47 research outputs found
Concurrent axon and myelin destruction differentiates X-linked adrenoleukodystrophy from multiple sclerosis
Cerebral disease manifestation occurs in about two thirds of males with X-linked adrenoleukodystrophy (CALD) and is fatally progressive if left untreated. Early histopathologic studies categorized CALD as an inflammatory demyelinating disease, which led to repeated comparisons to multiple sclerosis (MS). The aim of this study was to revisit the relationship between axonal damage and myelin loss in CALD. We applied novel immunohistochemical tools to investigate axonal damage, myelin loss and myelin repair in autopsy brain tissue of eight CALD and 25 MS patients. We found extensive and severe acute axonal damage in CALD already in prelesional areas defined by microglia loss and relative myelin preservation. In contrast to MS, we did not observe selective phagocytosis of myelin, but a concomitant decay of the entire axon-myelin unit in all CALD lesion stages. Using a novel marker protein for actively remyelinating oligodendrocytes, breast carcinoma-amplified sequence (BCAS) 1, we show that repair pathways are activated in oligodendrocytes in CALD. Regenerating cells, however, were affected by the ongoing disease process. We provide evidence that—in contrast to MS—selective myelin phagocytosis is not characteristic of CALD. On the contrary, our data indicate that acute axonal injury and permanent axonal loss are thus far underestimated features of the disease that must come into focus in our search for biomarkers and novel therapeutic approaches
Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness
OBJECTIVE: To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). METHODS: We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts. RESULTS: In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. INTERPRETATION: We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease
Pentoxifylline as an adjunct therapy in children with cerebral malaria
<p>Abstract</p> <p>Background</p> <p>Pentoxifylline (PTX) affects many processes that may contribute to the pathogenesis of severe malaria and it has been shown to reduce the duration of coma in children with cerebral malaria. This pilot study was performed to assess pharmacokinetics, safety and efficacy of PTX in African children with cerebral malaria.</p> <p>Methods</p> <p>Ten children admitted to the high dependency unit of the Kilifi District Hospital in Kenya with cerebral malaria (Blantyre coma score of 2 or less) received quinine plus a continuous infusion of 10 mg/kg/24 hours PTX for 72 hours. Five children were recruited as controls and received normal saline instead of PTX. Plasma samples were taken for PTX and tumour necrosis factor (TNF) levels. Blantyre Coma Score, parasitemia, hematology and vital signs were assessed 4 hourly.</p> <p>Results</p> <p>One child (20%) in the control group died, compared to four children (40%) in the PTX group. This difference was not significant (p = 0.60). Laboratory parameters and clinical data were comparable between groups. TNF levels were lower in children receiving PTX.</p> <p>Conclusions</p> <p>The small sample size does not permit definitive conclusions, but the mortality rate was unexpectedly high in the PTX group.</p
A case report of delayed cortical infarction adjacent to sulcal clots after traumatic subarachnoid hemorrhage in the absence of proximal vasospasm
Background Cortical ischemic lesions represent the predominant pathomorphological pattern of focal lesions after aneurysmal subarachnoid hemorrhage (aSAH). Autopsy studies suggest that they occur adjacent to subarachnoid blood and are related to spasm of small cortical rather than proximal arteries. Recent clinical monitoring studies showed that cortical spreading depolarizations, which induce cortical arterial spasms, are involved in lesion development. If subarachnoid blood induces adjacent cortical lesions, it would be expected that (i) they also develop after traumatic subarachnoid hemorrhage (tSAH), and (ii) lesions after tSAH can occur in absence of angiographic vasospasm, as was found for aSAH. Case presentation An 86-year-old woman was admitted to our hospital with fluctuating consciousness after hitting her head during a fall. The initial computed tomography (CT) was significant for tSAH in cortical sulci. On day 8, the patient experienced a secondary neurological deterioration with reduced consciousness and global aphasia. Whereas the CT scan on day 9 was still unremarkable, magnetic