Mitochondrial DNA (mt DNA) A3243G mutation associated with an annular perimacular retinal atrophy

Résumé:Background:La mutation 3243 de 1'ADN mitochondrial est associee avec le syndrome l\/HDD (surdite, diabète transmis par la mère) et le syndrome MELAS (Myopathie, Encéphalopathie, acidose Lactique et attaques cérébrales). Elle est aussi associe à des troubles cardiaques, digestifs, endo- et exocrines. Nous rapportons deux cas de maculopathie associée à cette mutation.Histoire et symptomes: pCas l: il s'agit d'une femme de 60 ans soufrant d'un diabète et d'une surdité sans plainte visuelle lors de la présentation. Son acuité visuelle était de 10/ l0 des deux yeux.Cas 2: il s'agit d'une femme de 54 ans souffrant d'une surdité et d'un diabète qui se plaint d'une baisse de vision principalement de l'oeil gauche. Son acuité visuelle était de 6/10 pour l'oeil droit et de 0.5/l0 pour l'oeil gauche.Les deux patientes présentaient une atrophie choriorétinienne aréolaire centrale. La patiente 1 a été suivie durant plus de 15 ans. Une évolution lente et progressive de la maculopathie a été observée. Lors de la dernière visite, l'acuité visuelle était de 6/ l0 dans les deux yeux. Elle présentait un handicap marqué des suites du scotome annulaire.Thérapie et pronostic:AucunConclusion:Les deux patientes présentaient une atrophie rétinienne annulaire périmaculaire. Les patients atteints d'une mutation 3243 de l'ADN mitochondrial devraient bénéficier d'un examen du fond d'oeil à la recherche d'une maculopahtie, même s'ils sont asymptomatiques.Inversement, la découverte d'une telle maculopathie géographique devrait suggérer la possibilité d'une mutation au locus 3243 de l'ADN mitochondrial, surtout en présence d'un diabète et/ou d'une surdité.

Prenatal brain atrophy due to a giant vein of Galen malformation.

We report a full-term newborn girl with a giant vein of Galen malformation and extreme cerebral atrophy of prenatal origin. She presented on the 3rd day of life with intractable congestive heart failure. The diagnosis of the vascular malformation was confirmed by ultrasound and magnetic resonance imaging.

Regenerative cell injection in denervated muscle reduces atrophy and enhances recovery following nerve repair.

INTRODUCTION: Functional muscle recovery after peripheral nerve injury is far from optimal, partly due to atrophy of the muscle arising from prolonged denervation. We hypothesized that injecting regenerative cells into denervated muscle would reduce this atrophy. METHODS: A rat sciatic nerve lesion was performed, and Schwann cells or adipose-derived stem cells, untreated or induced to a "Schwann-cell-like" phenotype (dASC), were injected into the gastrocnemius muscle. Nerves were either repaired immediately or capped to prevent muscle reinnervation. One month later, functionality was measured using a walking track test, and muscle atrophy was assessed by examining muscle weight and histology. RESULTS: Schwann cells and dASC groups showed significantly better scores on functional tests when compared with injections of growth medium alone. Muscle weight and histology were also significantly improved in these groups. CONCLUSION: Cell injections may reduce muscle atrophy and could benefit nerve injury patients.

Mitochondrial DNA (mtDNA) A 3243G mutation associated with an annular perimacular retinal atrophy

BACKGROUND: A point mutation at the locus 3243 of the mitonchondrial DNA (mtDNA) is associated with either the MIDD syndrome (maternally inherited diabetes, deafness), the MELAS syndrome (myopathy, encephalitis, lactic acidosis, stroke) or cardiac, digestive, endocrine or exocrine dysfunctions. We report a peculiar maculopathy in two patients with an mtDNA 3243 mutation. HISTORY AND SIGNS: Case 1: A visually asymptomatic 40-year-old woman was examined for screening of diabetic retinopathy. Visual acuity was 10 / 10 in both eyes. Case 2: A 54-year-old woman with deafness and diabetes complained of visual loss. Visual acuity was 6 / 10 for the right eye and 0.5 / 10 for the left eye. Both patients exhibited a chorioretinal areolar atrophy. Case 1 was followed over 15 years and exhibited a slow progression of the maculopathy with moderate loss of visual acuity to 6 / 10 in both eyes, but marked handicap from the annular scotoma. THERAPY AND OUTCOME: None. CONCLUSION: Both patients presented a perimacular annular retinal atrophy. Patients harbouring mtDNA 3243 mutation should be examined for the presence of a maculopathy, even if they are asymptomatic. Conversely, the finding of such a geographic maculopathy should suggest the possibility of a point mutation at the locus 3243 of the mitochondrial DNA, especially in the presences of diabetes mellitus and/or deafness

Disentangling in vivo the effects of iron content and atrophy on the ageing human brain.

