The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
Schizophrenia (SZ) and autism spectrum disorder (ASD) share deficits in emotion processing. In order to identify convergent and divergent mechanisms, we investigated facial emotion recognition in SZ, high-functioning ASD (HFASD), and typically developed controls (TD). Different degrees of task difficulty and emotion complexity (face, eyes; basic emotions, complex emotions) were used. Two Benton tests were implemented in order to elicit potentially confounding visuo-perceptual functioning and facial processing. Nineteen participants with paranoid SZ, 22 with HFASD and 20 TD were included, aged between 14 and 33years. Individuals with SZ were comparable to TD in all obtained emotion recognition measures, but showed reduced basic visuo-perceptual abilities. The HFASD group was impaired in the recognition of basic and complex emotions compared to both, SZ and TD. When facial identity recognition was adjusted for, group differences remained for the recognition of complex emotions only. Our results suggest that there is a SZ subgroup with predominantly paranoid symptoms that does not show problems in face processing and emotion recognition, but visuo-perceptual impairments. They also confirm the notion of a general facial and emotion recognition deficit in HFASD. No shared emotion recognition deficit was found for paranoid SZ and HFASD, emphasizing the differential cognitive underpinnings of both disorders.
Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.
This study broadly examines executive (EF) and visuo-motor function in 30 adolescent and adult individuals with high-functioning autism spectrum disorder (ASD) in comparison to 28 controls matched for age, gender, and IQ. ASD individuals showed impaired spatial working memory, whereas planning, cognitive flexibility, and inhibition were spared. Pure movement execution during visuo-motor information processing also was intact. In contrast, execution time of reading, naming, and of visuo-motor information processing tasks including a choice component was increased in the ASD group. Results of this study are in line with previous studies reporting only minimal EF difficulties in older individuals with ASD when assessed by computerized tasks. The finding of impaired visuo-motor information processing should be accounted for in further neuropsychological studies in ASD.
Cutaneous and systemic plasmacytosis is a rare disorder observed mainly in Japanese that features an infiltration of mature plasma cells in various organ systems. In addition to the skin, lymph nodes and bone marrow are regularly affected. Laboratory tests show a polyclonal hypergammaglobulinemia. The cutaneous morphology is characterized by red to dark brown macules, papules and plaques a few centimeters in diameter, usually distributed symmetrically on the face, neck and back. Etiology and pathogenesis are not known. It is speculated that a reactive dysfunction of plasma cells may be triggered by various stimuli, such as interleukin 6. Treatment of cutaneous and systemic plasmacytosis is difficult. A standardized treatment concept does not yet exist. Topical corticosteroids and calcineurin inhibitors are mainly used.
Acquired reactive perforating dermatosis is characterized by umbilicated erythematous papules and plaques with firmly adherent crusts. Histopathological examination shows a typical cup-shaped ulceration in the epidermis containing cellular debris and collagen. There is transepidermal elimination of degenerated material with basophilic collagen bundles. The etiology and pathogenesis of acquired reactive perforating dermatosis are unclear. Metabolic disorders and malignancies are associated with this dermatosis. Associated pruritus is regarded as a key pathogenic factor. Constant scratching may cause a repetitive trauma to the skin. This pathogenesis may involve a genetic predisposition. The trauma may lead to degeneration of the collagen bundles. Treatment of acquired reactive perforating dermatosis follows a multimodal approach. Apart from the treating any underlying disease, treatment of pruritus is a major goal. Systemic steroids and retinoids, as well as UVB phototherapy are well-established treatment options. Some patients may also benefit from oral allopurinol.
Lichen planus is characterized by lichenoid, polygonal papules with fine white lines, called Wickham striae. Lesions most commonly occur on the limbs and on the dorsal aspect of the trunk. At the same time often leukoplakia of mucous membranes as well as nail disorders are seen. There are numerous variants of lichen planus which can be distinguished from the classical form on the basis of morphology and distribution of the lesions. The typical primary lesion of lichen planus may be replaced by other forms, such as patches, hyperkeratoses, ulcerations, or bullous lesions. Moreover, distribution patterns of these lesions may vary and include erythrodermic, inverse or linear arrangements. In contrast to these numerous clinical features, histologic findings remain characteristic in the variants, so that the diagnosis can be made securely. Differential diagnoses of lichen planus include diverse dermatoses such as bullous pemphigoid or paronychia.
Congenital malalignment of the big toe nail is based on a lateral deviation of the nail plate. This longitudinal axis shift is due to a deviation of the nail matrix, possibly caused by increased traction of the hypertrophic extensor tendon of the hallux. Congenital malalignment of the big toe nail is typically present at birth. Ingrown toenails and onychogryphosis are among the most common complications. Depending on the degree of deviation, conservative or surgical treatment may be recommended.
Leukemia cutis is an extramedullary manifestation of leukemia. The frequency and age distribution depend on the leukemia subtype. The clinical and morphological findings have a wide range of cutaneous manifestations and may present with nodular lesions and plaques. Rare manifestations include erythematous macules, blisters and ulcers which can each occur alone or in combination. Apart from solitary or grouped lesions, leukemia cutis may also present with an erythematous rash in a polymorphic clinical pattern. Consequently, leukemia cutis has to be distinguished from numerous differential diagnoses, i. e. cutaneous metastases of visceral malignancies, lymphoma, drug eruptions, viral infections, syphilis, ulcers of various origins, and blistering diseases. In the oral mucosa, gingival hyperplasia is the main differential diagnosis. The knowledge of the clinical morphology is of tremendously importance in cases in which leukemia was not yet known.
