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Clinical Neuropathology 2002Four members of a family were found to carry the A3243G mtDNA mutation. Clinical features varied from typical MELAS to myoclonic epilepsy to simple deafness without...
Four members of a family were found to carry the A3243G mtDNA mutation. Clinical features varied from typical MELAS to myoclonic epilepsy to simple deafness without neurological signs. Several other members of the family had symptoms consistent with a mitochondrial disease. Muscle biopsy in 3 of the 4 patients showed the most prominent mitochondrial alterations with partial deficiency of cytochrome c oxidase in the case with the mildest phenotype. Mitochondrial DNA analysis detected a variable percentage of A3243G mutation, roughly correlating with the phenotype. The interesting feature of the family lies in the great intrafamilial variability of the severity of clinical expression, encompassing MELAS and MERRF features, associated with the A3243G mtDNA mutation. A search for the most common mtDNA mutations is recommended in all patients featuring incomplete MELAS or MERRF syndromes and in all familial cases presenting minimal clinical signs.
Topics: Adult; Biopsy; DNA Mutational Analysis; DNA, Mitochondrial; Female; Genetic Carrier Screening; Humans; MELAS Syndrome; MERRF Syndrome; Male; Middle Aged; Muscle, Skeletal; Pedigree; Phenotype; RNA, Transfer, Leu
PubMed: 12005255
DOI: No ID Found -
Pediatric Neurology Jan 1996Myoclonic epilepsy with ragged-red fiber syndrome has been associated with a mitochondrial DNA base substitution at nucleotide 8344 in the mitochondrial tRNA(Lys) gene....
Myoclonic epilepsy with ragged-red fiber syndrome has been associated with a mitochondrial DNA base substitution at nucleotide 8344 in the mitochondrial tRNA(Lys) gene. In several reported series, adult patients with these mutations have mild to moderate symptoms that progress slowly over many years. We describe a girl with MERRF syndrome who had an unusually rapid and severe clinical course, with onset of symptoms at age 7 years and death by age 14 years of overwhelming lactic acidosis. Postmortem tissue biopsy revealed variable but generally high percentages of mutant mitochondrial genomes in multiple organ systems. Twenty-one other members of her family were tested for the mutation and had varying percentages in leukocytes.
Topics: Acidosis, Lactic; Adolescent; Adult; Brain; Child; DNA, Mitochondrial; Fatal Outcome; Female; Humans; Leukocytes; MERRF Syndrome; Muscle, Skeletal; Muscle, Smooth; Neurologic Examination; Phenotype; RNA, Transfer, Lys; Spinal Cord
PubMed: 8652018
DOI: 10.1016/0887-8994(95)00226-x -
The Canadian Journal of Neurological... Sep 2009Mitochondrial disorders (MIDs) are an increasingly recognized condition. The second most frequently affected organ in MIDs is the central nervous system. One of the most... (Review)
Review
Mitochondrial disorders (MIDs) are an increasingly recognized condition. The second most frequently affected organ in MIDs is the central nervous system. One of the most prevalent clinical CNS manifestations of MIDs is ataxia. Ataxia may be even the dominant manifestation of a MID. This is why certain MIDs should be included in the classification of heredoataxias or at least considered as differentials of classical heredoataxias. MIDs due to mutations of the mitochondrial DNA, which develop ataxia include the MERRF, NARP, MILS, or KSS syndrome. More rarely, ataxia may be a feature of MELAS, LHON, PS, MIDD, or MSL. MIDs due to mutations of the nuclear DNA, which develop ataxia include LS, SANDO, SCAE, AHS, XSLA/A, IOSCA, MIRAS, MEMSA, or LBSL syndrome. More rarely ataxia can be found in AD-CPEO, AR-CPEO, MNGIE, DIDMOAD, CoQ-deficiency, ADOAD, DCMA, or PDC-deficiency. MIDs most frequently associated with ataxia are the non-syndromic MIDs. Syndromic and non-syndromic MIDs with ataxia should be delineated from classical heredoataxias to initiate appropriate symptomatic or supportive treatment.
