Distinct Clinical Syndrome Research Articles

Biosynthesis of glycosaminoglycans: associated disorders and biochemical tests.

Glycosaminoglycans (GAG) are long, unbranched heteropolymers with repeating disaccharide units that make up the carbohydrate moiety of proteoglycans. Six distinct classes of GAGs are recognized. Their synthesis follows one of three biosynthetic pathways, depending on the type of oligosaccharide linker they contain. Chondroitin sulfate, dermatan sulfate, heparan sulfate, and heparin sulfate contain a common tetrasaccharide linker that is O-linked to specific serine residues in core proteins. Keratan sulfate can contain three different linkers, either N-linked to asparagine or O-linked to serine/threonine residues in core proteins. Finally, hyaluronic acid does not contain a linker and is not covalently attached to a core protein. Most inborn errors of GAG biosynthesis are reported in small numbers of patients. To date, in 20 diseases, convincing evidence for pathogenicity has been presented for mutations in a total of 16 genes encoding glycosyltransferases, sulfotransferases, epimerases or transporters. GAG synthesis defects should be suspected in patients with a combination of characteristic clinical features in more than one connective tissue compartment: bone and cartilage (short long bones with or without scoliosis), ligaments (joint laxity/dislocations), and subepithelial (skin, sclerae). Some produce distinct clinical syndromes. The commonest laboratory tests used for this group of diseases are analysis of GAGs, enzyme assays, and molecular testing. In principle, GAG analysis has potential as a general first-line diagnostic test for GAG biosynthesis disorders.

Genetics of frontotemporal dementia in Asia: Advancing knowledge through collaboration.

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder characterized by selective involvement of the frontal and temporal lobes, where non-Alzheimer disease (AD) pathology is expected. FTD encompasses 3 distinct clinical syndromes including behavioral variant FTD (bvFTD) characterized by prominent behavioral abnormalities, and 2 language variants (semantic variant and nonfluent variant) collectively known as primary progressive aphasia (PPA). The most common FTD subtype, bvFTD, may manifest with disinhibition, compulsive/perseverative behavior, overeating, apathy, and emotional blunting. FTD is known in Western populations to be the second most common cause of dementia in those younger than 65 years.1 In Asian populations, FTD appears to be far less common, being the third most common cause of young-onset dementia in some cohorts behind AD and vascular dementia.2 The proportion of Asian patients with FTD who have a positive family history ranges from 9.5% to 20%,2–4 considerably lower than the 30% to 50% seen in Caucasian populations.5

Vector and reservoir control for preventing leishmaniasis.

