MERRF Syndrome
Lipomatosis, Multiple Symmetrical
MELAS Syndrome
RNA, Transfer, Lys
Epilepsies, Myoclonic
Mitochondrial Encephalomyopathies
RNA, Transfer, Leu
Kearns-Sayre Syndrome
A novel system for assigning the mode of inheritance in mitochondrial disorders using cybrids and rhodamine 6G. (1/51)
When normal human cultured skin fibroblasts were treated with the fluorescent dye rhodamine 6G (R6G), there was a drastic reduction in numbers of intact mitochondria and electron transport chain enzyme activities, despite the fact that mitochondrial DNA (mtDNA) was still present in treated cells. We used this observation to develop a novel system for generating cybrids. When cultured skin fibroblast cells from a patient with the mitochondrial encephalopathy and ragged-red fibers (MERRF) syndrome harboring the A8344G mtDNA mutation and which showed a severe reduction in cytochrome c oxidase activity were treated with R6G and fused to enucleated HeLaCOT cells, the resulting cybrid clones showed recovery of cytochrome c oxidase activity, and were shown to have mtDNA derived solely from the HeLaCOT cell line. R6G has significant advantages over ethidium bromide in removing the mitochondrial elements from cultured cells, and the results reported here demonstrate that this strategy can be used to determine the origin of the genetic defect in patients with electron transport chain abnormalities. (+info)Defective kinetics of cytochrome c oxidase and alteration of mitochondrial membrane potential in fibroblasts and cytoplasmic hybrid cells with the mutation for myoclonus epilepsy with ragged-red fibres ('MERRF') at position 8344 nt. (2/51)
We have investigated pathogenic effects of the tRNA(Lys) A8344G mutation associated with the syndrome myoclonus epilepsy with ragged-red fibres (MERRF) by using fibroblasts and fibroblast-derived cytoplasmic hybrid cells harbouring different percentages of mutated mitochondrial DNA (mtDNA). The activity of cytochrome c oxidase (COX) in patient fibroblasts with 89% mutated mtDNA was decreased to 20% of the control levels. COX exhibited altered kinetics, with a decreased V(max) for both the low-affinity and high-affinity phases; however, the K(m) values were not significantly changed. The substrate-dependent synthesis of ATP was decreased to 50% of the control. Analysis of the mitochondrial membrane potential, DeltaPsi, in digitonin-treated cells with tetramethylrhodamine methyl ester (TMRM) with the use of flow cytometry showed a 80% decrease in DeltaPsi at state 4 and an increased sensitivity of DeltaPsi to an uncoupler in fibroblasts from the patient. The investigation of transmitochondrial cytoplasmic hybrid clones derived from the patient's fibroblasts enabled us to characterize the relationship between heteroplasmy of the MERRF mutation, COX activity and DeltaPsi. Within the range of 87-73% mutated mtDNA, COX activity was decreased to 5-35% and DeltaPsi was decreased to 6-78%. These results demonstrate that the MERRF mutation affects COX activity and DeltaPsi in different proportions with regard to mutation heteroplasmy and indicate that the biochemical manifestation of the MERRF mutation exerts a very steep threshold of DeltaPsi inhibition. (+info)Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations: a potential pathogenic mechanism. (3/51)
Mitochondrial encephalomyopathies caused by mitochondrial DNA (mtDNA) defects are a genetically and phenotypically heterogeneous group of disorders. The site, percentage and distribution of mutations do not explain the overall clinical heterogeneity that is found. Apoptosis (programmed cell death) is an evolutionarily conserved mechanism that is essential for tissue development and homeostasis. Dysregulation of apoptosis has been implicated in the pathogenesis of various human diseases, such as cancer and autoimmune and neurodegenerative disorders. Recent in vitro evidence has indicated the central role of mitochondria in the apoptotic process. We investigated the occurrence of apoptosis in muscle biopsies of 36 patients carrying different mtDNA mutations and four patients with inclusion body myositis and mitochondrial abnormalities. Apoptotic features, mainly localized in cytochrome c oxidase-negative fibres, were observed in muscle fibres of patients carrying a high percentage of single mtDNA deletions (>40%) and of tRNA point mutations (>70%). By contrast, no apoptotic changes were observed in inclusion body myositis and in patients carrying mutations of mtDNA structural genes. Our study suggests that apoptosis is not simply a means whereby cells with dysfunctional mitochondria are eliminated, but that it seems to play a role in the pathogenesis of mitochondrial disorders associated with mtDNA defects affecting mitochondrial protein synthesis. The imbalance and relative abundances of nuclear-encoded and mtDNA-encoded subunits may favour cytochrome c inactivation and release. Cytochrome c, together with respiratory chain dysfunction, could activate apoptotic pathways that, in turn, inhibit the rate of mitochondrial translation and the importation of nuclear-encoded mitochondrial protein precursors. This vicious circle may amplify the biochemical defects and tissue damage and contribute to the modulation of clinical features. (+info)Defect in modification at the anticodon wobble nucleotide of mitochondrial tRNA(Lys) with the MERRF encephalomyopathy pathogenic mutation. (4/51)
A mitochondrial tRNA(Lys) gene mutation at nucleotide position 8344 is responsible for the myoclonus epilepsy associated with ragged-red fibers (MERRF) subgroup of mitochondrial encephalomyopathies. Here, we show that normally modified uridine at the anticodon wobble position remains unmodified in the purified mutant tRNA(Lys). We have reported a similar modification defect at the same position in two mutant mitochondrial tRNAs(Leu)(UUR) in another subgroup, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), indicating this defect is common in the two kinds of tRNA molecules with the respective mutations of the two major mitochondrial encephalomyopathies. We therefore suggest the defect in the anticodon is responsible, through the translational process, for the pathogenesis of mitochondrial diseases. (+info)Cytochrome oxidase immunohistochemistry: clues for genetic mechanisms. (5/51)
Cytochrome c oxidase (COX) is encoded by three mitochondrial and nine nuclear genes. COX deficiency is genetically heterogeneous but current diagnostic methods cannot easily distinguish between mitochondrial and nuclear defects. We hypothesized that there may be differential expression of COX subunits depending on the underlying mutation. COX subunit expression was investigated in five patients with known mtDNA mutations. Severe and selective reduction of mtDNA-encoded COX subunits I and II was consistently observed in all these patients and was restricted to COX-deficient fibres. Immunostaining of nuclear-encoded subunits COX IV and Va was normal, whilst subunit VIc, also nuclear-encoded, was decreased. Twelve of 36 additional patients with histochemically defined COX deficiency also had this pattern of staining, suggesting that they had mtDNA defects. Clinical features in this group were heterogeneous, including infantile encephalopathy, multisystem disease, cardiomyopathy and childhood-onset isolated myopathy. The remaining patients did not have the same pattern of immunostaining. Fourteen had reduced staining of all subunits, whilst 10 had normal staining of all subunits despite reduced enzyme activity. Patients with COX deficiency secondary to mtDNA mutations have a specific pattern of subunit loss, but the majority of children with COX deficiency do not have this pattern of subunit loss and are likely to have nuclear gene defects. (+info)Simultaneous A8344G heteroplasmy and mitochondrial DNA copy number quantification in myoclonus epilepsy and ragged-red fibers (MERRF) syndrome by a multiplex molecular beacon based real-time fluorescence PCR. (6/51)
The association of a particular mitochondrial DNA (mtDNA) mutation with different clinical phenotypes is a well-known feature of mitochondrial diseases. A simple genotype-phenotype correlation has not been found between mutation load and disease expression. Tissue and intercellular mosaicism as well as mtDNA copy number are thought to be responsible for the different clinical phenotypes. As disease expression of mitochondrial tRNA mutations is mostly in postmitotic tissues, studies to elucidate disease mechanisms need to be performed on patient material. Heteroplasmy quantitation and copy number estimation using small patient biopsy samples has not been reported before, mainly due to technical restrictions. In order to resolve this problem, we have developed a robust assay that utilizes Molecular Beacons to accurately quantify heteroplasmy levels and determine mtDNA copy number in small samples carrying the A8344G tRNA(Lys) mutation. It provides the methodological basis to investigate the role of heteroplasmy and mtDNA copy number in determining the clinical phenotypes. (+info)Wobble modification defect in tRNA disturbs codon-anticodon interaction in a mitochondrial disease. (7/51)
