The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Salvatore Dimauro - One of the best experts on this subject based on the ideXlab platform.
-
Mitochondrial Encephalomyopathy Due to a Novel Mutation in ACAD9
JAMA neurology, 2013Co-Authors: Caterina Garone, Maria Alice Donati, Michele Sacchini, Beatriz Garcia-diaz, Claudio Bruno, Sarah E. Calvo, Vamsi K. Mootha, Salvatore DimauroAbstract:IMPORTANCE Mendelian forms of complex I deficiency are usually associated with fatal infantile Encephalomyopathy. Application of “MitoExome” sequencing (deep sequencing of the entire Mitochondrial genome and the coding exons of >1000 nuclear genes encoding the Mitochondrial proteome) allowed us to reveal an unusual clinical variant of complex I deficiency due to a novel homozygous mutation in ACAD9. The patient had an infantile-onset but slowly progressive Encephalomyopathy and responded favorably to riboflavin therapy.
-
infantile Mitochondrial Encephalomyopathy due to a novel mutation in acad9 p03 017
Neurology, 2013Co-Authors: Caterina Garone, Maria Alice Donati, Michele Sacchini, Sarah E. Calvo, Vamsi K. Mootha, Beatriz Garciadiaz, Salvatore DimauroAbstract:OBJECTIVE: To identify causative gene variants of early-onset complex I deficiency. BACKGROUND: Complex I deficiency is the most common respiratory chain defect with early-onset fatal Encephalomyopathy. Although many molecular defects have been described both in structural subunits and in assembly factors, the genetic diagnosis remains unknown in a large cohort of patients. DESIGN/METHODS: We carried out biochemical and molecular studies in muscle and cultured fibroblasts from a patient with infantile Mitochondrial Encephalomyopathy. Next generation exome sequencing with a Mitochondrial gene library (MitoExome) was applied to identify the molecular defect. RESULTS: A 9-year-old Italian boy had severe infantile-onset myopathy with exercise intolerance, weakness, muscle wasting. He also had mental retardation and severe complex I deficiency. Metabolic workup showed increased levels of plasma lactic acid, acylcarnitine C0, and alanine, and thyroid dysfunction. EMG was compatible with a myopathic process and muscle biopsy revealed Mitochondrial proliferation. Cardiac function was normal and there were no abnormalities of brain MRI. Biochemical studies showed severe complex I and moderate complex III deficiencies both in muscle and in fibroblasts. Western blot analysis of mtDNA-encoded respiratory chain components showed reduced protein level of complex I. MitoExome sequencing revealed a new homozygous mutation in ACAD9 gene (p.R414C) that was confirmed by Sanger sequence and found in heterozygosity in both parents. Improvement of muscle strength was reported after treatment with high-dose riboflavin. CONCLUSIONS: ACAD9 is a complex I assembly factor whose defects have been associated with a protean clinical spectrum spanning from pure myopathy with exercise intolerance and lactic acidosis to rapidly progressive Encephalomyopathy and hypertrophic cardiomyopathy. Our case contributes adds to the clinical heterogeneity of ACAD9 deficiency and confirms the importance of assembly factors in causing complex I deficiency. Disclosure: Dr. Garone has nothing to disclose. Dr. Donati has nothing to disclose. Dr. Sacchini has nothing to disclose. Dr. Calvo has nothing to disclose. Dr. Garcia-Diaz has nothing to disclose. Dr. Mootha has nothing to disclose. Dr. DiMauro has received personal compensation in an editorial capacity for MedLink Neurology.
-
a novel mutation in the Mitochondrial dna cytochrome b gene mtcyb in a patient with Mitochondrial Encephalomyopathy lactic acidosis and strokelike episodes syndrome
Journal of Child Neurology, 2013Co-Authors: Valentina Emmanuele, Evangelia Sotiriou, Purificacion Gutierrez Rios, Jaya Ganesh, Rebecca Ichord, Reghan A Foley, Orhan H Akman, Salvatore DimauroAbstract:Mutations in the Mitochondrial DNA cytochrome b gene (MTCYB) have been commonly associated with isolated Mitochondrial myopathy and exercise intolerance, rarely with multisystem disorders, and only once with a parkinsonism/Mitochondrial Encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) overlap syndrome. Here, we describe a novel mutation (m.14864 T>C) in MTCYB in a 15-year-old girl with a clinical history of migraines, epilepsy, sensorimotor neuropathy, and strokelike episodes, a clinical picture reminiscent of MELAS. The mutation, which changes a highly conserved cysteine to arginine at amino acid position 40 of cytochrome b, was heteroplasmic in muscle, blood, fibroblasts, and urinary sediment from the patient but absent in accessible tissues from her asymptomatic mother. This case demonstrates that MTCYB must be included in the already long list of Mitochondrial DNA genes that have been associated with the MELAS phenotype.