Topics: Ataxia; DNA, Mitochondrial; Humans; Mitochondria; Mutation
PubMed: 19831121
DOI: 10.1017/s0317167100008027 -
European Journal of Neurology Nov 2009Aim of this review is to discuss recent findings concerning the management of stroke-like episodes (SLEs) in patients with mitochondrial disorders (MIDs). Various... (Review)
Review
Aim of this review is to discuss recent findings concerning the management of stroke-like episodes (SLEs) in patients with mitochondrial disorders (MIDs). Various databases were searched for appropriate literature. SLEs are a dominant feature of MIDs and occur most frequently in MELAS-syndrome, less frequently in MERRF-syndrome, Kearns-Sayre-syndrome, or Leigh-syndrome. SLEs occur at all ages and are frequently accompanied by other cerebral abnormalities. Clinically, SLEs mimic ischemic stroke but not on imaging studies and concerning the management. The morphological equivalent on MRI is the stroke-like-lesion, representing a vasogenic edema (hyperintensity on T2, diffusion-weighted imaging and apparent diffusion coefficient in the acute and subacute or chronic stage, most frequently in the parieto-occipital region, surpassing vascular territories). For diagnostic and therapeutic reasons SLEs need to be clearly delineated from ischemic stroke and cerebral bleeding. Though there is no causal therapy available, symptomatic and general measures can help to resolve the clinical manifestations. In conclusion this review shows that SLEs are a dominant feature of some syndromic or non-syndromic MIDs. The most effective strategy for the treatment of SLEs appears to be the application of L-arginine, coenzyme-Q, steroids, edaravone, creatine-monohydrate, or dichloracetate.
Topics: Brain; Brain Diseases, Metabolic, Inborn; Diagnosis, Differential; Humans; Magnetic Resonance Imaging; Mitochondria; Stroke
PubMed: 19780807
DOI: 10.1111/j.1468-1331.2009.02789.x -
Free Radical Biology & Medicine Nov 2015Mitochondria are a source of reactive oxygen species (ROS). Mitochondrial diseases are the result of inherited defects in mitochondrially expressed genes. One potential... (Review)
Review
Mitochondria are a source of reactive oxygen species (ROS). Mitochondrial diseases are the result of inherited defects in mitochondrially expressed genes. One potential pathomechanism for mitochondrial disease is oxidative stress. Oxidative stress can occur as the result of increased ROS production or decreased ROS protection. The role of oxidative stress in the five most common inherited mitochondrial diseases, Friedreich ataxia, LHON, MELAS, MERRF, and Leigh syndrome (LS), is discussed. Published reports of oxidative stress involvement in the pathomechanisms of these five mitochondrial diseases are reviewed. The strongest evidence for an oxidative stress pathomechanism among the five diseases was for Friedreich ataxia. In addition, a meta-analysis was carried out to provide an unbiased evaluation of the role of oxidative stress in the five diseases, by searching for "oxidative stress" citation count frequency for each disease. Of the five most common mitochondrial diseases, the strongest support for oxidative stress is for Friedreich ataxia (6.42%), followed by LHON (2.45%), MELAS (2.18%), MERRF (1.71%), and LS (1.03%). The increased frequency of oxidative stress citations was significant relative to the mean of the total pool of five diseases (p<0.01) and the mean of the four non-Friedreich diseases (p<0.0001). Thus there is support for oxidative stress in all five most common mitochondrial diseases, but the strongest, significant support is for Friedreich ataxia.
Topics: Humans; Mitochondrial Diseases; Oxidative Stress; Reactive Oxygen Species
PubMed: 26073122
DOI: 10.1016/j.freeradbiomed.2015.05.039 -
Clinical Genetics Jan 2009The hallmarks of the myoclonic epilepsy with ragged red fibers (MERRF) syndrome are myoclonic epilepsy, ataxia and ragged red fibres detected on muscle biopsy. We...
The hallmarks of the myoclonic epilepsy with ragged red fibers (MERRF) syndrome are myoclonic epilepsy, ataxia and ragged red fibres detected on muscle biopsy. We present a case of a 25-year-old male who first presented to his general practitioner at the age of 22 years with myoclonic jerks affecting the arms and legs, fatigue and mild ataxia. He was found to carry an A>G transition at nucleotide 8344 in mitochondrial DNA. This mutation is the most common cause of the MERRF syndrome, found in more than 80% of affected patients. Our patient had the diagnosis tattooed on his arm, both out of frustration at how few people had heard of it, and as a way of accepting that his condition was a part of who he was. Although the MERRF syndrome is one of the more common forms of mitochondrial encephalomyopathy, with a prevalence estimated at between 0.25 and 0.39 per 100,000, it is still a rare disorder. We are always striving to increase the public's understanding of these important conditions. Our patient has perhaps helped more than most towards this aspiration.
Topics: DNA, Mitochondrial; Humans; MERRF Syndrome; Male; Tattooing; Young Adult
PubMed: 19128396
DOI: 10.1111/j.1399-0004.2008.01103.x -
Journal of the Neurological Sciences Apr 2006The treatment of progressive myoclonic epilepsy (PME) is largely empirical, even though valproic acid (VPA) is usually considered the drug of first choice. However, VPA...
