Gene/Protein Disease Symptom Drug Enzyme Compound
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 11,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An 11-year-old girl and a 25-year-old woman were both initially referred to a neurologist with 'common' neurological problems: The girl suffered from tics, and later epilepsy, and her serum lactate concentration was elevated. She had unilateral hyperintensity of the left cerebral cortex and later developed diabetes mellitus. The woman had muscle weakness, diabetes mellitus and ptosis. In both patients, the problems turned out to be an expression of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The first patient died at 18 years of age during an epileptic seizure with severe metabolic disturbances. The second patient developed bilateral perceptive hearing loss, epilepsy and cardiomyopathy and she was repeatedly admitted to hospital with stroke-like episodes. She died at 46 years of age. Both patients had the MELAS A3243G point mutation. MELAS is a maternally inherited mitochondrial disorder. The age of onset and symptoms are highly variable, even within one family. To date there are no curative treatment options for the disease. Diagnosing MELAS is important though, for optimising the treatment of the individual symptoms and genetic counselling.
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PMID:[Unexceptional symptoms as expression of MELAS]. 2108 56

Mutations in the heart and muscle isoform of adenine nucleotide translocator 1 (ANT1) are associated with autosomal-dominant progressive external opthalmoplegia (adPEO) clinically characterized by exercise intolerance, ptosis and muscle weakness. The pathogenic mechanisms underlying the mitochondrial myopathy caused by ANT1 mutations remain largely unknown. In yeast, expression of ANT1 carrying mutations corresponding to the human adPEO ones causes a wide range of mitochondrial abnormalities. However, functional studies of ANT1 mutations in mammalian cells are lacking, because they have been hindered by the fact that ANT1 expression leads to apoptotic cell death in commonly utilized replicating cell lines. Here, we successfully express functional ANT1 in differentiated mouse myotubes, which naturally contain high levels of ANT1, without causing cell death. We demonstrate, for the first time in these disease-relevant mammalian cells, that mutant human ANT1 causes dominant mitochondrial defects characterized by decreased ADP-ATP exchange function and abnormal translocator reversal potential. These abnormalities are not due to ANT1 loss of function, because knocking down Ant1 in myotubes causes functional changes different from ANT1 mutants. Under certain physiological conditions, mitochondria consume ATP to maintain membrane potential by reversing the ADP-ATP transport. The modified properties of mutant ANT1 can be responsible for disease pathogenesis in adPEO, because exchange reversal occurring at higher than normal membrane potential can cause excessive energy depletion and nucleotide imbalance in ANT1 mutant muscle cells.
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PMID:adPEO mutations in ANT1 impair ADP-ATP translocation in muscle mitochondria. 2158 54

Maintenance and replication of mitochondrial DNA require the concerted action of several factors encoded by nuclear genome. The mitochondrial helicase Twinkle is a key player of replisome machinery. Heterozygous mutations in its coding gene, PEO1, are associated with progressive external ophthalmoplegia (PEO) characterised by ptosis and ophthalmoparesis, with cytochrome c oxidase (COX)-deficient fibres, ragged-red fibres (RRF) and multiple mtDNA deletions in muscle. Here we describe clinical, histological and molecular features of two patients presenting with mitochondrial myopathy associated with PEO. PEO1 sequencing disclosed two novel mutations in exons 1 and 4 of the gene, respectively. Although mutations in PEO1 exon 1 have already been described, this is the first report of mutation occurring in exon 4.
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PMID:Two novel mutations in PEO1 (twinkle) gene associated with chronic external ophthalmoplegia. 2168 31

Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial myopathy commonly caused by deleterious changes in the mitochondrial DNA (mtDNA). We describe a 45-year-old man who was referred to us for investigation of progressive ptosis. We performed a multiplex ligation-dependent probe amplification (MLPA) assay of mtDNA from muscle tissue and peripheral blood leukocytes, and followed up with gap-polymerase chain reaction (PCR) and direct sequence analysis. Results showed a deletion of a 4,407 bp segment in the mtDNA region, ranging from nucleotide position 8,577 in the MT-ATP6 gene to nucleotide position 12,983 in the MT-ND5 gene. To the best of our knowledge, this is the first report of a CPEO patient with a large novel deletion of mtDNA genetically confirmed by MLPA assay. MLPA can be a feasible platform for clinical laboratories to detect large deletion mutations in the mtDNA for suspected cases.
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PMID:Multiplex ligation-dependent probe amplification (MLPA) assay for the detection of mitochondrial DNA deletion in chronic progressive external ophthalmoplegia (CPEO). 2216 10

