Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas

<p>Abstract</p> <p>Background</p> <p>Meningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the <it>NF2 </it>locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas.</p> <p>Methods</p> <p>We compared 73 meningiomas presenting as sporadic solitary (64), sporadic multiple (5) and familial multiple (4) tumors using genomic profiling by array comparative genomic hybridization (array CGH).</p> <p>Results</p> <p>Sporadic solitary meningiomas revealed genomic rearrangements consistent with at least two mechanisms of tumor initiation, as unsupervised cluster analysis readily distinguished tumors with chromosome 22 deletion (associated with loss of the <it>NF2 </it>tumor suppressor) from those without chromosome 22 deletion. Whereas sporadic meningiomas without chromosome 22 loss exhibited fewer chromosomal imbalance events overall, tumors with chromosome 22 deletion further clustered into two major groups that largely, though not perfectly, matched with their benign (WHO Grade I) or advanced (WHO Grades II and III) histological grade, with the latter exhibiting a significantly greater degree of genomic imbalance (P < 0.001). Sporadic multiple meningiomas showed a frequency of genomic imbalance events comparable to the atypical grade solitary tumors. By contrast, familial multiple meningiomas displayed no imbalances, supporting a distinct mechanism for the origin for these tumors.</p> <p>Conclusion</p> <p>Genomic profiling can provide an unbiased adjunct to traditional meningioma classification and provides a basis for exploring the different genetic underpinnings of tumor initiation and progression. Most importantly, the striking difference observed between sporadic and familial multiple meningiomas indicates that genomic profiling can provide valuable information for differential diagnosis of subjects with multiple meningiomas and for considering the risk for tumor occurrence in their family members.</p

Iatrogenic and toxic myopathies

There has been increasing awareness of the adverse effects of therapeutic agents and exogenous toxins on the structure and function of muscle. The resulting clinical syndrome varies from one characterized by muscle pain to profound myalgia, paralysis, and myoglobinuria. Because toxic myopathies are potentially reversible, their prompt recognition may reduce their damaging effects or prevent a fatal outcome. Interest in the toxic myopathies, however, derives not only from their clinical importance but also from the fact that they serve as useful experimental models in muscle research. Morphological and biochemical studies have increased our understanding of the basic cellular mechanisms of myotoxicity. Toxins may produce, for instance, necrotizing, lysosomal-related, inflammatory, anti-microtubular, mitochondrial, hypokalemia-related, or protein synthesis-related muscle damag

Congenital myasthenia in Brahman calves caused by homozygosity for a CHRNE truncating mutation

To elucidate the genetic defect in four previously reported related Brahman calves with severe myasthenic weakness, we determined the genomic structure of the gene encoding the bovine c-subunit (bovCHRNE) of the acetylcholine receptor (AChR). Amplification of DNA isolated from paraplast-embedded tissue samples from one of the myasthenic calves and subsequent sequencing of all bovCHRNE exons revealed a homozygous 20-bp deletion within exon 5 (470del20). The deletion causes a frame shift followed by a premature stop codon in the predicted bovCHRNE protein. Thus, the 470del20 mutation reported here leads to a non-functional allele, explaining the impairment of neuromuscular transmission observed in the affected Brahman calves. With a survival time limited to only several months, the effect on neuromuscular transmission was more pronounced in the calves than that observed in humans homozygous for truncating CHRNE mutations. This may be due to a different capacity to express the fetal-type AChR after bir

Periodic limb movements during REM sleep in multiple sclerosis: a previously undescribed entity

Christian Veauthier,1 Gunnar Gaede,2,3 Helena Radbruch,2 Joern-Peter Sieb,4,5 Klaus-Dieter Wernecke,6,7 Friedemann Paul2,8 1Interdisciplinary Center of Sleep Medicine, Charit&eacute; University Medicine Berlin, Germany; 2NeuroCure Clinical Research Center, Charit&eacute; University Medicine Berlin, Germany; 3Department of Neurology, St Joseph Hospital Berlin-Weissensee, Berlin, Germany; 4Department of Neurology, HELIOS Hanseklinikum Stralsund, Stralsund, Germany; 5Department of Neurology, University Hospital Bonn, Bonn, Germany; 6CRO SOSTANA GmbH, Berlin, Germany; 7Institute of Medical Biometry, Charit&eacute; University Medicine Berlin, Berlin, Germany; 8Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charit&eacute; University Medicine Berlin, Berlin, Germany Background: There are few studies describing periodic limb movement syndrome (PLMS) in rapid eye movement (REM) sleep in patients with narcolepsy, restless legs syndrome, REM sleep behavior disorder, and spinal cord injury, and to a lesser extent, in insomnia patients and healthy controls, but no published cases in multiple sclerosis (MS). The aim of this study was to investigate PLMS in REM sleep in MS and to analyze whether it is associated with age, sex, disability, and laboratory findings. Methods: From a study of MS patients originally published in 2011, we retrospectively analyzed periodic limb movements (PLMs) during REM sleep by classifying patients into two subgroups: PLM during REM sleep greater than or equal to ten per hour of REM sleep (n=7) vs less than ten per hour of REM sleep (n=59). A univariate analysis between PLM and disability, age, sex, laboratory findings, and polysomnographic data was performed. Results: MS patients with more than ten PLMs per hour of REM sleep showed a significantly higher disability measured by the Kurtzke expanded disability status scale (EDSS) (P=0.023). The presence of more than ten PLMs per hour of REM sleep was associated with a greater likelihood of disability (odds ratio 22.1; 95% confidence interval 3.5&ndash;139.7; P&lt;0.0001), whereas there were no differences in laboratory and other polysomnographic findings. Conclusion: PLMs during REM sleep were not described in MS earlier, and they are associated with disability measured by the EDSS. Keywords: restless legs syndrome, spinal cord, sleep disorders, disability, clinical neurophysiology, polysomnography&nbsp

Toxic myopathies: muscle biopsy features Miopatia tóxica: biópsia muscular

Several drugs and toxic substances can cause muscular abnormalities and are frequent causes of acquired myopathies. We present a series of 32 patients, predominance of young adult patients, diagnosed with toxic myopathy. The most common substances inducing myopathy were corticosteroids (56.2%) followed by the propoxyphene, neuroleptics, zidovudine and drug-induced hypokalemia. The investigation showed normal serum creatine kinase levels in 65.4%, myopathic pattern of the needle electromyography in 40% and the more frequent histological diagnosis of the muscle biopsy was type 2 fiber atrophy (59.3%). Clinical features, etiology, course of the disease, serum levels of muscular enzymes, electromyographic features and, especially, muscle biopsy features are discussed.<br>Diversos medicamentos e substâncias tóxicas podem causar alterações musculares e são causas freqüentes de miopatia adquirida. Apresentamos uma série de 32 pacientes, predomínio de pacientes adulto jovens, com miopatia tóxica. As substâncias mais relacionadas com a miopatia foram os corticosteróides (56,2%) seguidos pelo propoxifeno, neurolépticos, zidovudina e drogas indutoras de hipocalemia. A investigação mostrou níveis normais de creatino quinase sérica em 65,4%, eletromiografia de agulha com padrão miopático em 40% e o mais freqüente diagnóstico histológico da biópsia muscular foi atrofia de fibras do tipo 2 (59,3%). As manifestações clínicas, etiologia, tempo de evolução, nível sérico das enzimas musculares, alterações da eletroneuromiografia e, especialmente, da biópsia muscular são discutidos