Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162671 (MELAS)
 587 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among 40 patients with ragged red fibers in muscle biopsy, all but two met criteria for one of the recognized mitochondrial myopathies: Kearns-Sayre syndrome (6 patients); other ophthalmoplegias (17): MELAS (3); MERRF (2); limb myopathy (5); and exercise intolerance (3). Two patients had MNGIE (mitochondrial myopathy with neuropathy, gastrointestinal symptoms and encephalopathy) and one had spinal muscular atrophy. The myopathy had features of facioscapulohumeral dystrophy in 4 patients. This analysis provides 4 lines of evidence to reinforce the view that, despite occasional "overlap" cases, distinct syndromes can be recognized. First, there are clinical differences. Second, KSS is almost never familial but MELAS and MERRF are often familial. Third, in this series, as in others, all deletions of mtDNA were found in patients with either KSS or non-familial PEO. With a possible single exception, none of the familial cases had KSS and no familial cases included a deletion of mtDNA. Others have found evidence of mtDNA point mutations in MERRF, and maternal inheritance suggests that point mutations will be found in MELAS. Finally, postmortem findings differ in KSS, MELAS, and MERRF. For all of these reasons, we believe it is useful to separate cases on clinical grounds. Deletions and point mutations of mtDNA are becoming defining characteristics of these syndromes.
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PMID:Clinical syndromes associated with ragged red fibers. 196 52

We report the clinical, pathological, and genetic findings of a case of MELAS syndrome. This was a man who died for metabolic failure at the age of 27 years. His familiar history was positive for hypoacusia and stroke. He was of short stature and presented mild mental retardation. Since the age of 21 he suffered from recurrent brain-ischemic lesions mainly in the occipital lobes, documented by repeated CT scans. The laboratory data and muscle biopsy disclosed lactic acidosis with ragged red fibres. Neurophysiological data and peripheral nerve biopsy showed an axonal neuropathy. A point mutation in the tRNALeu(UUR) gene of mitochondrial DNA was detected in 5 post-mortem tissues and in muscle biopsy. No defects of mitochondrial respiratory chain were detected. The histological and ultrastructural studies of the brain showed multiple and heterogeneous ischemic lesions with no obvious alterations of cerebral blood vessels. These lesions do not correspond to the vascular territories of main cerebral arteries. Our observations support the hypothesis that local metabolic alterations would play a crucial role in the pathogenesis of cerebral ischemic lesions in MELAS. The correlation between genetic, biochemical, and pathological data are discussed.
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PMID:Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). 926 44

Diabetes mellitus associated with mitochondrial tRNA mutation at position 3243(DM-Mt3243) is a new disease. Patients have a distinctly different picture from MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). During observations at the Saiseikai Central Hospital, the following findings were noted in DM-Mt3243 patients: DM-Mt3243 patients are diagnosed earlier with diabetes, compared to NIDDM (non-insulin dependent diabetes mellitus) controls without family history. DM-Mt3243 patients often need insulin more often than NIDDM controls without family history. Post-treatment neuropathy and insulin edema are often found in DM-Mt3243, and the two phenomena possibly have a similar pathophysiology related to mitochondrial dysfunction. Ambiguous psychiatric disorders of functional psychosis are observed frequently in DM-Mt3243. Mild headache is common in DM-Mt3243 cases. Ambiguous neuromuscular abnormalities such as sleep disturbance, paresthesia of the legs, edema of the legs, and palpitation may be symptoms associated with mitochondrial dysfunction in DM-Mt3243. Coenzyme Q may be effective in the relief of these neuromuscular symptoms.
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PMID:Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation: clinical features and coenzyme Q10 treatment. 926 20