Elastolysis mediodermalis is a rare disorder typically observed in middle-aged women. Sites of predilection are the trunk and upper arms. The clinical picture varies and may appear as cigarette paper-like wrinkling, perifollicular protrusions or reticular erythema. In contrast to the different clinical morphology, there is a consistent histology, i. e. localized, band-shaped, and rarely focal loss of elastic fibers in the middle dermis. The etiology of elastolysis mediodermalis is unclear. UV radiation or immunological mechanisms may increase the release of matrix metalloproteinases, leading to a degradation of elastic fibers. There is no effective treatment for this condition.
The article on chondrodermatitis nodularis chronica helicis summarizes various clinical pictures and differential diagnoses of this entity. This lesion is usually characterized by a solid or cystic nodule but ulcerations or crusts may also occur. The most common differential diagnoses include benign or malignant tumours, which are often confused with chondrodermatitis nodularis chronica helicis. The characteristic pain associated with this condition may serve as an important diagnostic clue in order to rule out other differential diagnoses. The therapy of chondrodermatitis nodularis chronica helices encompasses several conservative as well as surgical treatment options.
Extramammary Paget disease is a rare malignant neoplasm. With regard to the pathogenesis, two prognostically different forms can be distinguished. The primary form of extramammary Paget disease is an in situ carcinoma of the apocrine gland ducts. In contrast, the secondary form is characterized by an intraepithelial spread due to an underlying carcinoma of the skin or other organ systems. Extramammary Paget disease occurs in older patients. The predilection sites include the entire anogenital skin and less often the axillary region. We present five different patients with this disease, thereby demonstrating its variation in clinical morphology. The lesion usually presents as an erythematous sharply defined spot. The polygonal borders, caused by the centrifugal growth of the tumor, may provide a diagnostic clue. The treatment of choice for extramammary Paget disease remains Mohs microscopic surgery. However, radiotherapy or topical applications may be alternative treatment options in selected cases. In patients with the secondary form of extramam-mary Paget disease, treatment of the primary tumor is the main approach.
Inflammatory liver disorders are often associated with a potentially tissue damaging complement activation directly at the main site of complement protein synthesis. As hepatocytes may be the primary target of complement attack, we investigated the expression and protective capacity of soluble and membrane-bound complement regulatory proteins in primary human hepatocytes (PHH). Isolated PHHs were analyzed for their basal and cytokine-induced complement regulator expression by cytofluorometry, rtPCR, confocal laser microscopy and ELISA. Susceptibility to complement-mediated cell lysis was investigated with cytotoxicity tests. In contrast to previous reports, PHHs expressed CD46, CD55, CD59, soluble CD59 (sCD59) and factor H (fH), but not CD35. A low basal expression of CD55 was strongly enhanced by IFN-gamma, IL-1 beta and TNF-alpha. The expression of CD59 could be augmented by IL-1 beta, IL-6 and TNF-alpha but was suppressed by IFN-gamma. CD46 expression was not significantly altered. PHHs synthesized fH and sCD59 and fH was detected on PHH surface after exposure to IL-1 beta. Inhibition experiments revealed that CD59 was most effective in protecting PHHs from complement attack. These data clearly indicate that PHHs are protected by multiple complement regulatory proteins, which are controlled by proinflammatory cytokines. CD59 appears to be pivotal in protecting PHHs against complement-mediated lysis.
According to DSM-IV TR and ICD-10, a diagnosis of autism or Asperger Syndrome precludes a diagnosis of attention-deficit/hyperactivity disorder (ADHD). However, despite the different conceptualization, population-based twin studies reported symptom overlap, and a recent epidemiologically based study reported a high rate of ADHD in autism and autism spectrum disorders (ASD). In the planned revision of the DSM-IV TR, dsm5 (www.dsm5.org), the diagnoses of autistic disorder and ADHD will not be mutually exclusive any longer. This provides the basis of more differentiated studies on overlap and distinction between both disorders. This review presents data on comorbidity rates and symptom overlap and discusses common and disorder-specific risk factors, including recent proteomic studies. Neuropsychological findings in the areas of attention, reward processing, and social cognition are then compared between both disorders, as these cognitive abilities show overlapping as well as specific impairment for one of both disorders. In addition, selective brain imaging findings are reported. Therapeutic options are summarized, and new approaches are discussed. The review concludes with a prospectus on open questions for research and clinical practice.
Ramsay Hunt syndrome is defined as herpes zoster oticus associated with an acute peripheral facial nerve paresis and quite often with other cranial nerve lesions. The combination of motor, sensory and autonomic involvement leads to a variety of neurological damage patterns, i. e. facial muscle paresis, hearing and balance disorders, sensory problems and disturbances of taste as well as lacrimal and nasal secretion. Additional variability of the clinical picture of Ramsay Hunt syndrome is produced by varying patterns of skin involvement explained by individual anastomoses between cranial and cervical nerves. Knowledge of these findings and an early diagnosis of Ramsay Hunt syndrome are important as prognosis of cranial nerve damage depends on the time at which acyclovir-corticosteroid therapy is started.
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