Myopathy, Encephalopathy, Lactic Acidosis And Stroke-like Episodes Research Articles

Linear cortical cystic lesions: Characteristic MR findings in MELAS patients

BackgroundMitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a progressive neurodegenerative disorder with stroke-like lesions. The common MRI findings are gyral swelling and high signal intensity on T2WI/FLAIR images crossing the vascular territories. We have observed a linear cystic lesion and a laminar necrosis in the affected cortices of MELAS patients. Herein, we evaluated these cortical MRI findings in each subtype of mitochondrial disease. Patients and methodsWe retrospectively reviewed the MRI findings of 71 consecutive patients with clinically and genetically confirmed mitochondrial diseases. The cortical cystic lesions and laminar necrotic lesions were evaluated on T1, T2, and FLAIR images in each subtype of mitochondrial disease, as were their clinical and other imaging characteristics. ResultsThe cortical cystic lesion was observed in 21 of the 71 patients (29.6%) with mitochondrial diseases. Laminar necrosis was detected in only three patients (4.2%). MELAS was the most frequent subtype with cortical cystic lesions, accounting for 81.0%, and all showed the linear pattern except for one patient whose pattern was beaded-like. ConclusionA cortical linear cystic lesion was a common MRI finding in our series of patients with mitochondrial disease, especially in those with MELAS, but laminar necrosis was not. These findings can help differentiate MELAS from infarction.

A-256 A Unique Bilingual Phenotype in the Context of Late Onset MELAS

Abstract Objective Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a progressive disease with typical onset before age 40 characterized by eventual neurocognitive deterioration. This case study highlights bilingual-bicultural neuropsychological principles within the Socially Responsible Neuropsychology (SRN) model to illustrate the phenotypic presentation of bilingual late-onset MELAS. Method The case is a 56-year-old, right-handed, bilingual Latino male (L1 Spanish, L2 English) with 16 years of education in his country of origin and 22 years as an industrial engineer in the U.S. At age 52, he was diagnosed with MELAS after an abrupt episode of olfactory hallucinations and dysgraphia in both languages. MRI revealed acute infarcts in the right parietal lobe and left cerebellum. He was referred for neuropsychological assessment 4 years later to evaluate reported neurocognitive decline and deterioration of L2, and to assist in targeted treatment planning. Results The clinical interview revealed significant decline in both receptive and expressive L2 English language capabilities, particularly relative to baseline as an industrial engineer, with relative sparing of L1 Spanish. Consistent with prior acute right hemisphere strokes, the neurocognitive profile also revealed lateralized impairment in visuospatial skills and memory. Notably verbal learning and memory in the mesial temporal system was preserved. Conclusions This case study illustrates how late L2 acquisition can lead to bilateral language representation, altering the phenotype of late-onset MELAS. Application of the SRN model highlights the importance of including background information regarding language acquisition and current language use to illustrate a unique bilingual MELAS phenotype and its impact on language loss and recovery.

Mechanisms Underlying Development of Taurine-Deficient Cardiomyopathy

Taurine is a ubiquitous β-amino acid that plays an essential role in ensuring normal mitochondrial and myocardial function. In the mitochondria, taurine reacts with a tRNA forming a 5-taurinomethyluridine conjugate that primarily regulates the biosynthesis of the mitochondria encoded protein, ND6, which serves as a subunit of complex I of the respiratory chain. Impaired formation of the taurine conjugate reduces activity of complex I and plays a central role in the pathophysiology of the mitochondrial disease MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The restoration of mitochondrial levels of the taurine conjugate enhances electron flux through the respiratory chain, thereby preventing at least some of the symptoms of MELAS. Taurine therapy also diminishes the severity of congestive heart failure, an observation that led to its approval for the treatment of congestive heart failure in Japan. The review article discusses the role of defective calcium handling, reduced ATP generation, enhanced oxidative stress and apoptosis in the development of taurine-deficient cardiomyopathy. Some patients suffering from congestive heart failure are taurine-deficient, an observation supporting the hypothesis that low taurine levels contribute to the severity of heart failure. Thus, mishandling of taurine leads to mitochondrial dysfunction, which is involved in the development of both MELAS and congestive heart failure.

Temporal bone histopathology in MELAS syndrome.