BackgroundLeishmaniasis is caused by the Leishmania parasite, and transmitted by infected phlebotomine sandflies. Of the two distinct clinical syndromes, cutaneous leishmaniasis (CL) affects the skin and mucous membranes, and visceral leishmaniasis (VL) affects internal organs. Approaches to prevent transmission include vector control by reducing human contact with infected sandflies, and reservoir control, by reducing the number of infected animals.ObjectivesTo assess the effects of vector and reservoir control interventions for cutaneous and for visceral leishmaniasis.Search methodsWe searched the following databases to 13 January 2015: Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS and WHOLIS, Web of Science, and RePORTER. We also searched trials registers for ongoing trials.Selection criteriaRandomized controlled trials (RCTs) evaluating the effects of vector and reservoir control interventions in leishmaniasis‐endemic regions.Data collection and analysisTwo review authors independently searched for trials and extracted data from included RCTs. We resolved any disagreements by discussion with a third review author. We assessed the quality of the evidence using the GRADE approach.Main resultsWe included 14 RCTs that evaluated a range of interventions across different settings. The study methods were generally poorly described, and consequently all included trials were judged to be at high or unclear risk of selection and reporting bias. Only seven trials reported clinical outcome data which limits our ability to make broad generalizations to different epidemiological settings and cultures.Cutaneous leishmaniasisOne four‐arm RCT from Afghanistan compared indoor residual spraying (IRS), insecticide‐treated bednets (ITNs), and insecticide‐treated bedsheets, with no intervention. Over 15 months follow‐up, all three insecticide‐based interventions had a lower incidence of CL than the control area (IRS: risk ratio (RR) 0.61, 95% confidence interval (CI) 0.38 to 0.97, 2892 participants, moderate quality evidence; ITNs: RR 0.32, 95% CI 0.18 to 0.56, 2954 participants, low quality evidence; ITS: RR 0.34, 95% CI 0.20 to 0.57, 2784 participants, low quality evidence). No difference was detected between the three interventions (low quality evidence). One additional trial of ITNs from Iran was underpowered to show a difference.Insecticide treated curtains were compared with no intervention in one RCT from Venezuela, where there were no CL episodes in the intervention areas over 12 months follow‐up compared to 142 in control areas (RR 0.00, 95% CI 0.00 to 0.49, one trial, 2938 participants, low quality evidence).Personal protection using insecticide treated clothing was evaluated by two RCTs in soldiers, but the trials were underpowered to reliably detect effects on the incidence of CL (RR 0.40, 95% CI 0.13 to 1.20, two trials, 558 participants, low quality evidence).Visceral leishmaniasisIn a single RCT of ITNs versus no intervention from India and Nepal, the incidence of VL was low in both groups and no difference was detected (RR 0.99, 95% CI 0.46 to 2.15, one trial, 19,810 participants, moderate quality evidence).Two trials from Brazil evaluated the effects of culling infected dogs compared to no intervention or IRS. Although they report a reduction in seroconversion over 18 months follow‐up, they did not measure or report effects on clinical disease.Authors' conclusionsUsing insecticides to reduce phlebotomine sandfly numbers may be effective at reducing the incidence of CL, but there is insufficient evidence from trials to know whether it is better to spray the internal walls of houses or to treat bednets, curtains, bedsheets or clothing.16 April 2019Update pendingStudies awaiting assessmentThe CIDG is currently examining a new search conducted in April 2019 for potentially relevant studies. These studies have not yet been incorporated into this Cochrane Review. All eligible published studies found in the last search (13 Jan, 2015) were included and one ongoing study was identified (see 'Characteristics of ongoing studies' section).

TDP-43 proteinopathies: pathological identification of brain regions differentiating clinical phenotypes.

The pathological sequestration of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) into cytoplasmic pathological inclusions characterizes the distinct clinical syndromes of amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia, while also co-occurring in a proportion of patients with Alzheimer's disease, suggesting that the regional concentration of TDP-43 pathology has most relevance to specific clinical phenotypes. This has been reflected in the three different pathological staging schemes for TDP-43 pathology in these different clinical syndromes, with none of these staging schemes including a preclinical phase similar to that which has proven beneficial in other neurodegenerative diseases. To apply each of these three staging schemes for TDP-43 pathology, the clinical phenotype must be known undermining the potential predictive value of the pathological examination. The present study set out to test whether a more unified approach could accurately predict clinical phenotypes based solely on the regional presence and severity of TDP-43 pathology. The selection of brain regions of interest was based on key regions routinely sampled for neuropathological assessment under current consensus criteria that have also been used in the three TDP-43 staging schemes. The severity of TDP-43 pathology in these regions of interest was assessed in four clinicopathological phenotypes: amyotrophic lateral sclerosis (n = 27, 47-78 years, 15 males), behavioural variant frontotemporal dementia (n = 15, 49-82 years, seven males), Alzheimer's disease (n = 26, 51-90 years, 11 males) and cognitively normal elderly individuals (n = 17, 80-103 years, nine males). Our results demonstrate that the presence of TDP-43 in the hypoglossal nucleus discriminates patients with amyotrophic lateral sclerosis with an accuracy of 98%. The severity of TDP-43 deposited in the anterior cingulate cortex identifies patients with behavioural variant frontotemporal dementia with an accuracy of 99%. This identification of regional pathology associated with distinct clinical phenotypes suggests key regions on which probabilistic pathological criteria, similar to those currently available for Alzheimer's disease and dementia with Lewy bodies, can be developed for TDP-43 proteinopathies. We propose and validate a simplified probabilistic statement that involves grading the presence of TDP-43 in the hypoglossal nucleus and the severity of TDP-43 in the anterior cingulate for the pathological identification of TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia.

Hypersensitivity to Aspirin and other NSAIDs: Diagnostic Approach in Patients with Chronic Rhinosinusitis.

Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) associated with chronic rhinosinusitis (CRS) and/or asthma comprises a distinct clinical syndrome referred to as NSAIDs exacerbated respiratory disease (NERD). Patients with NERD tend to have more severe course of both upper (CRS and nasal polyps) and lower airway (asthma) diseases and are usually recalcitrant to conventional treatment modalities. Diagnosing and phenotyping of patients with NERD are critical for prevention of drug-induced adverse reactions and open novel options for management of underlying chronic airway inflammatory diseases. Diagnosis of NERD is based on detailed clinical history confirmed by challenge with aspirin, but new diagnostic approaches are currently being developed. This review article focuses on the diagnostic approach to a patient with CRS and hypersensitivity to NSAIDs, emphasizing the importance of diagnosis for proper patient’s management.

JC virus granule cell neuronopathy: A cause of infectious cerebellar degeneration

JC virus (JCV) infection of glial cells can lead to progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. A newly described phenotype of the infection is infection of neurons. This distinct clinical and radiological syndrome is named JCV granule cell neuronopathy, characterized by exclusive or predominant cerebellar atrophy. We report the clinical and radiological longitudinal findings of 5 HIV-infected patients referred to us between September 2004 and November 2011 who exhibited JCV granule cell neuronopathy (4 probable cases and 1 possible). The association of immunocompromised status, progressive cerebellar syndrome, MRI abnormalities with cortical cerebellar atrophy and cerebrospinal fluid positive for JCV on PCR allowed for a highly probable diagnosis. The reversal of the immunocompromised status is the only way to stop the disease evolution. Motor functioning can remain impaired, but the illness itself, unlike progressive multifocal leukoencephalopathy, does not seem to threaten life.

Klebsiella Pneumoniae Liver Abscesses and A Distinct Invasive Syndrome: Case Reports and Review of The Literature

Introduction: Over the past 20 years there has been an increasing awareness of a distinct invasive clinical syndrome caused by Klebsiella pneumoniae in patients from Asian descent. Case presentation: Here we report two cases of invasive K.pneumoniae infection in Asian patients who both presented in Glasgow, UK, with liver abscesses within a 6‐month period. Conclusion: Clinicians should be vigilant for mucoid strains of K. pneumoniae isolated from patients with liver abscesses of Asian descent and thorough in their investigation for metastatic complications.

Nephrology Crossword: Genetics and glomerulopathies

ACROSS 3. Monoclonal antibody used in the treatment of atypical hemolytic uremic syndrome, a disorder caused by mutations in regulatory components of complement system. 5. Protein originally identified in lymphocytes but also critical in slit diaphragm structure and assembly; mutations in encoding gene result in proteinuric renal disease and foot process effacement (abbv). 7. Syndrome of isolated glomerular hematuria caused by mutations in type IV collagen (abbv). 9. First ion channel to be implicated in hereditary nephrotic syndrome and focal segmental glomerulosclerosis (FSGS); mutation results in increased calcium influx, which disrupts podocyte structure and function (abbv). 10. Gene critical for normal embryonic development of the urogenital system and kidneys; mutation results in nephrotic syndrome, urogenital anomalies, and predisposition to urogenital tumors (abbv). 11. Transmembrane protein critical to slit diaphragm structure and podocyte function; mutations in encoding gene cause congenital nephrotic syndrome of Finnish type. 15. Distinct clinical syndrome of hematuria, proteinuria, sensorineural deafness, and ocular abnormality caused by mutations in type 4 collagen family. 16. Gene encoding glomerular basement membrane (GBM) protein laminin b2; mutation results in clinical syndrome of ocular defects (microcoria), neurological abnormalities, and mesangial sclerosis with onset shortly after birth (abbv). 17. Gene identified to confer additional risk for FSGS and glomerulosclerosis from secondary causes in African Americans (abbv). DOWN 1. Mutation in encoded protein __ results in dysregulation of cross-linking of actin filaments in podocyte foot processes and presents as FSGS. 2. Mutation in the encoding gene results in __ enzyme deficiency and accumulation of glycol-sphingolipids, presents as renal failure in the third to sixth decade. 4. Gene critical in dorsoventral patterning of the vertebrae limb; mutations cause nail patella syndrome (abbv). 6. Recently identified mutation that results in hemolytic uremic syndrome without complement activation, suggesting alternate pathophysiological mechanisms1 (abbv). 8. __ deficiency causes abnormalities of lipid metabolism and proteinuric kidney disease with foamy appearance of GBM secondary to lipid deposition (abbv). 12. Hairpin-shaped protein of podocytes; mutation results in malfunction of slit diaphragm and steroid-resistant nephrotic syndrome in children. 13. Mutation in this gene results in defective podocyte development, diffuse mesangial sclerosis, and infantile nephrotic syndrome (abbv). 14. Mutation in this formin gene causes mislocalization of encoded protein, resulting in FSGS in early adolescence to adulthood (abbv). http://www.kidney-international.org m a k e y o u r d i a g n o s i s