We previously showed that in mitochondrial tRNA(Lys) with an A8344G mutation responsible for myoclonus epilepsy associated with ragged-red fibers (MERRF), a subgroup of mitochondrial encephalomyopathic diseases, the normally modified wobble base (a 2-thiouridine derivative) remains unmodified. Since wobble base modifications are essential for translational efficiency and accuracy, we used mitochondrial components to estimate the translational activity in vitro of purified tRNA(Lys) carrying the mutation and found no mistranslation of non-cognate codons by the mutant tRNA, but almost complete loss of translational activity for cognate codons. This defective translation was not explained by a decline in aminoacylation or lowered affinity toward elongation factor Tu. However, when direct interaction of the codon with the mutant tRNA(Lys) defective anticodon was examined by ribosomal binding analysis, the wild-type but not the mutant tRNA(Lys) bound to an mRNA- ribosome complex. We therefore concluded that the anticodon base modification defect, which is forced by the pathogenic point mutation, disturbs codon- anticodon pairing in the mutant tRNA(Lys), leading to a severe reduction in mitochondrial translation that eventually could result in the onset of MERRF. (+info)Histochemical and molecular genetic study of MELAS and MERRF in Korean patients. (8/51)
Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode (MELAS) and myoclonic epilepsy and ragged-red fibers (MERRF) are rare disorders caused by point mutation of the tRNA gene of the mitochondrial genome. To understand the pathogenetic mechanism of MELAS and MERRF, we studied four patients. Serially sectioned frozen muscle specimens with a battery of histochemical stains were reviewed under light microscope and ultrastructural changes were observed under electron microscope. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed and the tRNA genes were sequenced to confirm mutations. In two patients with MELAS, strongly succinyl dehydrogenase positive blood vessels (SSVs) and many cytochrome oxidase (COX) positive ragged-red fibers (RRFs) were observed, and A3243G mutations were found from the muscle samples. In two patients with MERRF, neither SSV nor COX positive RRFs were seen and A8344G mutations were found from both muscle and blood samples. In the two MERRF families, the identical mutation was observed among family members. The failure to detect the mutation in blood samples of the MELAS suggests a low mutant load in blood cells. The histochemical methods including COX stain are useful for the confirmation and differentiation of mitochondrial diseases. Also, molecular biological study using muscle sample seems essential for the confirmation of the mtDNA mutation. (+info)Myoclonic Epilepsy with Ragged Red Fibers (MERRF) is a rare mitochondrial disorder, which is a group of genetic disorders that affect the energy production within cells. It is characterized by multiple symptoms including myoclonus (jerky, involuntary muscle spasms), epilepsy (recurrent seizures), ataxia (lack of coordination and balance), dementia, and weakness. The name "MERRF" comes from the characteristic finding of "ragged red fibers" in muscle biopsies when viewed under a microscope using special stains. These fibers are abnormal muscle cells containing clusters of abnormal mitochondria. MERRF is caused by mutations in the mitochondrial DNA, most commonly the A8344G point mutation in the MT-TK gene. It is typically inherited from the mother and can affect multiple organs throughout the body.
Multiple Symmetrical Lipomatosis is a rare condition characterized by the growth of multiple, symmetrical fatty tumors (lipomas) beneath the skin. These lipomas are typically slow-growing and benign, but their large number and symmetric distribution can lead to significant cosmetic concerns and, in some cases, functional impairment.
