Integrated omics analysis of sweat reveals an aberrant amino acid metabolism pathway in Vogt–Koyanagi–Harada disease

Vogt–Koyanagi–Harada (VKH) disease is an autoimmune disease leading to visual impairment. Its pathogenic mechanisms remain poorly understood. Our purpose was to investigate the distinctive protein and metabolic profiles of sweat in patients with VKH disease. In the present study, proteomics and metabolomics analysis was performed on 60 sweat samples (30 VKH patients and 30 normal controls) using liquid chromatography tandem mass spectrometry. Parallel reaction monitoring (PRM) analysis was used to validate the results of our omics analysis. In total, we were able to detect 716 proteins and 175 metabolites. Among them, 116 proteins (99 decreased and 17 increased) were observed to be significantly different in VKH patients when compared to controls. Twenty-one differentially expressed metabolites were identified in VKH patients, of which 18 included choline, L-tryptophan, betaine and L-serine were reduced, while the rest were increased. Our multi-omics strategy reveals an important role for the amino acid metabolic pathway in the pathogenesis of VKH disease. Significant differences in proteins and metabolites were identified in the sweat of VKH patients and, to some extent, an aberrant amino acid metabolism pathway may be a pathogenic factor in the pathogenesis of VKH disease.     

Bardet–Biedl syndrome

Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, learning difficulties and hypogonadism. Many associated minor features can be helpful in making a diagnosis and are important in the clinical management of BBS. The diagnosis is based on clinical findings and can be confirmed by sequencing of known disease-causing genes in 80% of patients. BBS genes encode proteins that localise to the cilia and basal body and are involved in cilia biogenesis and function. Mutations lead to defective cilia accounting in part for the pleiotropic effects observed in BBS. We provide an overview of BBS including the clinical findings, current understanding of cilia biology, and a practical approach to diagnosis, genetic counselling and up-to-date management.     

Kleine–Levin syndrome

Kleine–Levin syndrome (KLS) is a rare sleep disorder. Most of the published studies have included only small numbers of patients. Therapeutic and diagnostic studies have the lowest evidence level. This study is a retrospective study including 15 KLS patients of the past 19 years. The patients had first symptoms in their early teens triggered by sleep deprivation, infections, and alcohol intake. Frequency ranged from 2–16/year, duration from 1–6 weeks. Liver enzymes, blood count, inflammatory markers, and magnetic resonance images were normal in all patients. Cerebral spinal fluid (CSF) hypocretin-1 was assessed in 6 patients. It was at the lower normal range in 2 patients and <?130 pg/ml in 2 other patients during an asymptomatic phase, while it was low in 2 patients (96–123 pg/ml) and normal in another patient during a symptomatic phase. Treatment with lithium was established in almost all patients and resulted in marked reduction or cessation of symptomatic episodes. The longest observation was 19 years with a relapse after cessation of lithium. Assessment of CSF hypocretin-1 during and outside of a symptomatic phase is recommended in the diagnostic workup of KLS; however, so far only the clinical course is helpful in establishing the diagnosis. Early treatment is recommended and has been found to be effective in the long course of the disease.     

The myeloarchitectonic studies on the human cerebral cortex of the Vogt–Vogt school, and their significance for the interpretation of functional neuroimaging data