Since the first identification in 1988 of pathogenic mitochondrial DNA (mtDNA) mutations, the mitochondrial diseases have emerged as a major clinical entity. The most striking feature of these disorders is their marked heterogeneity, which extends to their clinical, biochemical, and genetic characteristics. The major mitochondrial encephalomyopathies include MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes), MERRF (myoclonic epilepsy with ragged red fibers), KSS/CPEO (Kearns-Sayre syndrome/chronic progressive external ophthalmoplegia), and NARP/MILS (neuropathy, ataxia, and retinitis pigmentosum/maternally inherited Leigh syndrome) and they typically present highly variable multisystem defects that usually involve abnormalities of skeletal muscle and/or the CNS. The primary emphasis here is to review recent investigations of these mitochondrial diseases from the standpoint of how the complexities of mitochondrial genetics and biogenesis might determine their varied features. In addition, the mitochondrial encephalomyopathies are compared and contrasted to Leber hereditary optic neuropathy, a mitochondrial disease in which the pathogenic mtDNA mutations produce a more uniform and focal neuropathology. All of these disorders involve, at some level, a mitochondrial respiratory chain dysfunction. Because mitochondrial genetics differs so strikingly from the Mendelian inheritance of chromosomes, recent research on the origin and subsequent segregation and transmission of mtDNA mutations is reviewed.
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PMID:Human mitochondrial diseases: answering questions and questioning answers. 977 Feb 97

Clinical and biochemical classifications of mitochondrial disorders have given way to an as yet incomplete genetic classification system based on alterations of the mitochondrial genome, the nuclear genome, or both. The first group includes mitochondrial disorders due to specific mutations of mitochondrial DNA such as the MELAS, MERRF or NARP encephalomyopathies, various conditions involving deafness (non-syndromic or associated with diabetes), Leber's optic neuropathy and a small group of cases of maternally transmitted Leigh's syndrome. All these diseases are transmitted through maternal line. conditions which are usually sporadic are due to deletion or duplication of mitochondrial DNA, and give rise to myopathies, with or without ophthalmoplegia, and to more complex disorders such as Kearns Sayre syndrome are also included. The second group is composed of all the mitochondrial disorders in which the nuclear genes which codify sub-units of mitochondrial DNA contain a genetic defect. This includes most cases of Leigh's syndrome, Alpers polydystrophies, the myoneurogastrointestinal syndrome, Barth's syndrome and Friedreich's disease. Amongst the disorders secondary to defects in communication between the nuclear and mitochondrial genomes is a progressive external ophthalmoplegic form with autosomal dominance which arises secondary to mutations on chromosomes 3 and 10. Further mitochondrial disorders due to faults in the relationship between the two genomes will probably be found in the near future.
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PMID:[Classification of mitochondrial diseases]. 981 May 85

Congenital disorders of glycosylation (CDG) and mitochondrial diseases are multisystem disorders with clinical characteristics that may overlap. We present four patients with CDG whose phenotypes suggested the diagnosis of a mitochondrial disease. Patients 1 and 2 are siblings with hemiplegic headache, stroke-like episodes, lactic acidaemia and history of maternal migraine; their initial clinical diagnosis was MELAS syndrome (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes). Patient 3 suffers from ataxia, neuropathy, ophtalmoplegia and retinitis pigmentosa suggestive of NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. Patient 4 presented with neurological regression mimicking Leigh disease, with ptosis, myoclonus, ataxia and brainstem and cerebellar atrophy. Screening for mitochondrial disease including enzyme and mtDNA investigations on muscle biopsy were performed on Patients 1, 2 and 4 with normal results. However, evidence for a glycosylation disorder was substantiated by an increased carbohydrate deficient transferrin (CDT). The isoelectric focussing pattern of serum sialotransferrin was typical of CDG type I in Patients 1, 2 and 3 and was shifted towards the less sialylated bands in case 4. A deficiency of phosphomanomutase (PMM) confirmed the diagnosis of CDG-Ia in Patients 1, 2 and 3, who are compound heterozygous for mutations R141H/T237M (Patients 1 and 2) and R141H/P113L (Patient 3). In Patient 4, PMM activity was normal, and further enzymatic and molecular studies are underway. As the search for the primary defect in mitochondrial diseases is often unsuccessful, the pool of mitochondrial patients that remain without definite diagnosis might include CDG cases. Routine screening for CDG may avoid precocious invasive investigations.
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PMID:Congenital disorders of glycosylation (CDG) may be underdiagnosed when mimicking mitochondrial disease. 1158 67

