebral metabolic effects, as measured by positron emission tomography, resulting in similar phenotypes. Reduced activity of one enzyme, however, may result in different phenotypes, depending on the severity of the defect and its tissue distribution. Moreover, the phenotypic expression of certain biochemical defects may be influenced by randomly occurring factors such as fever, which may increase metabolic demand and result in more deleterious cellular metabolic effects.
Topics: Adolescent; Adult; Brain; Cerebral Cortex; Cerebrovascular Circulation; Child; Child, Preschool; Epilepsies, Myoclonic; Female; Glucose; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria, Muscle; Muscles; Nervous System; Pedigree; Skin; Tissue Distribution; Tomography, Emission-Computed
PubMed: 2508988
DOI: 10.1093/brain/112.5.1231 -
Annals of the New York Academy of... May 2005The COII/tRNA(Lys) intergenic 9-bp deletion (MIC9D) of mitochondrial DNA (mtDNA) has been established as a genetic polymorphism for Asian-Pacific populations. We...
The COII/tRNA(Lys) intergenic 9-bp deletion (MIC9D) of mitochondrial DNA (mtDNA) has been established as a genetic polymorphism for Asian-Pacific populations. We investigated whether this small mtDNA deletion is co-transmitted with human diseases such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and myoclonic epilepsy with ragged-red fibers (MERRF) syndromes. Forty unrelated Taiwanese families, including 12 families with MERRF and A8344G mtDNA mutation and 28 families with MELAS and A3243G mutation of mtDNA, respectively, were recruited in this study. In addition, 199 healthy subjects were recruited as control. We found that the frequency of occurrence of mtDNA with the MIC9D polymorphism in healthy subjects was 21% (41/199). However, the incidence of the MIC9D polymorphism was 67% (8/12) among the probands of all the families with MERRF syndrome (P = 0.001; OR = 8) and 39% (11/28) among the probands of the families with MELAS syndrome (P = 0.038; OR = 2). This finding indicates that the frequency of occurrence of mtDNA with the MIC9D polymorphism in patients with MERRF or MELAS syndrome is higher than that of healthy subjects. The prevalence of mitochondrial encephalomyopathies in relation to the MIC9D polymorphism of mtDNA in Taiwanese population is discussed.
Topics: Asian People; Base Pairing; Base Sequence; DNA, Mitochondrial; Electron Transport Complex IV; Humans; MELAS Syndrome; MERRF Syndrome; Molecular Sequence Data; Polymorphism, Genetic; RNA, Transfer, Lys; Sequence Deletion; Taiwan
PubMed: 15965049
DOI: 10.1196/annals.1338.058 -
Neurology International Apr 2022Ataxia is increasingly being recognized as a cardinal manifestation in primary mitochondrial diseases (PMDs) in both paediatric and adult patients. It can be caused by... (Review)
Review
Ataxia is increasingly being recognized as a cardinal manifestation in primary mitochondrial diseases (PMDs) in both paediatric and adult patients. It can be caused by disruption of cerebellar nuclei or fibres, its connection with the brainstem, or spinal and peripheral lesions leading to proprioceptive loss. Despite mitochondrial ataxias having no specific defining features, they should be included in hereditary ataxias differential diagnosis, given the high prevalence of PMDs. This review focuses on the clinical and neuropathological features and genetic background of PMDs in which ataxia is a prominent manifestation.
PubMed: 35466209
DOI: 10.3390/neurolint14020028 -
Biochimica Et Biophysica Acta Jul 2004By convention, the term "mitochondrial diseases" refers to disorders of the mitochondrial respiratory chain, which is the only metabolic pathway in the cell that is... (Review)
Review
By convention, the term "mitochondrial diseases" refers to disorders of the mitochondrial respiratory chain, which is the only metabolic pathway in the cell that is under the dual control of the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). Therefore, a genetic classification of the mitochondrial diseases distinguishes disorders due to mutations in mtDNA, which are governed by the relatively lax rules of mitochondrial genetics, and disorders due to mutations in nDNA, which are governed by the stricter rules of mendelian genetics. Mutations in mtDNA can be divided into those that impair mitochondrial protein synthesis in toto and those that affect any one of the 13 respiratory chain subunits encoded by mtDNA. Essential clinical features for each group of diseases are reviewed. Disorders due to mutations in nDNA are more abundant not only because most respiratory chain subunits are nucleus-encoded but also because correct assembly and functioning of the respiratory chain require numerous steps, all of which are under the control of nDNA. These steps (and related diseases) include: (i) synthesis of assembly proteins; (ii) intergenomic signaling; (iii) mitochondrial importation of nDNA-encoded proteins; (iv) synthesis of inner mitochondrial membrane phospholipids; (v) mitochondrial motility and fission.