-
does the patient have a Mitochondrial Encephalomyopathy
Journal of Child Neurology, 1999Co-Authors: Salvatore Dimauro, Eduardo Bonilla, Darryl C De VivoAbstract:The ubiquitous nature of mitochondria, the dual genetic control of the respiratory chain, and the peculiar rules of Mitochondrial genetics contribute to explain the extraordinary clinical heterogeneity of disorders associated with defects of oxidative phosphorylation (Mitochondrial encephalomyopathies). To provide a practical approach to the diagnostic challenge posed by these conditions, we critically review the following criteria: (1) clinical presentation; (2) family history; (3) laboratory data; (4) neuroradiologic patterns; (5) standardized exercise testing; (6) muscle morphology; (7) muscle biochemistry; and (8) molecular genetic screening. Judicious sequential application of these tools should provide help in recognizing patients with Mitochondrial disease and define the biochemical and molecular basis of the disorder for each patient. This knowledge is indispensable for accurate genetic counseling and prenatal diagnosis and is a prerequisite for the development of rational therapies, which are still woefully inadequate.
-
the Mitochondrial trna leu uur mutation in Mitochondrial Encephalomyopathy lactic acidosis and strokelike episodes melas genetic biochemical and morphological correlations in skeletal muscle
American Journal of Human Genetics, 1992Co-Authors: Carlos T Moraes, Salvatore Dimauro, Eduardo Bonilla, Enzo Ricci, Eric A SchonAbstract:Mitochondrial Encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) has recently been associated with an A----G transition at position 3243 within the Mitochondrial tRNA(Leu(UUR)) gene. Besides altering the tRNA(Leu(UUR)) sequence, this point mutation lies within a DNA segment responsible for transcription termination of the rRNA genes. We have studied the distribution and expression of mutant mtDNAs in muscle biopsies from MELAS patients. Histochemical, immunohistochemical, and single-fiber PCR analysis showed that ragged-red fibers (RRF) are associated both with high levels of mutant Mitochondrial genomes (greater than 85% mutant mtDNA) and with a partial cytochrome c oxidase deficiency. By quantitative in situ hybridization, the steady-state ratios of mRNAs:rRNAs were found to be similar to controls in six of eight patients studied. In two other patients the relative levels of heavy-strand mRNAs were slightly increased, but a patient with myoclonic epilepsy and RRF also exhibited a similar increase. These results directly correlate the A----G transition at mtDNA position 3243 with muscle Mitochondrial proliferation, partial respiratory-chain impairment, decreased Mitochondrially synthesized protein content, and no specific alterations in Mitochondrial ratios of mRNAs:rRNAs.
Massimo Zeviani - One of the best experts on this subject based on the ideXlab platform.
-
severe x linked Mitochondrial Encephalomyopathy associated with a mutation in apoptosis inducing factor
American Journal of Human Genetics, 2010Co-Authors: Daniele Ghezzi, Pio Dadamo, Irina F Sevrioukova, Federica Invernizzi, Costanza Lamperti, Marina Mora, Francesca Novara, Orsetta Zuffardi, Graziella Uziel, Massimo ZevianiAbstract:We investigated two male infant patients who were given a diagnosis of progressive Mitochondrial Encephalomyopathy on the basis of clinical, biochemical, and morphological features. These patients were born from monozygotic twin sisters and unrelated fathers, suggesting an X-linked trait. Fibroblasts from both showed reduction of respiratory chain (RC) cIII and cIV, but not of cI activities. We found a disease-segregating mutation in the X-linked AIFM1 gene, encoding the Apoptosis-Inducing Factor (AIF) mitochondrion-associated 1 precursor that deletes arginine 201 (R201 del). Under normal conditions, mature AIF is a FAD-dependent NADH oxidase of unknown function and is targeted to the Mitochondrial intermembrane space (this form is called AIFmit). Upon apoptogenic stimuli, a soluble form (AIFsol) is released by proteolytic cleavage and migrates to the nucleus, where it induces “parthanatos,” i.e., caspase-independent fragmentation of chromosomal DNA. In vitro, the AIFR201 del mutation decreases stability of both AIFmit and AIFsol and increases the AIFsol DNA binding affinity, a prerequisite for nuclear apoptosis. In AIFR201 del fibroblasts, staurosporine-induced parthanatos was markedly increased, whereas re-expression of AIFwt induced recovery of RC activities. Numerous TUNEL-positive, caspase 3-negative nuclei were visualized in patient #1's muscle, again indicating markedly increased parthanatos in the AIFR201 del critical tissues. We conclude that AIFR201 del is an unstable mutant variant associated with increased parthanatos-linked cell death. Our data suggest a role for AIF in RC integrity and mtDNA maintenance, at least in some tissues. Interestingly, riboflavin supplementation was associated with prolonged improvement of patient #1's neurological conditions, as well as correction of RC defects in mutant fibroblasts, suggesting that stabilization of the FAD binding in AIFmit is beneficial.