Emergence in Taiwan of novel norovirus GII.4 variants causing acute gastroenteritis and intestinal haemorrhage in children

Norovirus is the leading cause of viral gastroenteritis globally. Norovirus genotype GII.4 is responsible for the majority of outbreaks, but new variants are continuously emerging. The objective of the study was to delineate the clinical manifestations and complications associated with these new norovirus GII.4 variants in children. We investigated norovirus infections from the community outbreak in October 2011-September 2012 and an earlier outbreak in 2006-2007, in northern Taiwan. Norovirus genotypes and their variants were validated using molecular methods. A norovirus outbreak started in mid-2011 and continued through 2012 in northern Taiwan. Hospitalized children infected by norovirus in 2012 showed a significantly higher incidence of intestinal haemorrhage, as indicated by grossly bloody faeces (P=0.012) and occult blood in faeces (P < 0.001), and also presented with more high fever >39 °C (P < 0.001), fever >38.5 °C (P < 0.001) and fever of any temperature >38 °C (P < 0.001), compared with children hospitalized in 2006-2007. Analysis of 20 near-full-length genome sequences indicated an emergence of GII.4 2012 variants in 2011-2012. Circulating noroviruses can be divided into two clusters: GII.4 2012a, which is identical to the newly reported strain GII.4 Sydney 2012, and GII.4 2012b, which is close to GII.4 2006b, the earlier predominant strain. The emerging new variants of norovirus GII.4 caused a distinct clinical syndrome of acute gastroenteritis with severe fever and a high rate of intestinal haemorrhage in children. The genetic diversity associated with changing clinical manifestations poses major obstacles to norovirus control.

SPTAN1 encephalopathy: distinct phenotypes and genotypes.

Recent progress in genetic analysis reveals that a significant proportion of cryptogenic epileptic encephalopathies are single-gene disorders. Mutations in numerous genes for early-onset epileptic encephalopathies have been rapidly identified, including in SPTAN1, which encodes α-II spectrin. The aim of this review is to delineate SPTAN1 encephalopathy as a distinct clinical syndrome. To date, a total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified. The major clinical features of SPTAN1 mutations include epileptic encephalopathy with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability. Brainstem and cerebellar atrophy and cerebral hypomyelination, as observed by magnetic resonance imaging, are specific hallmarks of this condition. A milder variant is characterized by generalized epilepsy with pontocerebellar atrophy. Only in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal region lead to dominant negative effects and these specific phenotypes. The last two spectrin repeats are required for α/β spectrin heterodimer associations and the mutations can alter heterodimer formation between the two spectrins. From these data we suggest that SPTAN1 encephalopathy is a distinct clinical syndrome owing to specific SPTAN1 mutations. It is important that this syndrome is recognized by pediatric neurologists to enable proper diagnostic work-up for patients.

Etiologic, phenomenologic, and endophenotypic overlap of schizophrenia and bipolar disorder.

This review examines the history of psychiatric nosology, with particular reference to the nineteenth-century origins of the concepts of manic-depressive illness and schizophrenia as distinct clinical syndromes and their evolution and diagnostic refinement over time. I document how the terminology applied to these entities has generated controversy, and discuss the ways in which the resulting diagnostic entities as defined by pure phenomenological symptom descriptors fail to capture discrete diagnostic distinctions, leading some researchers to posit an illness continuum rather than separate disorders. Furthermore, the two syndromes overlap substantially on multiple biologic measures, and clarity is lacking as to the underlying etiology and pathology necessary to move from descriptions of clinical syndromes to diseases. I next examine how biologically based classifications agnostic to conventional diagnostic schemes may be useful and how these are being implemented in practice, and conclude by summarizing where such approaches are likely to lead.