The human cerebral cortex contains numerous myelinated fibres, many of which are concentrated in tangentially organized layers and radially oriented bundles. The spatial organization of these fibres is by no means homogeneous throughout the cortex. Local differences in the thickness and compactness of the fibre layers, and in the length and strength of the radial bundles renders it possible to recognize areas with a different myeloarchitecture. The neuroanatomical subdiscipline aimed at the identification and delineation of such areas is known as myeloarchitectonics. There is another, closely related neuroanatomical subdiscipline, named cytoarchitectonics. The aims and scope of this subdiscipline are the same as those of myeloarchitectonics, viz. parcellation. However, this subdiscipline focuses, as its name implies, on the size, shape and arrangement of the neuronal cell bodies in the cortex, rather than on the myelinated fibres. At the beginning of the twentieth century, two young investigators, Oskar and Cécile Vogt founded a centre for brain research, aimed to be devoted to the study of the (cyto + myelo) architecture of the cerebral cortex. The study of the cytoarchitecture was entrusted to their collaborator Korbinian Brodmann, who gained great fame with the creation of a cytoarchitectonic map of the human cerebral cortex. Here, we focus on the myeloarchitectonic studies on the cerebral cortex of the Vogt–Vogt school, because these studies are nearly forgotten in the present attempts to localize functional activations and to interprete findings in modern neuroimaging studies. Following introductory sections on the principles of myeloarchitectonics, and on the achievements of three myeloarchitectonic pioneers who did not belong to the Vogt–Vogt school, the pertinent literature is reviewed in some detail. These studies allow the conclusion that the human neocortex contains about 185 myeloarchitectonic areas, 70 frontal, 6 insular, 30 parietal, 19 occipital, and 60 temporal. It is emphasized that the data available, render it possible to compose a myeloarchitectonic map of the human neocortex, which is at least as reliable as any of the classic architectonic maps. During the realization of their myeloarchitectonic research program, in which numerous able collaborators were involved, the Vogts gradually developed a general concept of the organization of the cerebral cortex. The essence of this concept is that this structure is composed of about 200 distinct, juxtaposed ‘Rindenfelder’ or ‘topistische Einheiten’, which represent fundamental structural as well as functional entities. The second main part of this article is devoted to a discussion and evaluation of this ‘Vogt–Vogt concept’. It is concluded that there is converging quantitative cytoarchitectonic, receptor architectonic, myeloarchitectonic, hodological, and functional evidence, indicating that this concept is essentially correct. The third, and final part of this article deals with the problem of relating particular cortical functions, as determined with neuroimaging techniques, to particular cortical structures. At present, these ‘translation’ operations are generally based on adapted, three-dimensional versions of Brodmann’s famous map. However, it has become increasingly clear that these maps do not provide the neuroanatomical precision to match the considerable degree of functional segregation, suggested by neuroimaging studies. Therefore, we strongly recommend an attempt at combining and synthesizing the results of Brodmann’s cytoarchitectonic analysis, with those of the detailed myeloarchitectonic studies of the Vogt–Vogt school. These studies may also be of interest for the interpretation of the myeloarchitectonic features, visualized in modern in vivo mappings of the human cortex.     

Proprioceptive sensitivity in Ehlers–Danlos syndrome patients

Reaching movements are rapidly adapted following training with rotated visual feedback of the hand. Our laboratory has also found that this visuomotor adaptation results in changes in estimates of felt hand position (proprioceptive recalibration) in the direction of the visuomotor distortion (Cressman and Henriques in J Neurophysiol 102:3505–3518, 2009; Cressman et al. in Exp Brain Res 205:533–544, 2010). In the current study, we investigated proprioceptive acuity and proprioceptive recalibration in a group of individuals with Ehlers–Danlos syndrome (EDS), a degenerative condition associated with collagen malformation. Some studies have suggested that these patients may have proprioceptive impairments, but the exact nature of the impairment is unclear (Rombaut et al. in Clin Rheumatol 29:289–295, 2010a). In this study, we measured the ability of EDS patients to estimate their felt hand position and tested whether these estimates changed following visuomotor adaptation. We found EDS patients were less precise in estimating their felt hand position in the peripheral workspace compared to healthy controls. Despite this poorer sensitivity, they recalibrated hand proprioception to the same extent as healthy controls. This is consistent with other populations who experience proprioceptive deficits (e.g. the elderly, Parkinson’s disease patients), suggesting that sensory noise does not influence the extent of either motor or sensory plasticity.     

Visual depth processing in Williams–Beuren syndrome

Patients with Williams–Beuren Syndrome (WBS, also known as Williams Syndrome) show many problems in motor activities requiring visuo-motor integration, such as walking stairs. We tested to what extent these problems might be related to a deficit in the perception of visual depth or to problems in using this information in guiding movements. Monocular and binocular visual depth perception was tested in 33 patients with WBS. Furthermore, hand movements to a target were recorded in conditions with and without visual feedback of the position of the hand. The WBS group was compared to a group of control subjects. The WBS patients were able to perceive monocular depth cues that require global processing, but about 49% failed to show stereopsis. On average, patients with WBS moved their hand too far when no visual feedback on hand position was given. This was not so when they could see their hand. Patients with WBS are able to derive depth from complex spatial relationships between objects. However, they seem to be impaired in using depth information for guiding their movements when deprived of visual feedback. We conclude that the problems that WBS patients have with tasks such as descending stairs are not due to an inability to judge distance.     

