Epilepsy in Leigh Syndrome With Mitochondrial DNA Mutations

Background: Leigh syndrome is a mitochondrial cytopathy that presents as a neurodegenerative disease with apparent manifestation in the central nervous system. The aim of the present study was to describe its dominant neurological clinical features and analyze data related to epilepsy in Leigh syndrome accompanied by a mitochondrial DNA mutation.Methods: Whole mitochondrial sequencing was performed on 125 patients clinically suspected of Leigh syndrome. Among them, 25 patients were identified to have mitochondrial DNA associated Leigh syndrome. Electroencephalography (EEG) findings, semiology, brain imaging findings, and biochemical results, were evaluated. We also compared brain magnetic resonance imaging findings and biochemical features in patients with Leigh syndrome based on the presence of epilepsy.Results: Clinical seizures were observed in 14 out of 25 enrolled patients (56%), with focal seizures being the most common type (6/14, 42.8%). All patients were found to have slow and disorganized background neural activity while eight exhibited epileptic discharges on EEG. Mutations at base pairs 10,191 and 8,993 were revealed in a relatively larger number of patients of Leigh syndrome with epilepsy. The presence of gastrointestinal symptoms was significantly more frequent in the epilepsy group (P = 0.042). Diffuse cerebral atrophy was significantly increased (P = 0.042) and cortex signal abnormalities were also increased (P = 0.033) in the epilepsy group.Conclusions: Patients with Leigh syndrome and mitochondrial DNA mutations had a high proportion of central nervous system comorbidities, though the prevalence of epilepsy in this population was not particularly high. Various types of seizure and EEG findings are common in those with Leigh syndrome. Future imaging studies involving more patients and proper mitochondrial DNA mutation analyses are needed to further evaluate the natural course of Leigh syndrome with epilepsy

Diderot et la lutte parlementaire au temps de l’Encyclopédie

Diderot, comme l’explique J. Proust, était politiquement — du moins pendant les années d’Encyclopédie — « absolutiste ». J. Lough montre pour sa part qu’il s’est « rangé du côté des Parlements dans leur lutte contre la monarchie absolue ». Le présent article, première partie d’une étude en deux volets, veut montrer en quoi ces deux jugements sont également recevables. Il expose de manière détaillée comment, par le biais de l’Encyclopédie, notamment dans le tome VIII, Diderot (puis, plus tard, Jaucourt ?) sont intervenus dans les durs conflits qui ont opposé les parlementaires jansénistes et le pouvoir royal. Alliance contre nature, ou conjonction logique d’intérêts, sur fond de suppression de la Compagnie de Jésus ? On voit apparaître dans cette affaire la figure importante et par certains aspects inquiétante de Le Paige, à qui Diderot s’est efforcé, à la fin des années soixante, de rendre service.Diderot and parliamentary struggles at the time of the EncyclopédieDiderot was, as J. Proust explains, politically ‘absolutist’, at least during the Encyclopédie years, while J. Lough shows that he took the Parlements’ side in their struggle against absolute monarchy. This article, the first of a two-part study, aims to show that these two judgements are equally valid. It studies in detail how, by means of the Encyclopédie, especially in volume VIII, Diderot (and later Jaucourt ?) took a stand in the hard-fought conflict between the Jansenist parliamentarians and the Crown. One can wonder whether this was an unnatural alliance or a logical union of interests against the background of the abolition of the Jesuists. In this affair we see emerging the important but slightly sinister figure of Le Paige, for whom Diderot did favours at the end of the 1760s