-
fastkd2 nonsense mutation in an infantile Mitochondrial Encephalomyopathy associated with cytochrome c oxidase deficiency
American Journal of Human Genetics, 2008Co-Authors: Daniele Ghezzi, Pio Dadamo, Erika Fernandezvizarra, Paolo Gasparini, Orly Elpeleg, Ann Saada, Valeria Tiranti, Massimo ZevianiAbstract:In two siblings we found a Mitochondrial Encephalomyopathy, characterized by developmental delay, hemiplegia, convulsions, asymmetrical brain atrophy, and low cytochrome c oxidase (COX) activity in skeletal muscle. The disease locus was identified on chromosome 2 by homozygosity mapping; candidate genes were prioritized for their known or predicted Mitochondrial localization and then sequenced in probands and controls. A homozygous nonsense mutation in the KIAA0971 gene segregated with the disease in the proband family. The corresponding protein is known as fas activated serine-threonine kinase domain 2, FASTKD2. Confocal immunofluorescence colocalized a tagged recombinant FASTKD2 protein with Mitochondrial markers, and membrane-potential-dependent in vitro Mitochondrial import was demonstrated in isolated mitochondria. In staurosporine-induced-apoptosis experiments, decreased nuclear fragmentation was detected in treated mutant versus control fibroblasts. In conclusion, we found a loss-of-function mutation in a gene segregating with a peculiar Mitochondrial Encephalomyopathy associated with COX deficiency in skeletal muscle. The corresponding protein is localized in the Mitochondrial inner compartment. Preliminary data indicate that FASTKD2 plays a role in Mitochondrial apoptosis.
-
a missense mutation in the Mitochondrial nd5 gene associated with a leigh melas overlap syndrome
Neurology, 2003Co-Authors: Marco Crimi, Massimo Zeviani, Sara Galbiati, Isabella Moroni, Andreina Bordoni, Maria Paola Perini, Eleonora Lamantea, M Sciacco, Ida Biunno, Maurizio MoggioAbstract:A 13084 A->T missense mutation in the Mitochondrial ND5 gene was identified in a 16-year-old boy affected with a progressive neurodegenerative disorder combining features of Leigh and MELAS (Mitochondrial Encephalomyopathy, lactic acidosis, and strokelike episodes) syndromes. Muscle biopsy analysis revealed partial complex I deficiency. The mutation presented a variable degree of heteroplasmy in the patient's tissues. This finding underlines the contribution of mtDNA-encoded complex I subunits in the etiology of complex I deficiency associated with encephalopathy.
-
a merrf melas overlap syndrome associated with a new point mutation in the Mitochondrial dna trna lys gene
European Journal of Human Genetics, 1993Co-Authors: Massimo Zeviani, Valeria Tiranti, F Muntoni, Nicola Savarese, Gigliola Serra, Franco Carrara, Caterina Mariotti, Stefano DidonatoAbstract:Several members of a three-generation kindred from Sardinia were affected by a maternally inherited syndrome characterized by features of both myoclonus epilepsy with ragged-red fibers (MERRF) and Mitochondrial Encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). Clinically, symptoms such as myoclonus epilepsy, neural deafness and ataxia were variably associated with stroke-like episodes and/or migrainous attacks. Morphologically, numerous MELAS-associated SDH-stained vessels were observed in muscle biopsies, either alone or in combination with ragged-red fibers, the morphological hallmark of MERRF. Sequence analysis of the mtDNA tRNA genes revealed the presence of a single, heteroplasmic T-->C transition at nt 8356, in the region of the tRNA(Lys) gene corresponding to the T-psi-C stem. The T-->C(8356) transition was exclusively found in the maternal lineage of our family, and the relative amount of the mutant mtDNA species in muscle was correlated with the severity of the clinical presentation. Therefore, we propose that the T-->C(8356) transition is responsible for the Mitochondrial Encephalomyopathy found in our family, and must be added to the expanding list of the pathogenetically relevant mutations of human mtDNA.