The tumors usually develop on the neck, shoulders, back, and abdomen, and they may also occur on the arms and legs. While the exact cause of Multiple Symmetrical Lipomatosis is not known, it has been associated with alcohol abuse and metabolic disorders. Treatment typically involves surgical removal of the lipomas, although this can be challenging due to their number and location. Recurrence of the tumors is also common.
A syndrome, in medical terms, is a set of symptoms that collectively indicate or characterize a disease, disorder, or underlying pathological process. It's essentially a collection of signs and/or symptoms that frequently occur together and can suggest a particular cause or condition, even though the exact physiological mechanisms might not be fully understood.
For example, Down syndrome is characterized by specific physical features, cognitive delays, and other developmental issues resulting from an extra copy of chromosome 21. Similarly, metabolic syndromes like diabetes mellitus type 2 involve a group of risk factors such as obesity, high blood pressure, high blood sugar, and abnormal cholesterol or triglyceride levels that collectively increase the risk of heart disease, stroke, and diabetes.
It's important to note that a syndrome is not a specific diagnosis; rather, it's a pattern of symptoms that can help guide further diagnostic evaluation and management.
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome is a rare inherited mitochondrial disorder that affects the body's energy production mechanisms. It is characterized by a combination of symptoms including recurrent headaches, vomiting, seizures, vision loss, hearing impairment, muscle weakness, and stroke-like episodes affecting primarily young adults.
The condition is caused by mutations in the mitochondrial DNA (mtDNA), most commonly the A3243G point mutation in the MT-TL1 gene. The symptoms of MELAS syndrome can vary widely among affected individuals, even within the same family, due to the complex inheritance pattern of mtDNA.
MELAS syndrome is typically diagnosed based on a combination of clinical features, laboratory tests, and genetic testing. Treatment is supportive and aimed at managing individual symptoms as they arise.
I'm happy to help! Here are the definitions for each of those terms:
1. RNA (Ribonucleic Acid): RNA is a nucleic acid that plays a crucial role in the process of gene expression. It carries genetic information from DNA to the ribosomes, where proteins are synthesized. RNA is made up of a long chain of nucleotides, just like DNA, but with some key differences in its structure and composition.
2. Transfer: In the context of biochemistry, "transfer" refers to the movement or transport of molecules from one location to another within a cell or between cells. This process is often facilitated by specific proteins or other molecular carriers.
3. Lys (Lysine): Lysine is an essential amino acid that cannot be synthesized by the human body and must be obtained through diet. It plays important roles in various biological processes, including protein synthesis, enzyme function, hormone production, and energy metabolism. In molecular biology, lysine is often used as a marker for certain types of modifications to proteins or nucleic acids.
Therefore, "RNA, Transfer, Lys" could refer to the transfer RNA (tRNA) molecule that carries a specific amino acid, such as lysine, to the ribosome during protein synthesis. The tRNA molecule recognizes a specific codon on the messenger RNA (mRNA) and brings the corresponding amino acid to the growing polypeptide chain, allowing for the translation of genetic information into a functional protein.
Myoclonic epilepsies are a group of epilepsy syndromes characterized by the presence of myoclonic seizures. A myoclonic seizure is a type of seizure that involves quick, involuntary muscle jerks or twitches. These seizures can affect one part of the body or multiple parts simultaneously and may vary in frequency and severity.
Myoclonic epilepsies can occur at any age but are more common in infancy, childhood, or adolescence. Some myoclonic epilepsy syndromes have a genetic basis, while others may be associated with brain injury, infection, or other medical conditions.
Some examples of myoclonic epilepsy syndromes include:
1. Juvenile Myoclonic Epilepsy (JME): This is the most common type of myoclonic epilepsy and typically begins in adolescence. It is characterized by myoclonic jerks, often occurring upon awakening or after a period of relaxation, as well as generalized tonic-clonic seizures.