Diderot et la lutte parlementaire au temps de l’Encyclopédie

On a pu rapprocher le nom de Diderot, auteur de l’article AUTORITÉ POLITIQUE de l’Encyclopédie (1751), et celui de Le Paige, principal animateur et idéologue de la résistance parlementaire (et) janséniste aux jésuites et au pouvoir royal. En effet, la modération inaccoutumée des Nouvelles ecclésiastiques, la feuille clandestine du mouvement, envers Diderot, chef du parti « encyclopédique ». pourrait être éclairée par l’attitude du philosophe qui, alors du côté des partisans de l’absolutisme, n’en est pas moins le défenseur décidé (mais nécessairement prudent) des droits de « remontrance » et de critique, sinon du contrôle politique du Parlement. L’étude détaillée des positions du parti janséniste (le « figurisme », les thèses de Le Gros), et des références de l’article de Diderot (notamment le modèle fourni par Henri IV et les Mémoires de Sully), montre des sources communes (Duguet) et des choix politiques proches qui, par-delà des différences doctrinales considérables et des oppositions frontales, peuvent expliquer de manifestes ménagements réciproques.Diderot and parliamentary struggles (final part)The name of Diderot, the author of the Encyclopédie article AUTORITÉ POLITIQUE (1751) has been linked to that of Le Paige, the main leader and ideologue of the parliamentary and Jansenist resistance to the Jesuits and royal power. The unusual rnoderation shown by the Nouvelles ecclésiastiques, the movement’s clandestine mouthpiece, towards Diderot, leader of the ‘Encyclopaedist’ party, may be explained by his attitude. Although Diderot was at the time on the side of absolutism, he was also a convinced (although necessarily careful) defender of the right of ‘remonstrance’ and criticism, if not the political control of the Parlement. A detailed study of the positions defended by the Jansenist party (‘figurism’, Le Gros’s theses) and of references to Diderot’s article (in particular the model constituted by Henry IV and Sully’s Memoirs) indicate their common sources (Duguet) and similar political choices ; this may explain the fact that despite doctrinal differences and frontal opposition, they clearly avoided attacking each other

Initial Experiences with Proton MR Spectroscopy in Treatment Monitoring of Mitochondrial Encephalopathy

PURPOSE: Mitochondrial encephalopathy (ME) is a rare disorder of energy metabolism. The disease course can roughly be evaluated by clinical findings. The purpose of this study was to evaluate metabolic spectral changes using proton MR spectroscopy (MRS), and to establish a way to monitor ME by neuroimaging. MATERIALS AND METHODS: Proton MRS data were retrospectively reviewed in 12 patients with muscle biopsy-confirmed ME (M : F = 7 : 5, Mean age = 4.8 years). All received 1H-MRS initially and also after a ketogenic diet and mitochondrial disease treatment cocktail (follow up average was 10.2 months). Changes of N-acetylaspartate/ creatine (NAA/Cr) ratio, choline/creatine (Cho/Cr) ratio, and lactate peak in basal ganglia at 1.2 ppm were evaluated before and after treatment. Findings on conventional T2 weighted MR images were also evaluated. RESULTS: On conventional MRI, increased basal ganglia T2 signal intensity was the most common finding with ME (n = 9, 75%), followed by diffuse cerebral atrophy (n = 8, 67%), T2 hyperintense lesions at pons and midbrain (n = 4, 33%), and brain atrophy (n = 2, 17%). Lactate peak was found in 4 patients; 2 had disappearance of the peak on follow up MRS. Quantitative analysis showed relative decrease of Cho/Cr ratio on follow up MRS (p = 0.0058, paired t-test, two-tailed). There was no significant change in NAA/Cr ratio. CONCLUSION: MRS is a useful tool for monitoring disease progression or improvement in ME, and decrease or disappearance of lactate peak and reduction of Cho/Cr fraction were correlated well with improvement of clinical symptoms.ope

Correlation of Serum Biomarkers and Magnetic Resonance Spectroscopy in Monitoring Disease Progression in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes Due to mtDNA A3243G Mutation

Background: Analysis of serum biomarkers and magnetic resonance spectroscopy (MRS) are useful for monitoring disease progression in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). We evaluated the correlation of serum biomarkers and MRS parameters during changes associated with stroke-like episodes.Methods: In 13 symptomatic MELAS patients carrying the A3243G mutation, we retrospectively obtained 207 voxels from 41 MRS studies, which were divided into three groups according to the temporal association with stroke-like episodes. The MRS NAA/Cr, Cho/Cr, NAA/Cho ratios, the presence of a lactate peak, serum biomarkers, serum lactate level and the pyruvate (Lac/Pyr) ratio were determined.Results: In regions with acute infarcts, the severity of serum Lac/Pyr and that of the MRS lactate peak (P = 0.0007) correlated; serum lactate (P = 0.02), severity of elevated serum lactate (P = 0.04), and serum Lac/Pyr (P = 0.02) correlated weakly. In previously infarcted regions, the severity of the MRS lactate peak and serum Lac/Pyr (P = 0.03), as well as the severity of serum Lac/Pyr (P = 0.02) were weakly correlated. In structurally normal regions, we found a weak to moderate negative correlation between serum lactate and MRS NAA/Cr (P = 0.008), and between the severity of elevated serum lactate and MRS NAA/Cr (P = 0.002) as well as MRS NAA/Cho (P = 0.02).Conclusions: MRS parameters correlate with specific serum biomarkers, and are useful for monitoring changes in brain metabolites, particularly as related to stroke-like episodes