Eleonora Lamantea - One of the best experts on this subject based on the ideXlab platform.
-
rnaseh1 mutations impair mtdna replication and cause adult onset Mitochondrial Encephalomyopathy
American Journal of Human Genetics, 2015Co-Authors: Aurelio Reyes, Eleonora Lamantea, Costanza Lamperti, Franco Carrara, Laura Melchionda, Alessia Nasca, Alice Zanolini, Mingyan Fang, Jianguo Zhang, Dario RonchiAbstract:Chronic progressive external ophthalmoplegia (CPEO) is common in Mitochondrial disorders and is frequently associated with multiple mtDNA deletions. The onset is typically in adulthood, and affected subjects can also present with general muscle weakness. The underlying genetic defects comprise autosomal-dominant or recessive mutations in several nuclear genes, most of which play a role in mtDNA replication. Next-generation sequencing led to the identification of compound-heterozygous RNASEH1 mutations in two singleton subjects and a homozygous mutation in four siblings. RNASEH1, encoding ribonuclease H1 (RNase H1), is an endonuclease that is present in both the nucleus and mitochondria and digests the RNA component of RNA-DNA hybrids. Unlike mitochondria, the nucleus harbors a second ribonuclease (RNase H2). All affected individuals first presented with CPEO and exercise intolerance in their twenties, and these were followed by muscle weakness, dysphagia, and spino-cerebellar signs with impaired gait coordination, dysmetria, and dysarthria. Ragged-red and cytochrome c oxidase (COX)-negative fibers, together with impaired activity of various Mitochondrial respiratory chain complexes, were observed in muscle biopsies of affected subjects. Western blot analysis showed the virtual absence of RNase H1 in total lysate from mutant fibroblasts. By an in vitro assay, we demonstrated that altered RNase H1 has a reduced capability to remove the RNA from RNA-DNA hybrids, confirming their pathogenic role. Given that an increasing amount of evidence indicates the presence of RNA primers during mtDNA replication, this result might also explain the accumulation of mtDNA deletions and underscores the importance of RNase H1 for mtDNA maintenance.
-
a slowly progressive Mitochondrial Encephalomyopathy widens the spectrum of aifm1 disorders
Neurology, 2015Co-Authors: Anna Ardissone, Isabella Moroni, Eleonora Lamantea, Giuseppe Piscosquito, Andrea Legati, Tiziana Langella, Barbara Garavaglia, Ettore Salsano, Laura Farina, Davide PareysonAbstract:To date, 3 AIFM1 (apoptosis inducing factor Mitochondrial 1, located on Xq26.1 ) mutations have been reported: 2 missense changes (c.923G>A/p.Gly308Glu; c.1478A>T/p.Glu493Val) and a 3-basepair deletion (c.601delAGA/p.Arg201del). Two mutations have been described in early-onset severe Mitochondrial Encephalomyopathy related to impaired oxidative phosphorylation.1,2 A third mutation is associated with Cowchock syndrome, or Charcot-Marie-Tooth X4 (CMTX4), a slowly progressive disorder characterized by axonal neuropathy, hearing loss, and mental retardation.3,4
-
identification of novel mutations in five patients with Mitochondrial Encephalomyopathy
Biochimica et Biophysica Acta, 2009Co-Authors: Lucia Valente, Eleonora Lamantea, Laura Farina, Graziella Uziel, Franco Carrara, Daniela Piga, Paola Cudia, Anna Zani, Lucia Morandi, Marina MoraAbstract:MELAS, MERRF, LHON and NARP, are well-established Mitochondrial syndromes associated with specific point mutations of Mitochondrial DNA (mtDNA). However, these recurrent mtDNA mutations account for only a minority of Mitochondrial disease cases. To evaluate the impact of novel mtDNA mutations, we performed mtDNA sequence analysis in muscle and other tissues of 240 patients with different Mitochondrial neuromuscular syndromes. We identified a total of 33 subjects with novel, private or uncommon mutations. Among these, five novel mutations were found in both paediatric and adult cases. We here report on the clinical description of these patients, as well as the biochemical and molecular genetic characterization of the corresponding mutations. Patients 1 and 2 showed changes in ND genes, patient 3 carried a heteroplasmic deletion in the COI gene, patients 4 and 5 carried heteroplasmic mutations in tRNA(Trp) and tRNA(Phe), respectively. Altogether, these data indicate that mtDNA analysis must become part of the routine screening for Mitochondrial disorders.
