The neuralgic amyotrophy consultation

Neuralgic amyotrophy is a distinct clinical syndrome with acute severe pain and patchy paresis in the shoulder and arm region. The clinical phenotype was recently found to be more comprehensive and the long-term prognosis less optimistic than usually assumed for many patients. The disorder can be idiopathic or hereditary in an autosomal dominant fashion, with only few phenotypical variations between the two. This article provides a practical overview of current knowledge on the clinical presentation, diagnosis, pathogenesis and the treatment of pain and complications

Alternative Splicing of sept9a and sept9b in Zebrafish Produces Multiple mRNA Transcripts Expressed Throughout Development

Background: Septins are involved in a number of cellular processes including cytokinesis and organization of the cytoskeleton. Alterations in human septin-9 (SEPT9) levels have been linked to multiple cancers, whereas mutations in SEPT9 cause the episodic neuropathy, hereditary neuralgic amyotrophy (HNA). Despite its important function in human health, the in vivo role of SEPT9 is unknown. Methodology/Principal Findings: Here we utilize zebrafish to study the role of SEPT9 in early development. We show that zebrafish possess two genes, sept9a and sept9b that, like humans, express multiple transcripts. Knockdown or overexpression of sept9a transcripts results in specific developmental alterations including circulation defects and aberrant epidermal development. Conclusions/Significance: Our work demonstrates that sept9 plays an important role in zebrafish development, an

Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel.

BACKGROUND: CMT-2 is a clinically and genetically heterogeneous group of peripheral axonal neuropathies characterized by slowly progressive weakness and atrophy of distal limb muscles resulting from length-dependent motor and sensory neurodegeneration. Classical giant axonal neuropathy (GAN) is an autosomal recessively inherited progressive neurodegenerative disorder of the peripheral and central nervous systems, typically diagnosed in early childhood and resulting in death by the end of the third decade. Distinctive phenotypic features are the presence of "kinky" hair and long eyelashes. The genetic basis of the disease has been well established, with over 40 associated mutations identified in the gene GAN, encoding the BTB-KELCH protein gigaxonin, involved in intermediate filament regulation. METHODS: An Illumina Human CytoSNP-12 array followed by whole exome sequence analysis was used to identify the disease associated gene mutation in a large consanguineous family diagnosed with Charcot-Marie-Tooth disease type 2 (CMT-2) from which all but one affected member had straight hair. RESULTS: Here we report the identification of a novel GAN missense mutation underlying the CMT-2 phenotype observed in this family. Although milder forms of GAN, with and without the presence of kinky hair have been reported previously, a phenotype distinct from that was investigated in this study. All family members lacked common features of GAN, including ataxia, nystagmus, intellectual disability, seizures, and central nervous system involvement. CONCLUSIONS: Our findings broaden the spectrum of phenotypes associated with GAN mutations and emphasize a need to proceed with caution when providing families with diagnostic or prognostic information based on either clinical or genetic findings alone

Fatigue, reduced sleep quality and restless legs syndrome in Charcot-Marie-Tooth disease: a web-based survey

To investigate the prevalence of fatigue, daytime sleepiness, reduced sleep quality, and restless legs syndrome (RLS) in a large cohort of patients with Charcot-Marie-Tooth disease (CMT) and their impact on health-related quality of life (HRQoL). Participants of a web-based survey answered the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the Multidimensional Fatigue Inventory, and, if the diagnostic criteria of RLS were met, the International RLS Severity Scale. Diagnosis of RLS was affirmed in screen-positive patients by means of a standardized telephone interview. HRQoL was assessed by using the SF-36 questionnaire. Age- and sex-matched control subjects were recruited from waiting relatives of surgical outpatients. 227 adult self-reported CMT patients answered the above questionnaires, 42.9% were male, and 57.1% were female. Age ranged from 18 to 78 years. Compared to controls (n = 234), CMT patients reported significantly higher fatigue, a higher extent and prevalence of daytime sleepiness and worse sleep quality. Prevalence of RLS was 18.1% in CMT patients and 5.6% in controls (p = 0.001). RLS severity was correlated with worse sleep quality and reduced HRQoL. Women with CMT were affected more often and more severely by RLS than male patients. With regard to fatigue, sleep quality, daytime sleepiness, RLS prevalence, RLS severity, and HRQoL, we did not find significant differences between genetically distinct subtypes of CMT. HRQoL is reduced in CMT patients which may be due to fatigue, sleep-related symptoms, and RLS in particular. Since causative treatment for CMT is not available, sleep-related symptoms should be recognized and treated in order to improve quality of life

Sex-differential genetic effect of phosphodiesterase 4D (PDE4D) on carotid atherosclerosis