Evidence from magnetic resonance imaging (MRI) studies shows that healthy aging is associated with profound changes in cortical and subcortical brain structures. The reliable delineation of cortex and basal ganglia using automated computational anatomy methods based on T1-weighted images remains challenging, which results in controversies in the literature. In this study we use quantitative MRI (qMRI) to gain an insight into the microstructural mechanisms underlying tissue ageing and look for potential interactions between ageing and brain tissue properties to assess their impact on automated tissue classification. To this end we acquired maps of longitudinal relaxation rate R1, effective transverse relaxation rate R2* and magnetization transfer - MT, from healthy subjects (n=96, aged 21-88 years) using a well-established multi-parameter mapping qMRI protocol. Within the framework of voxel-based quantification we find higher grey matter volume in basal ganglia, cerebellar dentate and prefrontal cortex when tissue classification is based on MT maps compared with T1 maps. These discrepancies between grey matter volume estimates can be attributed to R2* - a surrogate marker of iron concentration, and further modulation by an interaction between R2* and age, both in cortical and subcortical areas. We interpret our findings as direct evidence for the impact of ageing-related brain tissue property changes on automated tissue classification of brain structures using SPM12. Computational anatomy studies of ageing and neurodegeneration should acknowledge these effects, particularly when inferring about underlying pathophysiology from regional cortex and basal ganglia volume changes.

Is there histomorphological evidence of plantar metatarsal fat pad atrophy in patients with diabetes?

The etiology of diabetic foot ulceration remains incompletely understood. Among other factors such as foot deformity in the presence of neuropathy, plantar fat pad atrophy has been identified as a contributory factor in diabetic foot ulceration. An association between fat pad atrophy and diabetic foot ulceration has been documented by imaging and histomorphological analysis of the calcaneal fat pad. However, histomorphological analysis of the metatarsal fat pad has not been performed to date. The present study entailed 14 patients with diabetes and 14 nondiabetic controls and was aimed at documenting histomorphological evidence for presumed plantar metatarsal fat pad atrophy in patients with diabetes. Histological stains and computer-assisted planimetry were performed on samples of metatarsal fat obtained during forefoot surgery. The histomorphological and planimetric analyses of adipocyte cross-sectional area and nuclear density demonstrated no differences between patients with diabetes and control patients. Our findings demonstrate that systemic atrophy of the metatarsal fat pad is not present in the diabetic foot and may not explain the structural changes previously proposed by noninvasive imaging. Level of Clinical Evidence: 3.

Hippocampal atrophy predicts conversion to dementia after STN-DBS in Parkinson's disease.

BACKGROUND: Hippocampal atrophy (HA) is a known predictor of dementia in Alzheimer's disease. HA has been found in advanced Parkinson's disease (PD), but no predicting value has been demonstrated yet. The identification of such a predictor in candidates for subthalamic deep brain stimulation (STN-DBS) would be of value. Our objective was to compare preoperative hippocampal volumes (HV) between PD patients who subsequently converted to dementia (PDD) after STN-DBS and those who did not (PDnD). METHODS: From a cohort of 70 consecutive STN-DBS treated PD patients, 14 converted to dementia over 25.6+/-20.2 months (PDD). They were compared to 14 matched controls (PDnD) who did not convert to dementia after 43.9+/-11.7 months. On the preoperative 3D MPRAGE MRI images, HV and total brain volumes (TBV) were measured by a blinded investigator using manual and automatic segmentation respectively. RESULTS: PDD had smaller preoperative HV than PDnD (1.95+/-0.29 ml; 2.28+/-0.33 ml; p<0.01). This difference reinforced after normalization for TBV (3.28+/-0.48, 3.93+/-0.60; p<0.01). Every 0.1 ml decrease of HV increased the likelihood to develop dementia by 24.6%. A large overlap was found between PD and PDnD HVs, precluding the identification of a cut-off score. CONCLUSIONS: As in Alzheimer's disease, HA may be a predictor of the conversion to dementia in PD. This preoperative predictor suggests that the development of dementia after STN-DBS is related to the disease progression, rather then the procedure. Further studies are needed to define a cut-off score for HA, in order to affine its predictive value for an individual patient.