Clinical features of gastroenteropancreatic tumours.

Gastroenteropancreatic (GEP) endocrine tumours (carcinoids and pancreatic islet cell tumours) are composed of multipotent neuroendocrine cells that exhibit a unique ability to produce, store, and secrete biologically active substances and cause distinct clinical syndromes. The classification of GEP tumours as functioning or non-functioning is based on the presence of symptoms that accompany these syndromes secondary to the secretion of hormones, neuropeptides and/or neurotransmitters (functioning tumours). Non-functioning tumours are considered to be neoplasms of neuroendocrine differentiation that are not associated with obvious symptoms attributed to the hypersecretion of metabolically active substances. However, a number of these tumours are either capable of producing low levels of such substances, which can be detected by immunohistochemistry but are insufficient to cause symptoms related to a clinical syndrome, or alternatively, they may secrete substances that are either metabolically inactive or inappropriately processed. In some cases, GEP tumours are not associated with the production of any hormone or neurotransmitter. Both functioning and non-functioning tumours can also produce symptoms due to mass effects compressing vital surrounding structures. Gastroenteropancreatic tumours are usually classified further according to the anatomic site of origin: foregut (including respiratory tract, thymus, stomach, duodenum, and pancreas), midgut (including small intestine, appendix, and right colon), and hindgut (including transverse colon, sigmoid, and rectum). Within these subgroups the biological and clinical characteristics of the tumours vary considerably, but this classification is still in use because a significant number of previous studies, mainly observational, have used it extensively.

Does aspirin-induced oxidative stress cause asthma exacerbation?

Aspirin-induced asthma (AIA) is a distinct clinical syndrome characterized by severe asthma exacerbations after ingestion of aspirin or other non-steroidal anti-inflammatory drugs. The exact pathomechanism of AIA remains unknown, though ongoing research has shed some light. Recently, more and more attention has been focused on the role of aspirin in the induction of oxidative stress, especially in cancer cell systems. However, it has not excluded the similar action of aspirin in other inflammatory disorders such as asthma. Moreover, increased levels of 8-isoprostanes, reliable biomarkers of oxidative stress in expired breath condensate in steroid-naïve patients with AIA compared to AIA patients treated with steroids and healthy volunteers, has been observed. This review is an attempt to cover aspirin-induced oxidative stress action in AIA and to suggest a possible related pathomechanism.

Highly Elevated IL-18 Is a Reliable Predictor of Progression to Hemophagocytic Syndrome in the Patients with Langerhans Cell Histiocytosis