We described a case of a patient with autosomal dominant progressive external ophthalmoplegia (PEO) who presented with the acute onset dysphagia, quadriparesis, ptosis and respiratory insufficiency following a cardiac procedure and mimicking a myasthenic crisis. A pathogenic mutation in the C10orf2 (PEO1) gene was confirmed. The unusual presentation of our patient contributes to expand the clinical phenotype of PEO1 mutations and reinforces the need to consider mitochondrial myopathy as differential diagnosis of myasthenia gravis even in the case of acute onset symptoms.
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PMID:Progressive external ophthalmoplegia (PEO) due to a mutation in the C10orf2 (PEO1) gene mimicking a myasthenic crisis. 2401 82

Chronic progressive external ophthalmoplegia is one of mitochondrial disorders, characterized by ptosis, limitation of eye movement, variably severe bulbar muscle weakness and proximal limb weakness. Chronic progressive external ophthalmoplegia complicated with acquired disease is extremely rare. We report a 44 years old male patient with more than 20 years of chronic progressive bilateral ptosis and limitation of eye movements manifested dysarthria, dysphagia and neck muscle weakness for 3 years. The first muscle biopsy showed red-ragged fibers and cytochrome c oxidase negative fibers as well as inflammatory cells infiltration. Electron microscopy revealed paracrystalline inclusions. Mitochondrial genetic analysis demonstrated a large-scale mtDNA deletion of m.8470_13446del4977. The patient was treated with prednisone. In a three-year follow-up study, the second biopsy was performed. Before the treatment, except bilateral ptosis and external ophthalmopelgia, this patient presented bulbar muscle weakness and neck muscle weakness. After treated with prednisone, the symptoms of dysphagia, dysarthria and neck muscle weakness were significantly improved, and the second biopsy showed only mitochondrial myopathy pathology but the inflammations disappeared. Here, we report a patient with chronic progressive external ophthalmoplegia complicated with inflammatory myopathy and after treated with prednisone as myositis, he had a significant therapeutic effect.
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PMID:Chronic progressive external ophthalmoplegia with inflammatory myopathy. 2567 60

Progressive external ophthalmoplegia (PEO), marked by progressive bilateral ptosis and diffuse reduction in ocular motility, represents a finding of mitochondrial myopathy rather than a true diagnosis. PEO often occurs with other systemic features of mitochondrial dysfunction that can cause significant morbidity and mortality. Accurate and early recognition of PEO is paramount for the optimal care of these patients. We present an evidence-based review of the presenting neuro-ophthalmic features, differential diagnosis, diagnostic tools, systemic implications, and treatment options for isolated PEO and other PEO-associated mitochondrial syndromes.
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PMID:Progressive External Ophthalmoplegia. 2707 53

Classically defined as bilateral, symmetric, and progressive ophthalmoparesis with myopathic ptosis, chronic progressive external ophthalmoplegia (CPEO) rarely has been reported in the absence of ptosis. We describe 2 patients with CPEO and without ptosis who presented with binocular diplopia related to small-angle esodeviations, poor fusional amplitudes, and slow saccades. In both cases, hematological studies and neuroimaging ruled out alternative etiologies, whereas muscle biopsy showed findings of mitochondrial myopathy.
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PMID:Chronic Progressive External Ophthalmoplegia in the Absence of Ptosis. 2711 Oct 92

We report on two novel mtDNA mutations in patients affected with mitochondrial myopathy. The first patient, a 44-year-old woman, had bilateral eyelid ptosis and the m.8305C>T mutation in the MTTK gene. The second patient, a 56-year-old man, had four-limb muscle weakness and the MTTM gene m.4440G>A mutation. Muscle biopsies in both patients showed ragged red fibers and numerous COX-negative fibers as well as a combined defect of complex I, III and IV activities. The two mutations were heteroplasmic and detected only in muscle tissue, with a higher mutation load in COX-negative fibers. Additionally, both mutations occurred in highly conserved mt-tRNA sites, and were not found by an in silico search in 30,589 human mtDNA sequences. Our report further expands the mutational and phenotypic spectrum of diseases associated with mutations in mitochondrial tRNA genes and reinforces the notion that mutations in mitochondrial tRNAs represent hot spots for mitochondrial myopathies in adults.
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PMID:Identification and characterization of the novel m.8305C>T MTTK and m.4440G>A MTTM gene mutations causing mitochondrial myopathies. 2948 11

Two patients with an m.8340G>A mitochondrial DNA variant have been reported with one patient showing ptosis, ophthalmoparesis and myopathy at 53% heteroplasmy and another with pigmentary retinopathy, cataracts and sensory neural deafness and slightly higher heteroplasmy (65%). Here we report that higher muscle mutant heteroplasmy (93%) for m.8340G>A is associated with ptosis, ophthalmoparesis and mitochondrial myopathy, thus confirming the initial phenotypic association and showing that heteroplasmy per se does not explain the phenotypic spectrum of disease associated with the m.8340G>A mutation.
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PMID:CPEO - Like mitochondrial myopathy associated with m.8340G>A mutation. 2950 85


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