ObjectivesDescribe the histopathology of the temporal bones in MELAS (myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes) syndrome. The syndrome results from a known point mutation in mitochondrial DNA.MethodsHistopathology analysis of a pair of temporal bones from the oldest surviving MELAS syndrome temporal bone donor. Histopathologic findings were correlated with known premortem clinical data.ResultsThe inner ears showed severe but incomplete atrophy of the stria vascularis for the length of the cochleae. In contrast, the organ of Corti and inner hair cells appeared intact with some loss of outer hair cells. Other than moderate loss at the basal turn, spiral ganglion cells numbers were normal. The vestibular neuroepithelium was mostly normal with the exception of moderate degeneration of the macula sacculi and partial collapse of the saccular wall on the right. The cerebral cortex had infarct‐like lesions with adjacent gliosis.ConclusionThis is an analysis of the oldest patient with MELAS syndrome to date, an addition to only two previously published patients. It supports the notion that hearing loss is a result of dysfunction of the stria vascularis and not loss of hair cells or neurons. Patterns of vestibular pathology are in agreement to in‐vivo measurements. These findings support auditory rehabilitation with cochlear implants and may be relevant to hearing loss due to other mitochondrial mutations.Level of evidence4

Apomorphine rescues reactive oxygen species-induced apoptosis of fibroblasts with mitochondrial disease

Mitochondrial disease is a genetic disorder in which individuals suffer from energy insufficiency. The various clinical phenotypes of mitochondrial disease include Leigh syndrome (LS), myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS). Thus far, no curative treatment is available, and effective treatment options are eagerly awaited. We examined the cell protective effect of an existing commercially available chemical library on fibroblasts from four patients with LS and MELAS and identified apomorphine as a potential therapeutic drug for mitochondrial disease. We conducted a cell viability assay under oxidative stress induced by L-butionine (S, R)-sulfoximine (BSO), a glutathione synthesis inhibitor. Among the chemicals of library, 4 compounds (apomorphine, olanzapine, phenothiazine and ethopropazine) rescued cells from death induced by oxidative stress much more effectively than idebenone, which was used as a positive control. The EC50 value showed that apomorphine was the most effective compound. Apomorphine also significantly improved all of the assessed oxygen consumption rate values by the extracellular flux analyzer for fibroblasts from LS patients with complex I deficiency. In addition, the elevation of the Growth Differentiation Factor-15 (GDF-15), a biomarker of mitochondrial disease, was significantly reduced by apomorphine. Among 441 apomorphine-responsive genes identified by the microarray, apomorphine induced the expression of genes that inhibit the mammalian target of rapamycin (mTOR) activity and inflammatory responses, suggesting that apomorphine induced cell survival via a new potential pathway. In conclusion, apomorphine rescued fibroblasts from cell death under oxidative stress and improved the mitochondrial respiratory activity and appears to be potentially useful for treating mitochondrial disease.

Isolated and repeated stroke-like episodes in a middle-aged man with a mitochondrial ND3 T10158C mutation: a case report

BackgroundMitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, is the most common phenotype of mitochondrial disease. It often develops in childhood or adolescence, usually before the age of 40, in a maternally-inherited manner. Mutations in mitochondrial DNA (mtDNA) are frequently responsible for MELAS.Case presentationA 55-year-old man, who had no family or past history of mitochondrial disorders, suddenly developed bilateral visual field constriction and repeated stroke-like episodes. He ultimately presented with cortical blindness, recurrent epilepsy and severe cognitive impairment approximately 6 months after the first episode. Genetic analysis of biopsied biceps brachii muscle, but not of peripheral white blood cells, revealed a T10158C mutation in the mtDNA-encoded gene of NADH dehydrogenase subunit 3 (ND3), which has previously been thought to be associated with severe or fatal mitochondrial disorders that develop during the neonatal period or in infancy.ConclusionA T10158C mutation in the ND3 gene can cause atypical adult-onset stroke-like episodes in a sporadic manner.

Mitochonic Acid 5 (MA-5), a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases.

Mitochondria are key organelles implicated in a variety of processes related to energy and free radical generation, the regulation of apoptosis, and various signaling pathways. Mitochondrial dysfunction increases cellular oxidative stress and depletes ATP in a variety of inherited mitochondrial diseases and also in many other metabolic and neurodegenerative diseases. Mitochondrial diseases are characterized by the dysfunction of the mitochondrial respiratory chain, caused by mutations in the genes encoded by either nuclear DNA or mitochondrial DNA. We have hypothesized that chemicals that increase the cellular ATP levels may ameliorate the mitochondrial dysfunction seen in mitochondrial diseases. To search for the potential drugs for mitochondrial diseases, we screened an in-house chemical library of indole-3-acetic-acid analogs by measuring the cellular ATP levels in Hep3B human hepatocellular carcinoma cells. We have thus identified mitochonic acid 5 (MA-5), 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid, as a potential drug for enhancing ATP production. MA-5 is a newly synthesized derivative of the plant hormone, indole-3-acetic acid. Importantly, MA-5 improved the survival of fibroblasts established from patients with mitochondrial diseases under the stress-induced condition, including Leigh syndrome, MELAS (myopathy encephalopathy lactic acidosis and stroke-like episodes), Leber's hereditary optic neuropathy, and Kearns-Sayre syndrome. The improved survival was associated with the increased cellular ATP levels. Moreover, MA-5 increased the survival of mitochondrial disease fibroblasts even under the inhibition of the oxidative phosphorylation or the electron transport chain. These data suggest that MA-5 could be a therapeutic drug for mitochondrial diseases that exerts its effect in a manner different from anti-oxidant therapy.