▪Introduction:Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of epidermal antigen-presenting cells such as dendritic cells (DCs). Historically, three distinct clinical syndromes have been described: eosinophilic granuloma (EG), Hand-Schuller-Christian disease and Letterer-Siwe disease (LSD). The disease has a broad spectrum of clinical behavior, from a mild self-limited form like EG-type LCH to an aggressive form associated with a high mortality rate like LSD-type LCH. Since one of the lethal complications of LCH is hemophagocytic syndrome (HPS), investigating a novel treatment approach for LCH associated HPS (LCH-HPS) is of paramount importance.We have reported the usefulness of cytokine profiles to differentiate HPS from various inflammatory diseases, in which macrophages/monocytes derived cytokines such as interleukin (IL)-18 and neopterin were highly elevated. Since clinical trials using neutralizing antibody to IL-18 in rheumatoid arthritis or plaque psoriasis are now underway, in this study, we examined cytokine profiles over time from six LCH cases and investigated the significance of IL-18 in the pathophysiology of HPS to establish a unique treatment strategy for LCH-HPS.Materials and Methods:The concentrations of serum IL-18 were measured in six patients with LCH, including three patients with EG-type LCH and three with LSD-type LCH. Diagnosis of LCH and HPS were based on clinical and histopathological findings. Serum IL-18 levels were measured by enzyme-linked immunosorbent assay (ELISA). Total RNA was extracted from tumor samples for analysis of IL-18 and LANGERIN mRNA expression. BRAF gene mutation was analyzed using DNA extracted from tumor cells as previously described.Results:Serum IL-18 level of LSD-type LCH was significantly higher than that of EG-type LCH (median 13,600 vs. 449, p<0.05) (Figure 1). In fact, two out of three LSD-type LCH cases developed LCH-HPS, whereas none of the cases with low level of IL-18 developed. When developed to HPS caused by various disorders, serum IL-18 concentrations became markedly increased as shown in Figure 1, suggesting that IL-18 plays a pivotal role in macrophage activation to develop HPS even in LCH. Serum concentration of IL-18 recovered to and maintained normal range after induction chemotherapy. We also observed a dominant increase of soluble tumor necrosis factor alpha-receptor type I (sTNF-RI) and type II (sTNF-RII) in LSD-LCH cases in addition to essential parameters for HPS: IL-18 and neopterin (Figure 2). This unique cytokine profile of LCH-HPS might be the cause of higher mortality rate (20%) compared to HPS caused by various disorders (5-10%).BRAF V600E mutation was detected in one of the three cases in each EG-type LCH and LSD-type LCH, suggesting that existence of BRAF V600E mutation does not correlate to the disease severity as previously reported.As recent studies demonstrated that LCH was originated from DCs, which were close to macrophages/monocytes systems, we hypothesized that LSD-type LCH tumor cells secret IL-18, and then directly initiate macrophage activation to develop HPS. To test this, we assessed IL-18 mRNA expression in tumor cells from LSD-type LCH by RT-PCR. LANGERIN mRNA expression was enhanced from all the LSD-type LCH tumor cells, however IL-18 mRNA did not seem to be derived from tumor cells, suggesting that LSD-type LCH cells themselves would trigger lethal HPS similar to lymphoma associated HPS.Conclusion:In conclusion, though LSD-type LCH tumor cells did not express IL-18 directly, the level of IL-18 was much higher in LSD-type LCH. Paying carful attention should be required to the patients with LSD-type LCH with highly elevated IL-18 to prevent the progression of lethal LCH-HPS. To hamper the macrophage activation, an application of IL-18 antibody may be clinically useful for the disease control of LCH-HPS. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies.

The authors sought to demonstrate that schizophrenia is a heterogeneous group of heritable disorders caused by different genotypic networks that cause distinct clinical syndromes. In a large genome-wide association study of cases with schizophrenia and controls, the authors first identified sets of interacting single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (SNP sets) regardless of clinical status. Second, they examined the risk of schizophrenia for each SNP set and tested replicability in two independent samples. Third, they identified genotypic networks composed of SNP sets sharing SNPs or subjects. Fourth, they identified sets of distinct clinical features that cluster in particular cases (phenotypic sets or clinical syndromes) without regard for their genetic background. Fifth, they tested whether SNP sets were associated with distinct phenotypic sets in a replicable manner across the three studies. The authors identified 42 SNP sets associated with a 70% or greater risk of schizophrenia, and confirmed 34 (81%) or more with similar high risk of schizophrenia in two independent samples. Seventeen networks of SNP sets did not share any SNP or subject. These disjoint genotypic networks were associated with distinct gene products and clinical syndromes (i.e., the schizophrenias) varying in symptoms and severity. Associations between genotypic networks and clinical syndromes were complex, showing multifinality and equifinality. The interactive networks explained the risk of schizophrenia more than the average effects of all SNPs (24%). Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.