<p>Abstract</p> <p>Background</p> <p>The phosphodiesterase 4D (PDE4D) gene was reported as a susceptibility gene to stroke. The genetic effect might be attributed to its role in modulating the atherogenic process in the carotid arteries. Using carotid intima-media thickness (IMT) and plaque index as phenotypes, the present study sought to determine the influence of this gene on subclinical atherosclerosis.</p> <p>Methods</p> <p>Carotid ultrasonography was performed on 1013 stroke-free subjects who participated in the health screening programs (age 52.6 ± 12.2; 47.6% men). Genotype distribution was compared among the high-risk (plaque index ≥ 4), low-risk (index = 1-3), and reference (index = 0) groups. We analyzed continuous IMT data and further dichotomized IMT data using mean plus one standard deviation as the cutoff level. Because the plaque prevalence and IMT values displayed a notable difference between men and women, we carried out sex-specific analyses in addition to analyzing the overall data. Rs702553 at the PDE4D gene was selected because it conferred a risk for young stroke in our previous report. Previous young stroke data (190 cases and 211 controls) with an additional 532 control subjects without ultrasonic data were shown as a cross-validation for the genetic effect.</p> <p>Results</p> <p>In the overall analyses, the rare homozygote of rs702553 led to an OR of 3.1 (p = 0.034) for a plaque index ≥ 4. When subjects were stratified by sex, the genetic effect was only evident in men but not in women. Comparing male subjects with plaque index ≥ 4 and those with plaque index = 0, the TT genotype was over-represented (27.6% vs. 13.4%, p = 0.008). For dichotomized IMT data in men, the TT genotype had an OR of 2.1 (p = 0.032) for a thicker IMT at the common carotid artery compared with the (AA + AT) genotypes. In women, neither IMT nor plaque index was associated with rs702553. Similarly, SNP rs702553 was only significant in young stroke men (OR = 1.8, p = 0.025) but not in women (p = 0.27).</p> <p>Conclusions</p> <p>The present study demonstrates a sex-differential effect of PDE4D on IMT, plaque index and stroke, which highlights its influence on various aspects of atherogenesis.</p

Conquering the complex world of human septins: implications for health and disease

Peterson EA and Petty EM. Conquering the complex world of human septins: implications for health and disease.Septins are highly conserved filamentous proteins first characterized in budding yeast and subsequently identified in must eukaryotes. Septins can bind and hydrolyze GTP, which is intrinsically related to their formation of septin hexamers and functional protein interactions. The human septin family is composed of 14 loci, SEPT1-SEPT14 , which encode dozens of different septin proteins. Their central GTPase and polybasic domain regions are highly conserved but they diverge in their N-terminus and/or C-terminus. The mechanism by which the different isoforms are generated is not yet well understood, but one can hypothesize that the use of different promoters and/or alternative splicing could give rise to these variants.Septins perform diverse cellular functions according to tissue expression and their interacting partners. Functions identified to date include cell division, chromosome segregation, protein scaffolding, cellular polarity, motility, membrane dynamics, vesicle trafficking, exocytosis, apoptosis, and DNA damage response. Their expression is tightly regulated to maintain proper filament assembly and normal cellular functions. Alterations of these proteins, by mutation or expression changes, have been associated with a variety of cancers and neurological diseases. The association of septins with cancer results from alterations of expression in solid tumors or translocations in leukemias [mixed lineage leukemia (MLL)]. Expression changes in septins have also been associated with neurological conditions such as Alzheimer's and Parkinson's disease, as well as retinopathies, hepatitis C, spermatogenesis and Listeria infection. Pathogenic mutations of SEPT9 were identified in the autosomal dominant neurological disorder hereditary neuralgic amyotrophy (HNA).Human septin research over the past decade has established their importance in cell biology and human disease. Further functional characterization of septins is crucial to our understanding of their possible diagnostic, prognostic, and therapeutic applications.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78622/1/j.1399-0004.2010.01392.x.pd

Septins Regulate Bacterial Entry into Host Cells

Background: Septins are conserved GTPases that form filaments and are required in many organisms for several processes including cytokinesis. We previously identified SEPT9 associated with phagosomes containing latex beads coated with the Listeria surface protein InlB. Methodology/Principal Findings: Here, we investigated septin function during entry of invasive bacteria in non-phagocytic mammalian cells. We found that SEPT9, and its interacting partners SEPT2 and SEPT11, are recruited as collars next to actin at the site of entry of Listeria and Shigella. SEPT2-depletion by siRNA decreased bacterial invasion, suggesting that septins have roles during particle entry. Incubating cells with InlB-coated beads confirmed an essential role for SEPT2. Moreover, SEPT2-depletion impaired InlB-mediated stimulation of Met-dependent signaling as shown by FRET. Conclusions/Significance: Together these findings highlight novel roles for SEPT2, and distinguish the roles of septin an

SEPTIN12 Genetic Variants Confer Susceptibility to Teratozoospermia

It is estimated that 10–15% of couples are infertile and male factors account for about half of these cases. With the advent of intracytoplasmic sperm injection (ICSI), many infertile men have been able to father offspring. However, teratozoospermia still remains a big challenge to tackle. Septins belong to a family of cytoskeletal proteins with GTPase activity and are involved in various biological processes e.g. morphogenesis, compartmentalization, apoptosis and cytokinesis. SEPTIN12, identified by c-DNA microarray analysis of infertile men, is exclusively expressed in the post meiotic male germ cells. Septin12+/+/Septin12+/− chimeric mice have multiple reproductive defects including the presence of immature sperm in the semen, and sperm with bent neck (defect of the annulus) and nuclear DNA damage. These facts make SEPTIN12 a potential sterile gene in humans. In this study, we sequenced the entire coding region of SEPTIN12 in infertile men (n = 160) and fertile controls (n = 200) and identified ten variants. Among them is the c.474 G>A variant within exon 5 that encodes part of the GTP binding domain. The variant creates a novel splice donor site that causes skipping of a portion of exon 5, resulting in a truncated protein lacking the C-terminal half of SEPTIN12. Most individuals homozygous for the c.474 A allele had teratozoospermia (abnormal sperm <14%) and their sperm showed bent tail and de-condensed nucleus with significant DNA damage. Ex vivo experiment showed truncated SEPT12 inhibits filament formation in a dose-dependent manner. This study provides the first causal link between SEPTIN12 genetic variant and male infertility with distinctive sperm pathology. Our finding also suggests vital roles of SEPT12 in sperm nuclear integrity and tail development