Peripheral neuropathy is one of the clinical manifestations of the MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) syndrome, but its frequency and phenotypic variability have not been properly characterised. We therefore studied the clinical and electrophysiological features of peripheral neuropathy in 32 patients with the 3243A > G mutation in mitochondrial DNA by using clinical examination, assessment of Neuropathy Symptom Score, Neuropathy Disability Score, and electrophysiological examinations. Seven patients (22 %; 95 % confidence interval, 9-40 %) fulfilled the electrodiagnostic criteria for polyneuropathy. Mixed axon loss and demyelinating sensorimotor neuropathy was the most common type of polyneuropathy, while one patient presented with uniform demyelinating sensorimotor polyneuropathy. Sensory more than motor neuropathy was diagnosed in four patients. Clinically and electrophysiologically confirmed carpal tunnel syndrome (CTS) occurred in three patients (9.4 %), suggesting a higher prevalence than in the general population. Patients with neuropathy were in general more severely affected than those without neuropathy, although no correlation was found between the presence of neuropathy and the degree of mutant heteroplasmy in muscle. Higher age and male gender were associated with an increased risk of neuropathy. Our results show that peripheral neuropathy is not uncommon in patients with the 3243A > G mutation, and they also may have an increased risk of CTS.
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PMID:Peripheral neuropathy in patients with the 3243A>G mutation in mitochondrial DNA. 1257 54

A 15-year-old girl presented with stroke and was found to have a mitochondrial mutation MELAS T3271C. As an infant, she had required casting and surgery for clubbed feet as well as physical therapy for camptodactyly and adducted thumbs. Despite some residual deformities, psychomotor development was normal, but she was extremely small for her age with height, weight, and head circumference below the third centile. A younger brother had similar distal arthrogryposis, but normal height and weight and no history of stroke though he had been diagnosed with attention deficit. The parents and another brother were clinically normal. While the observation of MELAS in a child with distal arthrogryposis could be co-incidental, it raises concern about the possible role of mitochondrial myopathy or neuropathy in causation of distal arthrogryposis.
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PMID:Mitochondrial mutation in a child with distal arthrogryposis. 1635 43

Ocular complications are common in the mitochondrial cytopathies and include optic atrophy and retinal degeneration. We retrospectively reviewed 80 patients with nonsyndromic mitochondrial cytopathies (ie, not Kearns-Sayre syndrome, myoclonus epilepsy associated with ragged red fibers [MERRF], mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes [MELAS], neuropathy ataxia and retinitis pigmentosa, Leigh disease, maternally inherited diabetes and deafness, and myoneurogastrointestinal disorder and encephalopathy) and found 10 cases of optic nerve hypoplasia. Optic nerve hypoplasia occurs in at least 12% of patients with nonsyndromic mitochondrial cytopathies. Although the exact pathogenesis of optic nerve hypoplasia in the context of mitochondrial cytopathy is unknown, we postulate that it is the result of excessive apoptosis during embryonic ganglion cell and/or axonal development from abnormal mitochondrial function and cellular energy metabolism.
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PMID:Association of optic nerve hypoplasia with mitochondrial cytopathies. 1709 61

Defects of the oxidative ATP production pathway lead to an amazing variety of disease phenotypes, ranging from childhood encephalomyopathies to hereditary tumor formation. A key enzyme of tricarboxylic cycle, fumarate hydratase (FH), is involved in encephalopathies, but also in leiomyoma formation, and occasionally also in various types of cancer. MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) and NARP (neuropathy ataxia retinitis pigmentosa) are progressive neurological disorders, caused by mitochondrial DNA mutations and respiratory chain (RC) deficiency. These diseases lead to disability and premature death, but not to tumorigenesis. We studied the cellular consequences of FH and RC deficiencies, aiming to identify general responses to energy metabolism defect and those specific for FH-deficiency, suggestively connected to tumorigenesis. Unlike in RC deficiency, the FH-deficient diploid human fibroblasts showed no signs of oxidative stress, but had a reduced redox state with high glutathione levels. The cytoplasmic FH isoform, previously described, but with an unknown function, was completely lacking in all FH-deficient lines. Fumarate was increased in two of our FH-lines, but accumulation of HIF-1alpha was not detected. Glycolysis was induced in both MELAS and in FH-deficiency. Accumulation of fumarate in primary fibroblasts did not activate a hypoxia response, suggesting that hypoxia activation due to fumarate accumulation may be a tissue-specific response. The lack of cytoplasmic form of FH and the reduced redox environment were typical for all FH-mutant lines, and their role in FH-related tumorigenesis requires further attention.
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PMID:Differential metabolic consequences of fumarate hydratase and respiratory chain defects. 1831 10


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