Genomic Analysis Yields Link Between Gene Networks, Schizophrenia Types

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessGenomic Analysis Yields Link Between Gene Networks, Schizophrenia TypesMoran MarkMoran MarkSearch for more papers by this authorPublished Online:16 Oct 2014https://doi.org/10.1176/appi.pn.2014.10b7AbstractThe study reveals many pathways to schizophrenia, which converge on eight classes of the disorder.Schizophrenia comprises a group of related disorders that present with distinct clinical syndromes, and those syndromes now appear to be associated with eight separate networks of genetic mutations. That’s the finding from a remarkable genetic analysis titled “Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies” posted September 15 in AJP in Advance. In a large genomewide association study of patients with schizophrenia and controls, researchers with the Molecular Genetics of Schizophrenia Consortium (an international group of researchers) examined single nucleotide polymorphisms (SNPs) that grouped or clustered together and assessed the risk for schizophrenia, comparing the DNA of 4,200 people with schizophrenia with that of 3,800 people without schizophrenia. They also looked at relationships between the SNP clusters and various ways that patients present symptomatically across three separate studies. Claude Robert Cloninger, M.D., says that the study results provide the basis for a reliable diagnostic test for susceptibility to schizophrenia, which may open the door for early detection of risk and intervention.Washington University School of MedicineClaude Robert Cloninger, M.D., of Washington University School of Medicine and an author of the study, explained that the methods used in the study break new ground. “Previous work on the genetics of schizophrenia had been able to measure only the extent to which individual genes contribute to the risk of schizophrenia, but the results have always been inconsistent from study to study and weak,” he said. “These studies were flawed in three major ways—they failed to consider the interactions of genes that have different effects depending on other genes with which they are combined; they failed to distinguish clinical variability among people with schizophrenia, which clinicians know varies widely in severity and symptoms; and they considered average effects of variables in groups of subjects, rather than focusing on what happens in individual people. All these points are critically important to psychiatrists because we treat individuals and need to distinguish the specific features that help us recognize that patients may have different causes of their illness and require different treatments.”Cloninger and colleagues used pattern-recognition techniques from bioinformatics that he said are powerful in identifying the underlying components that are hidden in complex data. They identified 42 SNP sets associated with a 70 percent or greater risk of schizophrenia and confirmed 34 (81 percent) or more in two independent samples. These SNP sets, or genotypic networks, were linked to the different ways that patients present with schizophrenia, yielding eight distinct clinical syndromes varying in symptoms and severity. “We found that these SNPs were markers for distinct sets of genes that influence brain development and neuronal signaling,” Cloninger told Psychiatric News. “Next we observed that the different sets of genes were strongly associated with distinct sets of clinical features. We could group these sets of clinical features into eight classes or subtypes of schizophrenia varying in severity and in combinations of positive and negative symptoms. This led us to conclude that schizophrenia was not one disease but really at least eight distinct disorders associated with different genes and distinct clinical features.“We repeated the analysis in two independent samples with very strong and consistent results in all three,” he said. Cloninger said the results have implications for early identification and possibly for prevention. “Our results provide the basis for a reliable diagnostic test for susceptibility to schizophrenia, which provides an opportunity for early detection of risk and interventions to promote health and well-being by targeting both the genes that are causal and providing experiences that could prevent illness or improve health,” he said. “We found that some genetic pathways increasing susceptibility involved deficient control of healthy brain development, and other pathways involved increased susceptibility to brain injury and toxicity. Regulation of the plasticity of glutamate receptors was important in some classes of schizophrenia and not others.“We are now able to focus on treatments appropriate for specific patients and soon should be able to provide a clinically practical test procedure that measures the genetic risk factors that lead to the diagnosis. That will allow us to tailor treatment to the causes of the disorder in individuals rather than just treat symptoms. Personalized treatment of the causes of illness should lead to stronger treatments with better clinical outcomes.” ■“Uncovering the Hidden Risk Architecture in the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies” can be accessed here. ISSUES NewArchived

Legionella Pneumonia: When to Suspect, Diagnostic Considerations, and Treatment Strategies for Hospital-Based Clinicians

Legionella species are fastidious gram-negative bacteria, ubiquitous in nature and associated with two distinct clinical syndromes: Legionnaire’s disease and Pontiac fever. Legionnaires’ disease is a severe multisystem disease comprised of fevers, rigors, headache, myalgias, dyspnea, delirium, and diarrhea, whereas Pontiac fever is a self-limited influenza-like illness. Either syndrome can occur during outbreaks, but typically only Legionnaires’ disease and pneumonia come to the attention of the emergency room physician or hospitalist. Here we describe an illustrative case of a 70-year-old female with COPD who presented to our hospital with severe Legionnaires’ disease. This article reviews the epidemiology and clinical manifestations of Legionnaires’ disease and updates the latest information on diagnostic approaches and treatment strategies for hospital-based clinicians and emergency department physicians alike.

Normal Cerebellar Metabolism in a Patient with Superficial Siderosis

Normal Cerebellar Metabolism in a Patient with Superficial Siderosis

Treatment of frontotemporal dementia.

Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative diseases with heterogeneous clinical presentations and two predominant types of underlying neuropathology. FTD typically comprises three distinct clinical syndromes: behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent variant primary progressive aphasia (nfvPPA). FTD also frequently overlaps both clinically and neuropathologically with three other neurodegenerative syndromes: corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). Each syndrome can be associated with one or more underlying neuropathological diagnoses and are referred to as frontotemporal lobar degeneration (FTLD). Although the various FTD syndromes can substantially differ in terms of clinical symptoms and underlying pathology, the symptoms can be broadly categorized into behavioral, cognitive and motor domains. Currently there are no Food and Drug Administration (FDA) approved therapies for the above syndromes except riluzole for ALS. FTD treatment strategies generally rely on off-label use of medications for symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. For behavioral symptoms, selective serotonin reuptake inhibitors may be effective, while case reports hint at possible efficacy with antipsychotics or anti-epileptics, but use of these latter agents is limited due to concerns regarding side effects. There are no effective therapies for cognitive complaints in FTD, which frequently involve executive function, memory, and language. Motor difficulties associated with FTD may present with parkinsonian symptoms or motor neuron disease, for which riluzole is indicated as therapy. Compared to idiopathic Parkinson's disease, FTD-related atypical parkinsonism is generally not responsive to dopamine replacement therapies, but a small percentage of patients may experience improvement with a trial of carbidopa-levodopa. Physical and occupational therapy remain an important corner stone of motor symptom management in FTD. Speech therapy may also help patients manage symptoms associated with aphasia, apraxia, and dysarthria. Recent advances in the understanding of FTLD pathophysiology and genetics have led to development of potentially disease-modifying therapies as well as symptomatic therapies aimed at ameliorating social and behavioral deficits.

Early Versus Late Acute Antibody-Mediated Rejection in Thai Kidney Transplant Patients: The Two Distinct Clinical Syndromes.

Background: Acute antibody-mediated rejection (AMR) is the leading cause of early and late renal allograft dysfunction. The purpose of this study was to compare the clinico-pathological features between early and late acute AMR in Thai kidney transplant patients. Method: We examined our kidney transplant recipients for acute AMR demonstrated on biopsy between January 2005 and December 2013. Patients who had glomerulitis and/or peritubular capillaritis were enrolled and stratified by early (≤ 3 months) and late acute AMR (> 3 months after transplantation). Results: Of 64 patients with biopsy-proven acute AMR, 27 cases of early acute AMR were analyzed for associated factors compared with 37 cases of late acute AMR. Early acute AMR was more common in older patients (46.5 ± 10.0 vs. 34.9 ± 9.8; p < 0.001), female recipients (66.7% vs. 32.4%; p = 0.007), deceased donor allografts (70.4% vs. 37.8%; p = 0.01), and highly sensitized patients (74.1% vs. 13.5%; p = 0.01). Non-adherence was observed in 9 cases (24.3%) with late acute AMR whereas none with early acute AMR (p = 0.01). Endothelialitis was more prevalent in early acute AMR (77.8% vs. 10.8%; p < 0.001). Transplant glomerulopathy and interstitial fibrosis/tubular atrophy, the pathological features of chronic changes, were already demonstrated in late acute AMR (70.3% and 13.5%, respectively) but none in early acute AMR (p < 0.001 and 0.05, respectively). Peritubular capillary C4d deposition were commonly revealed in late acute (70.3% vs. 25.9%; p <0.001, respectively). Donor specific antibodies (DSA) were significantly evidenced in late acute AMR (67.6% vs 37%; p = 0.01). Anti-HLA class II (mostly anti-HLA DQ) was more common than class I (62.2% vs 21.6%; p = 0.003) in late acute AMR while anti-HLA class I (mostly anti-HLA A) was more prevalent than class II (29.6% vs 11.1%; p = 0.09) in early acute AMR. The patients with stable graft function at one year after anti-humoral treatment were observed in 21 cases (77.8%) with early acute AMR but only 13 cases (35.1%) with late acute AMR (p = 0.001). Conclusion: Despite similar pathological findings, early and late acute AMR are distinct clinical syndromes. Late acute AMR has worse prognosis than early acute AMR.