KLLN epigenotype–phenotype associations in Cowden syndrome

Germline KLLN promoter hypermethylation was recently identified as a potential genetic etiology of the cancer predisposition syndrome, Cowden syndrome (CS), when no causal PTEN gene mutation was found. We screened for KLLN promoter methylation in a large prospective series of CS patients and determined the risk of benign and malignant CS features in patients with increased methylation both with and without a PTEN mutation/variant of unknown significance. In all, 1012 CS patients meeting relaxed International Cowden Consortium criteria including 261 PTEN mutation-positive CS patients, 187 PTEN variant-positive CS patients and 564 PTEN mutation-negative CS patients, as well as 111 population controls were assessed for germline KLLN promoter methylation by MassARRAY EpiTYPER analysis. KLLN promoter methylation was analyzed both as a continuous and a dichotomous variable in the calculation of phenotypic risks by stepwise logistic regression and Kaplan–Meier/standardized incidence ratio methods, respectively. Significantly increased KLLN promoter methylation was seen in CS individuals with and without a PTEN mutation/VUS compared with controls (P<0.001). Patients with high KLLN promoter methylation have increased risks of all CS-associated malignancies compared with the general population. Interestingly, KLLN-associated risk of thyroid cancer appears to be gender and PTEN status dependent. KLLN promoter methylation associated with different benign phenotypes dependent on PTEN status. Furthermore, increasing KLLN promoter methylation is associated with a greater phenotype burden in mutation-negative CS patients. Germline promoter hypermethylation of KLLN is associated with particular malignant and benign CS features, which is dependent on the PTEN mutation status.     

Differential diagnosis of Bartter syndrome,Gitelman syndrome,and pseudo–Bartter/Gitelman syndrome based on clinical characteristics

PurposePhenotypic overlap exists among type III Bartter syndrome (BS), Gitelman syndrome (GS), and pseudo-BS/GS (p-BS/GS), which are clinically difficult to distinguish. We aimed to clarify the differences between these diseases, allowing accurate diagnosis based on their clinical features.MethodsA total of 163 patients with genetically defined type III BS (n = 30), GS (n = 90), and p-BS/GS (n = 43) were included. Age at diagnosis, sex, body mass index, estimated glomerular filtration rate, and serum and urine electrolyte concentrations were determined.ResultsPatients with p-BS/GS were significantly older at diagnosis than those with type III BS and GS. Patients with p-BS/GS included a significantly higher percentage of women and had a lower body mass index and estimated glomerular filtration rate than did patients with GS. Although hypomagnesemia and hypocalciuria were predominant biochemical findings in patients with GS, 17 and 23% of patients with type III BS and p-BS/GS, respectively, also showed these abnormalities. Of patients with type III BS, GS, and p-BS/GS, 40, 12, and 63%, respectively, presented with chronic kidney disease.ConclusionsThis study clarified the clinical differences between BS, GS, and p-BS/GS for the first time, which will help clinicians establish differential diagnoses for these three conditions.     

Revertant somatic mosaicism in the Wiskott–Aldrich syndrome

Up to 11% of patients affected with Wiskott–Aldrich syndrome (WAS) have presented with somatic mosaicism due to spontaneous in vivo reversion to normal of the original mutation or second-site compensatory mutations that restored production of the WAS gene product. The reasons underlying the high prevalence of this phenomenon in WAS are unclear and may include strong selective advantage of revertant cells over mutated populations, abnormally high general mutation rate and/or increased susceptibility of specific WAS gene sequences to DNA polymerase errors. Additional studies in human samples and in vitro/in vivo models of the disease will likely yield further insights into the mechanisms responsible for the occurrence of revertant mosaicism in WAS and elucidate additional biological characteristics of the WAS gene and protein.     

Diagnostic and therapeutic management of Churg–Strauss syndrome

Churg–Strauss syndrome is a rare small-vessel vasculitis that is associated with asthma, granulomatous inflammation, peripheral/tissue eosinophilia and a positive antineutrophil cytoplasmic antibody status (in approximately 40% of patients). The disease can be organ- and life-threatening, either due to tissue eosinophil infiltration such as myocarditis or due to vasculitis manifestations, for example glomerulonephritis. Furthermore, life-threatening disease can also occur due to the side effects of immunosuppression, for example, infection. A thorough diagnostic work-up should be performed in order to identify all organs involved and to rule out other disorders with similar features, such as hypereosinophilic syndrome. Therapeutic management is conducted according to disease stage and activity. Glucocorticoids remain the mainstay of therapy; however, further immunosuppressants (e.g., cyclophosphamide for life-threatening disease) are usually required. Future promising therapy options target cytokines involved in the disease process, such as IL-5.