Genotype-phenotype correlations in pediatric patients with myotonic dystrophy type 1

Purpose Myotonic dystrophy, also known as dystrophia myotonica (DM), is an autosomal dominant disorder with 2 genetically distinct forms. DM type 1 (DM1) is the more common form and is caused by abnormal expansion of cytosine/thymine/guanine (CTG) repeats in the DM protein kinase (DMPK) gene. Our study aimed to determine whether the age of onset is correlated with CTG repeat length in a population of pediatric patients with DM1. Methods We retrospectively identified 30 pediatric patients with DM1 that underwent DMPK testing, of which the clinical data of 17 was sufficient. The cohort was divided into 2 subgroups based on the clinical phenotype (congenital-onset vs. late-onset) and number of CTG repeats (<1,000 vs. ≥1,000). Results We found no significant difference between the age of onset and CTG repeat length in our pediatric patient population. Based on clinical subgrouping, we found that the congenital-onset subgroup was statistically different with respect to several variables, including prematurity, rate of admission to neonatal intensive care unit, need for respiratory support at birth, hypotonia, dysphagia, ventilator dependence, and functional status on last visit, compared to the late-onset subgroup. Based on genetic subgrouping, we found a single variable (poor feeding in neonate) that was significantly different in the large CTG subgroup than that in the small CTG subgroup. Conclusion Clinical variables exhibiting statistically significant differences between the subgroups should be focused on prognosis and designing tailored management approaches for the patients; our findings will contribute to achieve this important goal for treating patients with DM1

Myocardial atrophy in children with mitochondrial disease and Duchenne muscular dystrophy

PurposeMitochondrial disease (MD) and Duchenne muscular dystrophy (DMD) are often associated with cardiomyopathy, but the myocardial variability has not been isolated to a specific characteristic. We evaluated the left ventricular (LV) mass by echocardiography to identify the general distribution and functional changes of the myocardium in patients with MD or DMD.MethodsWe retrospectively evaluated the echocardiographic data of 90 children with MD and 42 with DMD. Using two-dimensional echocardiography, including time-motion (M) mode and Doppler measurements, we estimated the LV mass, ratio of early to late mitral filling velocities (E/A), ratio of early mitral filling velocity to early diastolic mitral annular velocity (E/Ea), stroke volume, and cardiac output. A "z score" was generated using the lambda-mu-sigma method to standardize the LV mass with respect to body size.ResultsThe LV mass-for-height z scores were significantly below normal in children with MD (-1.02±1.52, P<0.001) or DMD (-0.82±1.61, P=0.002), as were the LV mass-for-lean body-mass z scores. The body mass index (BMI)-for-age z scores were far below normal and were directly proportional to the LV mass-for-height z scores in both patients with MD (R=0.377, P<0.001) and those with DMD (R=0.330, P=0.033). The LV mass-for-height z score correlated positively with the stroke volume index (R=0.462, P<0.001) and cardiac index (R=0.358, P<0.001).ConclusionLV myocardial atrophy is present in patients with MD and those with DMD and may be closely associated with low BMI. The insufficient LV mass for body size might indicate deterioration of systolic function in these patients

Congenital muscular dystrophy type 1A with residual merosin expression

Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder characterized by hypotonia, elevated serum creatine kinase level, delayed motor milestones, white matter changes observed by brain magnetic resonance imaging, and normal intelligence. A mutation in the laminin α2 (LAMA2) gene, located at 6q22-23, is a genetic cause of MDC1A. Patients have merosin (laminin α2)-deficient skeletal muscles. However, the degree of merosin expression ranges from total absence to partial reduction. Patients with residual merosin expression have more variable and milder phenotypes than those with absolute merosin deficiency. We observed a Korean girl with MDC1A with residual merosin expression. Clinical presentation of this patient was typical except for late onset of the disease and external capsule involvement. Immunohistochemical staining of muscle fibers including merosin, is important to evaluate patients with hypotonia, delayed motor development, and abnormal white matter changes