Etude clinique et analyse de liaison au locus 3q28 de deux familles suisses avec atrophie optique dominante de Kjer (OPA1) [Clinical study and genetic 3q28 locus linkage in 2 Swiss families with Kjer dominant optic atrophy (OPA1)]

METHODS: We examined 20 patients from 2 unrelated Swiss families to describe their clinical phenotype. In addition, a linkage analysis was performed in an attempt to confirm the reported genetic homogeneity of this condition as well as to refine its genomic localization. RESULTS: Two point analysis provided a cumulative LOD-score of 3.03 with marker D3S 2305. The absence of recombination precluded further refinement of the disease interval. CONCLUSIONS: Our data confirm the genetic homogeneity and the extreme variability of expression, occasionally mimicking low tension glaucoma.

Laser scanning evaluation of atrophy after autologous free muscle transfer.

Denervated muscle tissue undergoes morphologic changes that result in atrophy. The amount of muscle atrophy after denervation following free muscle transfer has not been measured so far. Therefore, the amount of muscle atrophy in human free muscle transfer for lower extremity reconstruction was measured in a series of 10 patients. Three-dimensional laser surface scanning was used to measure flap volume changes 2 weeks as well as 6 and 12 months after the operation. None of the muscles transferred was re-innervated.All muscles healed uneventfully without signs of compromised perfusion resulting in partial flap loss. The muscle volume decreased to 30 ± 4% and 19 ± 4% 6 and 12 months, respectively, after the operation, ie, the volume decreased by approximately 80% within a 12-month period.Denervated free muscle flap tissue undergoes massive atrophy of approximately 80%, mostly within the first 6 months.

Macular dystrophy associated with the mitochondrial DNA A3243G mutation: pericentral pigment deposits or atrophy? Report of two cases and review of the literature.

BACKGROUND: The A3243G point mutation in mitochondrial DNA (mtDNA) is associated with MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) and MIDD syndromes (maternally inherited diabetes and deafness). Both MELAS and MIDD patients can present with visual symptoms due to a retinopathy, sometimes before the genetic diagnosis is made. CASE PRESENTATION: Patient 1: 46 year-old woman with diabetes mellitus and hearing loss was referred for an unspecified maculopathy detected during screening evaluation for diabetic retinopathy. Visual acuity was 20/20 in both eyes. Fundus examination showed bilateral macular and peripapillary hyperpigmented/depigmented areas.Patient 2: 45 year-old woman was referred for recent vision loss in her left eye. History was remarkable for chronic fatigue, migraine and diffuse muscular pain. Visual acuity was 20/20 in her right eye and 20/30 in her left eye. Fundus exhibited several nummular perifoveal islands of retinal pigment epithelium atrophy and adjacent pale deposits in both eyes.Retinal anatomy was investigated with autofluorescence, retinal angiography and optical coherence tomography. Retinal function was assessed with automated static perimetry, full-field and multifocal electroretinography and electro-oculography. Genetic testing of mtDNA identified a point mutation at the locus 3243. CONCLUSION: Observation of RPE abnormalities in the context of suggestive systemic findings should prompt mtDNA testing.

Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy

Skeletal muscle size is tightly regulated by the synergy between anabolic and catabolic signalling pathways which, in humans, have not been well characterized. Akt has been suggested to play a pivotal role in the regulation of skeletal muscle hypertrophy and atrophy in rodents and cells. Here we measured the amount of phospho-Akt and several of its downstream anabolic targets (glycogen synthase kinase-3beta (GSK-3beta), mTOR, p70(s6k) and 4E-BP1) and catabolic targets (Foxo1, Foxo3, atrogin-1 and MuRF1). All measurements were performed in human quadriceps muscle biopsies taken after 8 weeks of both hypertrophy-stimulating resistance training and atrophy-stimulating de-training. Following resistance training a muscle hypertrophy ( approximately 10%) and an increase in phospho-Akt, phospho-GSK-3beta and phospho-mTOR protein content were observed. This was paralleled by a decrease in Foxo1 nuclear protein content. Following the de-training period a muscle atrophy (5%), relative to the post-training muscle size, a decrease in phospho-Akt and GSK-3beta and an increase in Foxo1 were observed. Atrogin-1 and MuRF1 increased after the hypertrophy and decreased after the atrophy phases. We demonstrate, for the first time in human skeletal muscle, that the regulation of Akt and its downstream signalling pathways GSK-3beta, mTOR and Foxo1 are associated with both the skeletal muscle hypertrophy and atrophy processes

Microcystic Macular Edema in Optic Nerve Atrophy: A Case Series.