A Case of Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MEALS) Syndrome with Intracardiac Thrombus

Myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a multisystem clinical syndrome manifested by mitochondrial myopathy, encephalopathy, lactic acidosis and recurrent stroke-like episodes. A 27-year-old female with MELAS syndrome presented with cerebral infarction. Echocardiography revealed a thrombus attached to the apex of the hypertrophied left ventricle, with decreased systolic function. The embolism of the intracardiac thrombus might have been the cause of stroke. There should be more consideration given to the increased possibility of intracardiac thrombus formation when a MELAS patient with cardiac involvement is encountered.

脳卒中様発作時のてんかん発作重積にL-arginineが有効であったmitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) の女児例

脳卒中様発作時のてんかん発作重積にL-arginineが有効であったmitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) の女児例

In vivo functional brain imaging and a therapeutic trial of l-arginine in MELAS patients

BackgroundMitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common type of mitochondrial disease and is characterized by stroke-like episodes (SEs), myopathy, lactic acidosis, diabetes mellitus, hearing-loss and cardiomyopathy. The causal hypotheses for SEs in MELAS presented to date are angiopathy, cytopathy and neuronal hyperexcitability. L-arginine (Arg) has been applied for the therapy in MELAS patients. Scope of reviewWe will introduce novel in vivo functional brain imaging techniques such as MRI and PET, and discuss the pathogenesis of SEs in MELAS patients. We will further describe here our clinical experience with L-arg therapy and discuss the dual pharmaceutical effects of this drug on MELAS. Major conclusionsAdministration of L-arg to MELAS patients has been successful in reducing neurological symptoms due to acute strokes and preventing recurrences of SEs in the chronic phase. L-Arg has dual pharmaceutical effects on both angiopathy and cytopathy in MELAS. General significanceIn vivo functional brain imaging promotes a better understanding of the pathogenesis and potential therapies for MELAS patients. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010.

Vascular involvement in the pathogenesis of mitochondrial encephalomyopathies

Objective: The aim of this study was to perform perfusion CT imaging in the acute phase of myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), to assess whether these patients had cerebral perfusion abnormalities. Furthermore, the pathology of muscle vessel was evaluated, to explore the role of vasculopathy and ischemic events in the pathogenesis of mitochondrial encephalomyopathies.Methods: Computed tomography perfusion (CTP) imaging was applied to the evaluation of brain perfusion during the symptomatic period of mitochondrial encephalomyopathies. Mitochondria structures in the blood vessels wall within muscle fibers were observed by light and electron microscopy analyses.Results: Neuroimaging studies demonstrated uni- and bilateral lesions predominantly in the occipital and temporal-parietal lobes. Compared with the healthy control subjects, significant decreases in cerebral blood flow and cerebral blood volume were noted in affected brain areas of individuals with MELAS. In particular, mean transit time and the time to peak were prolonged both in lesion and non-lesion brain areas. Muscle pathology showed large granular deposits on vessel wall as demonstrated by succinic acid dehydrogenase staining. Electron microscopy of blood vessels revealed swelling of cristae and a striking increase in the number of mitochondria in the smooth muscle and endothelial cells.Conclusion: Insufficient cerebral perfusion or vascular reserve and secondary metabolic dysfunction may represent an important feature of the pathogenesis of the stroke-like episodes in MELAS.