Topics: DNA, Mitochondrial; Electron Transport; Gene Rearrangement; Genome, Human; Humans; MELAS Syndrome; MERRF Syndrome; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Phenotype; Point Mutation; Retinitis Pigmentosa
PubMed: 15282178
DOI: 10.1016/j.bbabio.2004.03.014 -
Journal of Child Neurology Oct 1994Recent advances in neuroepidemiologic and molecular biological techniques have facilitated a growing understanding of the role that inherited factors play in... (Review)
Review
Recent advances in neuroepidemiologic and molecular biological techniques have facilitated a growing understanding of the role that inherited factors play in epileptogenesis. During the last few years linkage analysis has mapped gene loci associated with the following epilepsy syndromes: benign familial neonatal convulsions, juvenile myoclonic epilepsy, Unverricht-Lundborg/Baltic/Mediterranean progressive myoclonic epilepsies, the juvenile form of ceroid lipofuscinosis, sialidosis I, and the myoclonus epilepsy with ragged red fibers (MERRF) syndrome. In addition, characterization of the inheritance patterns of other syndromes such as childhood epilepsy with occipital paroxysms and febrile convulsions has improved. It is apparent that a significant amount of clinical and genetic heterogeneity exists, which emphasizes the importance of accurate clinical classification. As genetic markers are found for well-defined groups of patients, traditional means of classification (seizure type, pathologic markers, progressive course, etc.) become less meaningful. It is proposed that the components of the phenotype of an epilepsy syndrome (eg, age of onset, seizure type, electroencephalographic pattern) may be controlled by multiple genes.
Topics: Adolescent; Cerebral Cortex; Child; Child, Preschool; Epilepsies, Myoclonic; Epilepsy; Genetic Linkage; Humans; Infant; Spasms, Infantile
PubMed: 7822747
DOI: 10.1177/0883073894009001041 -
Acta Haematologica 2007At onset mitochondrial disorders (MID) frequently manifest as a mono-organic problem but turn into multisystem disease during the disease course in most of the cases.... (Review)
Review
At onset mitochondrial disorders (MID) frequently manifest as a mono-organic problem but turn into multisystem disease during the disease course in most of the cases. Organs/tissues most frequently affected in MID are the cerebrum, peripheral nerves, and the skeletal muscle. Additionally, most of the inner organs may be affected alone or in combination. Hematological manifestations of MID include aplastic, megaloblastic, or sideroblastic anemia, leukopenia, neutropenia, thrombocytopenia, or pancytopenia. In single cases either permanent or recurrent eosinophilia has been observed. Hematological abnormalities may occur together with syndromic or nonsyndromic MIDs. Syndromic MIDs, in which hematological manifestations predominate, are the Pearson syndrome (pancytopenia), Kearns-Sayre syndrome (anemia), Barth syndrome (neutropenia), and the autosomal recessive mitochondrial myopathy, lactic acidosis and sideroblastic anemia syndrome. In single cases with Leigh's syndrome, MERRF (myoclonic epilepsy and ragged-red fiber) syndrome, Leber's hereditary optic neuropathy, and Friedreich's ataxia anemia has been described. Anemia, leukopenia, thrombocytopenia, eosinophilia, or pancytopenia can frequently also be found in nonsyndromic MIDs with or without involvement of other tissues. Therapy of blood cell involvement in MID comprises application of antioxidants, vitamins, iron, bone marrow-stimulating factors, or substitution of cells.
Topics: Hematologic Diseases; Hematopoiesis; Humans; Mitochondria; Mitochondrial Diseases; Syndrome
PubMed: 17637511
DOI: 10.1159/000105676 -
Muscle & Nerve Aug 1994A 66-year-old woman with hereditary deafness and multiple symmetric lipomas presented with ataxia, slight myopathy, and neuropathy. Molecular genetic analysis of...
A 66-year-old woman with hereditary deafness and multiple symmetric lipomas presented with ataxia, slight myopathy, and neuropathy. Molecular genetic analysis of mitochondrial DNA revealed the adenine to guanine transition at position 8344 in the tRNA gene for lysine that has been associated with the myoclonic epilepsy and ragged red fiber (MERRF) syndrome. The deafness was transmitted by the patient's father and may have been an unrelated autosomal defect rather than a paternally transmitted mitochondrial point mutation.
Topics: Aged; Ataxia; DNA, Mitochondrial; Female; Humans; Lipoma; MERRF Syndrome; Pedigree; Point Mutation; Restless Legs Syndrome
PubMed: 8041403
DOI: 10.1002/mus.880170815 -
Biochemical and Biophysical Research... Mar 2007We report a patient with myoclonic epilepsy who underwent muscle biopsy for suspected mitochondrial disease (myoclonic epilepsy with ragged-red fibers, MERRF). In spite...
We report a patient with myoclonic epilepsy who underwent muscle biopsy for suspected mitochondrial disease (myoclonic epilepsy with ragged-red fibers, MERRF). In spite of normal histochemical studies and of the absence of a severe COX deficiency, the molecular analysis showed the common MERRF mutation (A8344G) in the tRNA(Lys) gene on mitochondrial DNA. The case serves to illustrate the importance of pursuing the proposed mitochondrial genetic abnormality, even in patients with normal biopsy findings.
Topics: Adolescent; Adult; Child; Humans; Levetiracetam; MERRF Syndrome; Male; Muscle Fibers, Fast-Twitch; Piracetam
PubMed: 17275787
DOI: 10.1016/j.bbrc.2007.01.099