Background:Microcystic macular edema can occur after optic neuropathies of various etiologies, and is easily demonstrated by OCT. We report a cohort of patients with microcystic macular edema. Patients and Methods: All patients with optic neuropathy and microcystic macular edema were enrolled. Demographics, visual function, retinal angiographies and OCT parameters were studied. Results: Nineteen patients (23 eyes) exhibited microcystic macular edema: 10 men/9 women, aged 17-91 years. Etiologies of optic nerve atrophy were compressive (5), inflammatory (4), glaucoma (3), ischemic (3), trauma (2), degenerative (1), and hereditary (1). Median visual acuity was 4/10 (NLP-12/10). Fluorescein angiography showed no leakage. Topography of the microcystic macular edema correlated with near infrared images but with visual field defects in only 26 %. OCT parameters were all abnormal. Conclusions: Microcystic macular edema is a non-specific manifestation from an optic neuropathy of any etiology. The precise mechanism leading to microcystic macular edema remains unknown but trans-synaptic retrograde degeneration with Müller cells dysfunction is likely.

Left temporal lobe epilepsy revealing left posterior cortical atrophy due to Alzheimer's disease.

Seizures can be an early symptom of Alzheimer's disease (AD) and can precede cognitive decline. Early epilepsy in AD can mimic transient epileptic amnesic syndrome (TEAS) or epileptic amnesic syndrome. We report the case of a patient who started a cerebrospinal fluid (CSF)-proven AD with partial seizures and TEAS that secondarily became a cortical posterior atrophy syndrome. CSF biomarkers showed a high amyloid production, amyloidopathy, and high level of total tau and p-Tau. This observation adds data to the complex AD-early epilepsy interactions and illustrates that atypical AD can cause a TEAS. Possible red flags for an underlying neurodegenerative process in TEAS are discussed.

Mikrozystisches Makulaödem bei Optikusatrophie: eine Fallserie Microcystic Macular Edema in Optic Nerve Atrophy: A Case Series.

Background:Microcystic macular edema can occur after optic neuropathies of various etiologies, and is easily demonstrated by OCT. We report a cohort of patients with microcystic macular edema. Patients and Methods: All patients with optic neuropathy and microcystic macular edema were enrolled. Demographics, visual function, retinal angiographies and OCT parameters were studied. Results: Nineteen patients (23 eyes) exhibited microcystic macular edema: 10 men/9 women, aged 17-91 years. Etiologies of optic nerve atrophy were compressive (5), inflammatory (4), glaucoma (3), ischemic (3), trauma (2), degenerative (1), and hereditary (1). Median visual acuity was 4/10 (NLP-12/10). Fluorescein angiography showed no leakage. Topography of the microcystic macular edema correlated with near infrared images but with visual field defects in only 26 %. OCT parameters were all abnormal. Conclusions: Microcystic macular edema is a non-specific manifestation from an optic neuropathy of any etiology. The precise mechanism leading to microcystic macular edema remains unknown but trans-synaptic retrograde degeneration with Müller cells dysfunction is likely. Zusammenfassung Hintergrund: Das mikrozystische Makulaödem kann im Rahmen einer Optikusatrophie jeglicher Ätiologie auftreten und ist leicht mit dem OCT zu erkennen. Wir berichten über eine Patientenkohorte mit mikrozystischem Makulaödem. Patienten und Methoden: Alle Patienten mit einer Optikusneuropathie und einem mikrozystischen Makulaödem wurden in diese Studie eingeschlossen. Die Demografie, die Sehfunktion, die Netzhautangiografie und die OCT-Parameter wurden untersucht. Ergebnisse: Neunzehn Patienten (23 Augen) hatten ein mikrozystisches Makulaödem: 10 Männer/9 Frauen im Alter von 17 bis 91 Jahren. Die Ursachen der Optikusatrophie waren Kompressionen (5), Entzündungen (4), Glaukom (3), Ischämien (3), Traumata (2), Degenerationen (1) und genetisch (1). Der mittlere Visus war 0,4 (keine Lichtwahrnehmung 1,2). In der Fluoreszenzangiografie fand sich keine Leckage. Das OCT des mikrozystischen Makulaödems korrelierte immer mit den Infrarot-Bildern (Nahaufnahme), jedoch nur in 26 % mit den Gesichtsfelddefekten. Alle OCT-Parameter waren abnormal. Schlussfolgerungen: Das mikrozystische Makulaödem ist eine unspezifische Manifestation einer Optikusneuropathie jeglicher Ätiologie. Der genaue Mechanismus, der zu einem mikrozystischen Makulaödem führt, ist unbekannt, eine trans-synaptische retrograde Degeneration mit Dysfunktion der Müller-Zellen ist jedoch wahrscheinlich.