Identifying sequence variants in the human mitochondrial genome using high-resolution melt (HRM) profiling

Identifying mitochondrial DNA (mtDNA) sequence variants in human diseases is complicated. Many pathological mutations are heteroplasmic, with the mutant allele represented at highly variable percentages. High-resolution melt (HRM or HRMA) profiling was applied to comprehensive assessment of the mitochondrial genome and targeted assessment of recognized pathological mutations. The assay panel providing comprehensive coverage of the mitochondrial genome utilizes 36 overlapping fragments (301-658 bp) that employ a common PCR protocol. The comprehensive assay identified heteroplasmic mutation in 33 out of 33 patient specimens tested. Allele fraction among the specimens ranged from 1 to 100%. The comprehensive assay panel was also used to assess 125 mtDNA specimens from healthy donors, which identified 431 unique sequence variants. Utilizing the comprehensive mtDNA panel, the mitochondrial genome of a patient specimen may be assessed in less than 1 day using a single 384-well plate or two 96-well plates. Specific assays were used to identify the myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) mutation m.3243A>G, myoclonus epilepsy, ragged red fibers (MERRF) mutation m.8344A>G, and m.1555A>G associated with aminoglycoside hearing loss. These assays employ a calibrated, amplicon-based strategy that is exceedingly simple in design, utilization, and interpretation, yet provides sensitivity to detect variants at and below 10% heteroplasmy. Turnaround time for the genotyping tests is about 1 hr.

Impaired Mitochondrial Function and Insulin Resistance of Skeletal Muscle in Mitochondrial Diabetes

OBJECTIVEImpaired muscular mitochondrial function is related to common insulin resistance in type 2 diabetes. Mitochondrial diseases frequently lead to diabetes, which is mostly attributed to defective β-cell mitochondria and secretion.RESEARCH DESIGN AND METHODSWe assessed muscular mitochondrial function and lipid deposition in liver (hepatocellular lipids [HCLs]) and muscle (intramyocellular lipids [IMCLs]) using 31P/1H magnetic resonance spectroscopy and insulin sensitivity and endogenous glucose production (EGP) using hyperinsulinemic-euglycemic clamps combined with isotopic tracer dilution in one female patient suffering from MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome and in six control subjects.RESULTSThe MELAS patient showed impaired insulin sensitivity (4.3 vs. 8.6 ± 0.5 mg · kg−1 · min−1) and suppression of EGP (69 vs. 94 ± 1%), and her baseline and insulin-stimulated ATP synthesis were reduced (7.3 and 8.9 vs. 10.6 ± 1.0 and 12.8 ± 1.3 μmol · l−1 · min−1) compared with those of the control subjects. HCLs and IMCLs were comparable between the MELAS patient and control subjects.CONCLUSIONSImpairment of muscle mitochondrial fitness promotes insulin resistance and could thereby contribute to the development of diabetes in some patients with the MELAS syndrome.

Effects of l -arginine on the acute phase of strokes in three patients with MELAS

The primary cause for strokelike episodes in young patients with MELAS (myopathy, encephalopathy, lactic acidosis, and strokelike episodes)—whether mitochondrial cytopathy, angiopathy, or both—remains controversial. Based on a hypothesis that strokelike episodes in MELAS are caused by segmental impairment of vasodilation in intracerebral arteries, we administered l-arginine to three patients with MELAS in the acute phase of stroke (within 1 hour of onset) and evaluated effects on clinical course, biochemical measurements, and functional cerebral hemodynamics according to 99mTc-ECD SPECT. ### Patients. Patient 1 was a 17-year-old woman referred to the hospital for periodic vomiting, hemiconvulsion, and short stature (below 2.7 SD). Patient 2 was an 18-year-old woman who was admitted to the hospital for generalized muscle weakness, periodic vomiting, hemiparesis, and short stature (below 1.5 SD). Patient 3 was a 15-year-old boy referred to our hospital for hemiblindness, hemiconvulsions, vomiting, and short stature (below 2.8 SD). All patients showed extensive calcification in the basal ganglia, lactic acidosis (3.8 to 5.6 mmol/L; normal range …

Quantification of OXPHOS Gene Transcripts during Muscle Cell Differentiation in Patients with Mitochondrial Myopathies

The transcript levels of nuclear and mitochondrial genes involved in oxidative phosphorylation were quantified in human myoblasts and myotubes cultured from biopsies of patients harboring either heteroplasmic point mutation or deletion of mitochondrial DNA. The transcript patterns were determined by two different methodologies, competitive reverse-transcription polymerase chain reaction and classical Northern blot analysis, both referred to the mitochondrial to nuclear DNA ratio. In myoblasts from the patients with MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and KSS (Kearns–Sayre) syndromes, both methodologies revealed an increase of mtDNA transcript levels. A higher level of the nuclear ATP synthase β transcript was observed in the MELAS patient cells and could be the consequence of a feedback effect of the mitochondrial DNA mutation. Moreover, the nuclear and mitochondrial transcript accumulation is more pronounced after myoblast differentiation. Thus, the OXPHOS expression is specifically altered in patients with mitochondrial diseases. The competitive RT-PCR, a rapid and sensitive technique, could be applied to investigation of mitochondrial myopathies.