Panel review of anaplastic oligodendroglioma from European Organization For Research and Treatment of Cancer Trial 26951: assessment of consensus in diagnosis, influence of 1p/19q loss, and correlations with outcome

The diagnosis of anaplastic oligodendroglioma (AOD) or anaplastic oligoastrocytoma (AOA) is subject to interobserver variation. The aim of this study was to estimate consensus in typing and grading of these tumors using tumor material collected in a large prospective randomized phase III study and to correlate the consensus diagnosis with the 1p/19q status of the tumors and the clinical outcome. The available pathology material of the first 150 patients, randomized into the European Organization for Research and Treatment of Cancer Trial 26951, was reviewed by an independent panel of 9 neuropathologists. The presence of deletions of 1p and 19q was assessed by fluorescence in situ hybridization with locus-specific probes. The panel reached consensus on the diagnosis of AOD in 52% of the tumors that had been diagnosed as AOD by the local pathologists, whereas only 8% of the local diagnosis of AOA was confirmed with consensus. The concordance on the panel diagnosis of AOD was high (intraclass correlation = 86%). The survival curves for AOD with 1p/19q loss, AOD without these losses, and AOA without 1p/19q loss ran separately in this order. The absence of necrosis and the presence of endothelial abnormalities were correlated with better outcomes. In multivariate analysis, patients' age, 1p/19q loss, and necrosis were identified as independent prognostic factors.     

Brain Neurons Express Ornithine Decarboxylase‐Activating Antizyme Inhibitor 2 with Accumulation in Alzheimer's Disease

Polyamines are small cationic molecules that in adult brain are connected to neuronal signaling by regulating inward‐rectifier K⁺‐channels and different glutamate receptors. Antizyme inhibitors (AZINs) regulate the cellular uptake of polyamines and activate ornithine decarboxylase (ODC), the rate‐limiting enzyme of polyamine synthesis. Elevated levels of ODC activity and polyamines are detected in various brain disorders including stroke and Alzheimer''s disease (AD).We originally reported a novel brain‐ and testis‐specific AZIN, called AZIN2, the distribution of which we have now studied in normal and diseased human brain by in situ hybridization and immunohistochemistry. We found the highest accumulation of AZIN2 in a pearl‐on‐the‐string‐like distribution along the axons in both the white and gray matter. AZIN2 was also detected in a vesicle‐like distribution in the somas of selected cortical pyramidal neurons. Double‐immunofluorescence staining revealed co‐localization of AZIN2 and N‐methyl D‐aspartate‐type glutamate receptors (NMDARs) in pyramidal neurons of the cortex. Moreover, we found accumulation of AZIN2 in brains affected by AD, but not by other neurodegenerative disorders (CADASIL or Lewy body disease). ODC activity is mostly linked to cell proliferation, whereas its regulation by AZIN2 in post‐mitotically differentiated neurons of the brain apparently serves different purposes. The subcellular distribution of AZIN2 suggests a role in vesicular trafficking.     

Early high-dose phenobarbital treatment for prevention of hypoxic-ischemic brain damage in very low birth weight infants

In a randomized prospective trial, we studied the effect of early high-dose phenobarbital treatment on the early (intraventricular hemorrhage) and late (neurodevelopmental abnormalities) manifestations of hypoxic-ischemic encephalopathy in preterm infants weighing 1500 g or less at birth. The first intravenous dose of 15 mg/kg was given at a mean age of 110 minutes, followed by 15 mg/kg after 4 hours and then by 5 mg/kg at 24-hour intervals for 5 days. The overall incidence of intraventricular hemorrhage was 32% in treated and 46% in control infants, a nonsignificant difference. An ultrasound brain scan at 9 months old revealed no significant difference in the incidence of ventricular dilatation between treated (19%) and control (29%) infants. At 27 months, a similar incidence of mild (10%) and severe (10%) neurodevelopmental handicaps was found in both treated and control groups. Since beneficial effects could not be documented by any of the criteria used, we conclude that routine administration of phenobarbital to low birth weight infants is not justified.     

Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice

Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases and the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. We have generated transgenic mice expressing mouse Twinkle with PEO patient mutations. Multiple mtDNA deletions accumulate in the tissues of these mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of the mice faithfully replicate all of the key histological, genetic, and biochemical features of PEO patients. Furthermore, the mice have progressive deficiency of cytochrome c oxidase in distinct neuronal populations. These "deletor" mice do not, however, show premature aging, indicating that subtle accumulation of mtDNA deletions and progressive respiratory chain dysfunction are not sufficient to accelerate aging. This model is a valuable tool for therapy development and testing for adult-onset mitochondrial disorders.     

Sensory neuropathy in infantile onset spinocerebellar ataxia (IOSCA)

Infantile onset spinocerebellar ataxia with sensory neuropathy is a new, inherited multisystem disorder discovered in 19 Finnish patients. In order to define the neuropathy of the disease, we measured sensory nerve action potentials and nerve conduction velocities in 18 patients, and recorded somatosensory evoked potentials (SEP) in 10 patients and performed a sural nerve biopsy in 13 patients. The fixed and teased nerve fascicles were examined by light and electron microscopy, and the whole transverse section of a nerve fascicle was photographed and enlarged for morphometric measurements. Our investigation revealed an early onset, rapidly progressive axonal neuropathy: the sensory action potentials were decreased after the age of 2 and a severe loss of mainly large myelinated fibers was found. © 1994 John & Sons, Inc.     

Distribution of a major connective tissue protein,fibronectin, in normal and neoplastic human nervous tissue

Summary Fibronectin is a cell surface-associated glycoprotein of various adherent cells in culture, and it has been found to be a major component of connective tissue matrix in human tissues. Reports on expression of fibronectin by cultured human astroglial cells prompted us to study its distribution in vivo. In human brain tissue fibronectin was located, as studied by immunofluorescence staining, to capillary vessel walls in a pattern corresponding both to the vessel lumen and the basement membrane of vessel wall. Glial or neuronal cells did not express fibronectin in the adult human brain. In human brain tumors of the glioma group occasional faint intercellular fluorescence was observed, probably due to leakage of fibronectin from the blood stream. A strong staining associated with the endothelial glomerulus-like proliferations was also observed in malignant gliomas. In peripheral nerves fibronectin fluorescence corresponding to the basement membranes of perineurial and Schwann cells was seen. An interesting feature was the intense staining at the nodes of Ranvier. In a well differentiated schwannoma of peripheral nerve an intercellular lamellar staining pattern was observed, corresponding to the basement membranes of the neoplastic cells. These results indicate that in the human nervous tissue fibronectin occurs only at sites of contact between the neuro-ectoderm and mesenchyme.     

Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions

Autosomal-inherited progressive external ophthalmoplegia (PEO) is an adult-onset disease characterized by the accumulation of multiple mitochondrial DNA (mtDNA) deletions in post-mitotic tissues. Mutations in six different genes have been described to cause the autosomal dominant form of the disease, but only mutations in the DNA polymerase gamma gene are known to cause autosomal recessive PEO (arPEO), leaving the genetic background of arPEO mostly unknown. Here we used whole-exome sequencing and identified compound heterozygous mutations, leading to two amino acid alterations R225W and a novel T230A in thymidine kinase 2 (TK2) in arPEO patients. TK2 is an enzyme of the mitochondrial nucleotide salvage pathway and its loss-of-function mutations have previously been shown to underlie the early-infantile myopathic form of mtDNA depletion syndrome (MDS). Our TK2 activity measurements of patient fibroblasts and mutant recombinant proteins show that the combination of the identified arPEO variants, R225W and T230A, leads to a significant reduction in TK2 activity, consistent with the late-onset phenotype, whereas homozygosity for R225W, previously associated with MDS, leads to near-total loss of activity. Our finding identifies a new genetic cause of arPEO with multiple mtDNA deletions. Furthermore, MDS and multiple mtDNA deletion disorders are manifestations of the same pathogenic pathways affecting mtDNA replication and repair, indicating that MDS-associated genes should be studied when searching for genetic background of PEO disorders.