resonance imaging (MRI) on day 10 revealed new cortical laminar infarcts adjacent to sulcal blood clots. Proximal vasospasm was ruled out using MR and CT angiography and Doppler sonography. CT on day 14 confirmed the delayed infarcts. Conclusions We describe a case of delayed cortical infarcts around sulcal blood clots after tSAH in the absence of proximal vasospasm, similar to results found previously for aSAH. As for aSAH, this case suggests that assessment of angiographic vasospasm is not sufficient to screen for risk of delayed infarcts after tSAH. Electrocorticography is suggested as a complementary method to monitor the hypothesized mechanism of spreading depolarizations
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Astrocytes and microglia in human type-II lissencephaly [poster presentation]
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Radial glia, astrocytes and microglia in human type-II lissencephaly [poster presentation]
Type-II lissencephaly (LIS-II) is a rare developmental disorder characterized by the excessive migration of neurons and glia, which breach the glia limitans and accumulate within the subarachnoid space. The cortical structure is completely disrupted, the meninges are thickened, and the surface of the brain presents with a ‘cobblestone-like’ appearance. LIS-II is found in Walker–Warburg syndrome (WWS), muscle–eye–brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD), autosomal recessive disorders all of which share features of congenital muscular dystrophy and ocular malformation. Genetic studies have found that abnormal protein glycosylation accounts at least partially, towards disturbances in neuronal migration in LIS-II. Aberrant interactions between neurons, mesenchyme and vasculature are also considered central to the pathogenesis of LIS-II. However, the contribution of glial cell populations towards pathology in LIS-II has not been characterized. Sections of the forebrain from 6 cases (19–31 gestational weeks) all with neuropathological features pathognomonic of LIS-II and WWS were immunoreacted with antisera to detect CD68, MHC-II (for microglia), and GFAP (for astrocytes), and histochemically with RCA-1 and tomato lectins (for microglia and blood vessels). Developing microglia and astrocytes were differentially affected in LIS-II. There was a clear distinction between early microglial maturation (induction of ramified morphology and ‘downregulated’ phenotype in these cells), and degenerative ‘gemistocytic’ changes affecting astrocytes within lower aspects of the cerebral wall. Ramified microglia were aligned with fibre tracts within the intermediate zone and continuing beyond the breach, but absent in neuro-vascular-mesenchymal masses found in upper regions. The lack of microglial activation or evidence of transitory ‘ameboid’ microglia within the telencephalon was quite remarkable, considering the gross abnormalities evident in the upper aspect of the cerebral mantle, and the ‘degenerative changes’ affecting differentiating astrocytes. It is clear that both microglial and astrocyte responses warrant further extensive investigation in relation to the neuronal disturbances found in lissencephaly
The effects of CDP-choline on newborn rat pups with experimental alcohol fetopathy. A Golgi study
Generally accepted features of alcoholic
fetopathy are delayed maturation and retarded dendritic
development of neocortex, hippocampus and cerebellum.
The present study investigates the effects of a membrane
stabilizing agent (CDP-choline) on Purkinje cells of
chronically alcohol intoxicated newborn rat pups,
employing a Golgi impregnation technique. Both quantitative
and qualitative data indicate that CDP-choline
modifies the alcohol induced lesion
Painful enlargement of the calf muscles in limb girdle muscular dystrophy type 2B (LGMD2B) with a novel compound heterozygous mutation in DYSF
Limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi Myopathy are caused by mutations in the dysferlin gene. The phenotype of these allelic disease variants can vary considerably. We report on an adolescent female with a severe and rapidly progressing clinical course of LGMD2B which has been suggested by the muscle histopathology and Western blot and proven by mutation analysis in the Dysferlin gene. We detected a novel compound heterozygous mutation of which one affects the extracellular part of the protein. This is the first report on a mutation in this region of dysferlin and might explain the unusual phenotype of the patient