2. Progressive Myoclonic Epilepsies (PME): These are rare inherited disorders that typically begin in childhood or adolescence and involve both myoclonic seizures and other types of seizures. PMEs often progress to include cognitive decline, movement disorders, and other neurological symptoms.
3. Lennox-Gastaut Syndrome (LGS): This is a severe form of epilepsy that typically begins in early childhood and involves multiple types of seizures, including myoclonic seizures. LGS can be difficult to treat and often results in cognitive impairment and developmental delays.
4. Myoclonic Astatic Epilepsy (MAE): Also known as Doose syndrome, MAE is a childhood epilepsy syndrome characterized by myoclonic seizures, atonic seizures (brief periods of muscle weakness or loss of tone), and other types of seizures. It often responds well to treatment with antiepileptic drugs.
The management of myoclonic epilepsies typically involves a combination of medication, lifestyle changes, and, in some cases, dietary modifications. The specific treatment plan will depend on the type of myoclonic epilepsy and its underlying cause.
Mitochondrial Encephalomyopathies are a group of genetic disorders that primarily affect the mitochondria, which are the energy-producing structures in cells. "Encephalo" refers to the brain, while "myopathy" refers to muscle disease. Therefore, Mitochondrial Encephalomyopathies are conditions that cause both neurological and muscular symptoms due to impaired mitochondrial function.
These disorders can affect any organ in the body, but they primarily impact the brain, nerves, and muscles. Symptoms may include muscle weakness, seizures, developmental delays, hearing loss, vision loss, heart problems, and lactic acidosis (a buildup of lactic acid in the blood).
Mitochondrial Encephalomyopathies can be caused by mutations in either the mitochondrial DNA or nuclear DNA. They are often inherited from the mother, as mitochondria are passed down through the maternal line. However, some cases can also result from new mutations that occur spontaneously.
Due to the complex nature of these disorders and their varying symptoms, diagnosis and treatment can be challenging. Treatment typically focuses on managing specific symptoms and may include medications, dietary changes, and physical therapy.
A transfer RNA (tRNA) molecule that carries the amino acid leucine is referred to as "tRNA-Leu." This specific tRNA molecule recognizes and binds to a codon (a sequence of three nucleotides in mRNA) during protein synthesis or translation. In this case, tRNA-Leu can recognize and pair with any of the following codons: UUA, UUG, CUU, CUC, CUA, and CUG. Once bound to the mRNA at the ribosome, leucine is added to the growing polypeptide chain through the action of aminoacyl-tRNA synthetase enzymes that catalyze the attachment of specific amino acids to their corresponding tRNAs. This ensures the accurate and efficient production of proteins based on genetic information encoded in mRNA.
Kearns-Sayre Syndrome (KSS) is a rare, progressive genetic disorder that affects the function of the mitochondria, which are the energy-producing structures in cells. It is classified as a type of mitochondrial myopathy and is typically associated with symptoms that appear before the age of 20.
The medical definition of Kearns-Sayre Syndrome includes the following criteria:
1. Onset before 20 years of age
2. Progressive external ophthalmoplegia (PEO), which is characterized by weakness and paralysis of the eye muscles, leading to drooping eyelids (ptosis) and limited eye movement
3. Retinitis pigmentosa, a degenerative condition affecting the retina that can lead to vision loss
4. A cardiac conduction defect, such as heart block
5. Ragged red fibers on muscle biopsy
6. At least one major criteria or two minor criteria must be present:
* Major criteria include cerebellar ataxia (lack of coordination), deafness, or increased protein in the cerebrospinal fluid
* Minor criteria include pigmentary retinopathy, heart block, or a high level of creatine kinase in the blood.
Kearns-Sayre Syndrome is caused by a single large-scale deletion of genes in the mitochondrial DNA and is usually sporadic, meaning it occurs randomly and is not inherited from parents. The condition can be diagnosed through genetic testing, muscle biopsy, or other clinical tests. Treatment is focused on managing symptoms and may include physical therapy, surgery for ptosis, hearing aids, and pacemakers for heart block.