The treatment of progressive myoclonic epilepsy (PME) is largely empirical, even though valproic acid (VPA) is usually considered the drug of first choice. However, VPA should be used with caution in PME due to mitochondrial dysfunction, i.e. in MERRF (myoclonic epilepsy with ragged red fibers) syndrome, because of its interaction with mitochondrial respiration and metabolism. Levetiracetam (LEV) treatment was started in combination with VPA in a patient with typical clinical, histological, and biochemical features of MERRF due to a mutation on the tRNA of Phenilalanine gene. The average myoclonus score improved dramatically, as well as the quality of life and no side effects were observed, even after having withdrawn VPA. LEV may benefit myoclonus in PME of mitochondrial origin without altering mitochondrial function, and it could be considered the drug of first choice for the treatment of myoclonus in MERRF.
Topics: Activities of Daily Living; Anticonvulsants; Atrophy; Brain; Drug Therapy, Combination; Female; Genetic Predisposition to Disease; Humans; Levetiracetam; MERRF Syndrome; Middle Aged; Mitochondria; Muscle, Skeletal; Mutation; Myoclonus; Phenylalanine; Piracetam; Quality of Life; RNA, Transfer; Treatment Outcome; Ubiquinone; Valproic Acid
PubMed: 16414077
DOI: 10.1016/j.jns.2005.11.021 -
Journal of Medical Genetics Oct 2010Myoclonic epilepsy with ragged-red fibres (MERRF) and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are established phenotypes of...
BACKGROUND
Myoclonic epilepsy with ragged-red fibres (MERRF) and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are established phenotypes of mitochondrial encephalomyopathy. The m.8356T>C transition in the mitochondrial tRNA(Lys) gene is a pathogenic mutations of MERRF. The m.3243A>G transition in the mitochondrial tRNA(Leu) gene is detected in most MELAS patients. Although previous analyses of double mutations in mitochondrial DNA (mtDNA) were useful for discussing their nature, many unsolved questions remain.
OBJECTIVE
To describe the clinical and genetic features of a family with the above mtDNA double-point mutations and discuss the role of double mtDNA mutations in diverse clinical features in the family.
PATIENTS AND METHODS
The proband was a 23-year-old woman with MERRF harbouring m.8356T>C and m.3243A>G transitions in mitochondrial tRNA genes. We assessed clinical aspects of her and those of her three relatives and performed mutation analyses on their mtDNA.
RESULTS
Phenotypes of the four patients were MERRF, MERRF/MELAS overlap syndrome and asymptomatic carrier. We hypothesise that the course of the phenotype of this family begins with MERRF and is followed by MELAS. This double mutation was heteroplasmic in blood of all four patients but with different rates in each patient, while m.8356T>C appeared homoplasmic and m.3243A>G was heteroplasmic in muscle of the two examined cases. No other mutations were detected in the total mtDNA sequence in this family.
CONCLUSIONS
This is the first reported case of a double-point mutation in mtDNA, both of which were heteroplasmic and pathogenic for the established phenotypes.
Topics: Adolescent; Adult; Brain; DNA Mutational Analysis; DNA, Mitochondrial; Female; Humans; MELAS Syndrome; MERRF Syndrome; Magnetic Resonance Imaging; Mitochondrial Encephalomyopathies; Pedigree; Phenotype; Point Mutation; Quadriceps Muscle; RNA, Transfer, Leu; RNA, Transfer, Lys; Young Adult
PubMed: 20610441
DOI: 10.1136/jmg.2009.072058 -
Journal of Pediatric Genetics Mar 2018Congenital hearing loss is one of the most common birth defects worldwide, with around 1 in 500 people experiencing some form of severe hearing loss. While over 400... (Review)
Review
Congenital hearing loss is one of the most common birth defects worldwide, with around 1 in 500 people experiencing some form of severe hearing loss. While over 400 different syndromes involving hearing loss have been described, it is important to be familiar with a wide range of syndromes involving hearing loss so an early diagnosis can be made and early intervention can be pursued to maximize functional hearing and speech-language development in the setting of verbal communication. This review aims to describe the presentation and genetics for some of the most frequently occurring syndromes involving hearing loss, including neurofibromatosis type 2, branchio-oto-renal syndrome, Treacher Collins syndrome, Stickler syndrome, Waardenburg syndrome, Pendred syndrome, Jervell and Lange-Nielsen syndrome, Usher syndromes, Refsum disease, Alport syndrome, MELAS, and MERRF.
PubMed: 29441214
DOI: 10.1055/s-0037-1617454