-
a missense mutation in the Mitochondrial nd5 gene associated with a leigh melas overlap syndrome
Neurology, 2003Co-Authors: Marco Crimi, Massimo Zeviani, Sara Galbiati, Isabella Moroni, Andreina Bordoni, Maria Paola Perini, Eleonora Lamantea, M Sciacco, Ida Biunno, Maurizio MoggioAbstract:A 13084 A->T missense mutation in the Mitochondrial ND5 gene was identified in a 16-year-old boy affected with a progressive neurodegenerative disorder combining features of Leigh and MELAS (Mitochondrial Encephalomyopathy, lactic acidosis, and strokelike episodes) syndromes. Muscle biopsy analysis revealed partial complex I deficiency. The mutation presented a variable degree of heteroplasmy in the patient's tissues. This finding underlines the contribution of mtDNA-encoded complex I subunits in the etiology of complex I deficiency associated with encephalopathy.
Michio Hirano - One of the best experts on this subject based on the ideXlab platform.
-
Mitochondrial Encephalomyopathy with coenzyme q10 deficiency
Neurology, 1997Co-Authors: Michio Hirano, Sara Shanske, Claudia Sobreira, R K Kelle, Ronald G Halle, E Davidso, Filippo M Santorelli, Armand F Miranda, Eduardo OnillaAbstract:Coenzyme Q10 (CoQ10) transfers electrons from complexes I and II of the Mitochondrial respiratory chain to complex III. There is one published report of human CoQ10 deficiency describing two sisters with encephalopathy, proximal weakness, myoglobinuria, and lactic acidosis. We report a patient who had delayed motor milestones, proximal weakness, premature exertional fatigue, and episodes of exercise-induced pigmenturia. She also developed partial-complex seizures. Serum creatine kinase was approximately four times the upper limit of normal and venous lactate was mildly elevated. Skeletal muscle biopsy revealed many ragged-red fibers, cytochrome c oxidase-deficient fibers, and excess lipid. In isolated muscle mitochondria, impaired oxygen consumption was corrected by the addition of decylubiquinone. During standardized exercise, ventilatory and circulatory responses were compatible with a defect of oxidation-phosphorylation, which was confirmed by near-infrared spectroscopy analysis. Biochemical analysis of muscle extracts revealed decreased activities of complexes I+II and I+III, while CoQ10 concentration was less than 25% of normal. With a brief course of CoQ10 (150 mg daily), the patient reported subjective improvement. The triad of CNS involvement, recurrent myoglobinuria, and ragged-red fibers should alert clinicians to the possibility of CoQ10 deficiency.
-
Topical Review: Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike Episodes (MELAS): Current Concepts:
Journal of child neurology, 1994Co-Authors: Michio Hirano, Steven G. PavlakisAbstract:Mitochondrial Encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome is one of many Mitochondrially inherited multisystem diseases. The features of 110 reported Mitochondrial Encephalomyopathy, lactic acidosis, and strokelike episodes patients are reviewed to define the clinical spectrum of this disease. The clinical disorder, in addition to emerging concepts of genetic etiology, is promoting our understanding of Mitochondrial functions. New knowledge may lead to more rational therapies. Finally, the recent revolution in the study of Mitochondrial diseases may further our understanding of other degenerative disorders and even aging.
-
topical review Mitochondrial myopathy encephalopathy lactic acidosis and strokelike episodes melas current concepts
Journal of Child Neurology, 1994Co-Authors: Michio Hirano, Steven G. PavlakisAbstract:Mitochondrial Encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome is one of many Mitochondrially inherited multisystem diseases. The features of 110 reported Mitochondrial Encephalomyopathy, lactic acidosis, and strokelike episodes patients are reviewed to define the clinical spectrum of this disease. The clinical disorder, in addition to emerging concepts of genetic etiology, is promoting our understanding of Mitochondrial functions. New knowledge may lead to more rational therapies. Finally, the recent revolution in the study of Mitochondrial diseases may further our understanding of other degenerative disorders and even aging. (J Child Neurol 1994;9:04-13).
Ingrid Tein - One of the best experts on this subject based on the ideXlab platform.
-
reversal of stroke like episodes with l arginine and meticulous perioperative management of renal transplantation in a patient with Mitochondrial Encephalomyopathy lactic acidosis and stroke like episodes melas syndrome case report
The Neurohospitalist, 2021Co-Authors: Ghalia Al Yazidi, Jaap Mulder, Christoph Licht, Elizabeth Harvey, James Robertson, Neal Sondheimer, Ingrid TeinAbstract:Mitochondrial Encephalomyopathy, lactic acidosis and stroke like episodes (MELAS) syndrome is a maternally inherited Mitochondrial disorder with recurrent non-arterial distribution stroke-like epis...
-
L-Arginine Affects Aerobic Capacity and Muscle Metabolism in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes) Syndrome
PLOS ONE, 2015Co-Authors: Lance H Rodan, Greg D. Wells, Jane E. Schneiderman, Laura Banks, Sara Thompson, Ingrid TeinAbstract:Objective To study the effects of L-arginine (L-Arg) on total body aerobic capacity and muscle metabolism as assessed by 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) in patients with MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes) syndrome. Methods We performed a case control study in 3 MELAS siblings (m.3243A>G tRNAleu(UUR) in MTTL1 gene) with different % blood mutant mtDNA to evaluate total body maximal aerobic capacity (VO2peak) using graded cycle ergometry and muscle metabolism using 31P-MRS. We then ran a clinical trial pilot study in MELAS sibs to assess response of these parameters to single dose and a 6-week steady-state trial of oral L-Arginine. Results At baseline (no L-Arg), MELAS had lower serum Arg (p = 0.001). On 31P-MRS muscle at rest, MELAS subjects had increased phosphocreatine (PCr) (p = 0.05), decreased ATP (p = 0.018), and decreased intracellular Mg2+ (p = 0.0002) when compared to matched controls. With L-arginine therapy, the following trends were noted in MELAS siblings on cycle ergometry: (1) increase in mean % maximum work at anaerobic threshold (AT) (2) increase in % maximum heart rate at AT (3) small increase in VO2peak. On 31P-MRS the following mean trends were noted: (1) A blunted decrease in pH after exercise (less acidosis) (2) increase in Pi/PCr ratio (ADP) suggesting increased work capacity (3) a faster half time of PCr recovery (marker of Mitochondrial activity) following 5 minutes of moderate intensity exercise (4) increase in torque. Significance These results suggest an improvement in aerobic capacity and muscle metabolism in MELAS subjects in response to supplementation with L-Arg. Intramyocellular hypomagnesemia is a novel finding that warrants further study. Classification of Evidence Class III evidence that L-arginine improves aerobic capacity and muscle metabolism in MELAS subjects. Trial Registration ClinicalTrials.gov NCT01603446.
-
Mitochondrial Encephalomyopathy lactic acidosis stroke like episodes melas clinical radiological pathological and genetic observations
Annals of Neurology, 1993Co-Authors: Betty Koo, Ingrid Tein, Laurence E Becker, Sylvester H Chuang, Frank Merante, Brian H Robinson, Daune Macgregor, Douglas Mcgreal, John Wherrett, William J LoganAbstract:We reviewed 10 patients (5 males, 5 females) with Mitochondrial Encephalomyopathy, lactic acidosis, and stroke-like episodes. The age of symptom onset ranged from 3 months to 12 years. All had lactic acidosis, multiple stroke-like events with secondary neurological deficits, radiological changes of progressive brain infarction, and muscle biopsy showing ragged-red fibers. In patients with earlier onset of symptoms (< 2 yr), involvement tended to be more diffuse, with failure to thrive and early onset of delayed development. Patients whose symptoms appeared later tended to have focal neurological deficits with migraine-like headache, and a rate of cognitive regression reflecting the rapidity of disease progression. Radiological changes included multiple areas of infarction with initial predilection for parietal occipital areas, progressing to generalized atrophy. Pathological findings in muscle biopsies included type 1 fiber predominance, ragged-red fibers, increased intermyofibrillar lipid deposition, and abnormal mitochondria. Four patients showed Mitochondrial DNA tRNA mutation at position 3,243. No difference was noted in clinical, radiological, or pathological findings in patients with and without this mutation, suggesting that multiple sites of point mutation may give rise to Mitochondrial Encephalomyopathy, lactic acidosis, and stroke-like episodes.