NRN1 Gene as a Potential Marker of Early-Onset Schizophrenia: Evidence from Genetic and Neuroimaging Approaches.

Included in the neurotrophins family, the Neuritin 1 gene (NRN1) has emerged as an attractive candidate gene for schizophrenia (SZ) since it has been associated with the risk for the disorder and general cognitive performance. In this work, we aimed to further investigate the association of NRN1 with SZ by exploring its role on age at onset and its brain activity correlates. First, we developed two genetic association analyses using a family-based sample (80 early-onset (EO) trios (offspring onset ≤ 18 years) and 71 adult-onset (AO) trios) and an independent case-control sample (120 healthy subjects (HS), 87 EO and 138 AO patients). Second, we explored the effect of NRN1 on brain activity during a working memory task (N-back task; 39 HS, 39 EO and 39 AO; matched by age, sex and estimated IQ). Different haplotypes encompassing the same three Single Nucleotide Polymorphisms(SNPs, rs3763180-rs10484320-rs4960155) were associated with EO in the two samples (GCT, TCC and GTT). Besides, the GTT haplotype was associated with worse N-back task performance in EO and was linked to an inefficient dorsolateral prefrontal cortex activity in subjects with EO compared to HS. Our results show convergent evidence on the NRN1 association with EO both from genetic and neuroimaging approaches, highlighting the role of neurotrophins in the pathophysiology of SZ.

[Eosinophilic esophagitis. A not so rare clinical case]. / Esofagitis eosinofílica. Un caso clínico no tan raro.

Eosinophilic esophagitis is a chronic disease of multifactorial aetiology locally mediated immune in which the form of presentation varies according to the age of the patient, being mainly signs of esophageal dysfunction. Diagnosis is made by histological criteria and treatment is based on diet and topical corticosteroid therapy and, in the event of stenosis, dilations are performed. An early diagnosis slows down the evolution, reduces complications and improves the prognosis.

Dysbindin-1 gene contributes differentially to early- and adult-onset forms of functional psychosis.

Dysbindin-1 is a relatively ubiquitous protein in the brain which is involved in the modulation of synaptic homeostasis. The dysbindin-1 gene (DTNBP1) has been associated with schizophrenia and bipolar disorder diagnoses. However, its contribution to the severity of the clinical and neurocognitive expression of these disorders remains controversial. We aimed to explore the association between DTNBP1 and the phenotypes which are more directly linked with the underlying biology, such as age at onset and neurocognitive impairment. The present family sample comprised 894 Caucasian individuals: 268 patients affected by functional psychosis [58% with illness onset before 18 years, mean age at onset (SD): 14.71 (2.10)], 483 parents and 143 siblings. Ten DTNBP1 single nucleotide polymorphisms were genotyped in all individuals and their transmission disequilibrium was tested in relation to: (i) the risk for psychosis; (ii) patients' age at onset; and (iii) familial neurocognitive performance (including IQ estimation and executive functioning). In early-onset families a 5-marker haplotype encompassing exons 2-4 and the surrounding introns was significantly over-transmitted to cases, while in adult-onset families two haplotypes corresponding to the region between introns 4 and 7 were over-transmitted to cases. Estimated IQ was associated with the rs760666 marker in the whole sample, whereas a significant association between executive functioning and the rs2619522 marker appeared in early-onset families. Our findings confirm the role of the dysbindin-1 gene in the risk for functional psychosis and show a differential haplotypic risk pattern in families with early as opposed to adult onset in the affected offspring.

Working memory in siblings of schizophrenia patients.

UNLABELLED: Working memory (WM) has hardly been explored in non-psychotic relatives of schizophrenic patients despite its potential suitability as a neurocognitive endophenotype. Indeed, WM modalities, components and processes have rarely been compared in the same group of relatives. The present study examined neurocognitive performance in healthy siblings of schizophrenic patients, including both spatial and verbal WM modalities and tests tapping maintenance (Spatial Span Backwards and CPT-IP d') and manipulative (Letters and Numbers Sequencing) WM processes. METHODS: 68 schizophrenia patients, 38 healthy siblings and 63 controls were assessed on IQ, attention, memory, WM, and executive functions. Cluster A symptoms were screened out in siblings and controls. RESULTS: Siblings had an intermediate performance between that of schizophrenic patients and controls. They performed worse than controls on IQ, LNS, animal naming, backwards spatial span, phonemic fluency, numbers d', and forward spatial span. DISCUSSION: Consistent with the WM literature in schizophrenia, both verbal and spatial WM differed significantly between siblings and controls, suggesting that WM deficits are modality independent. Our results failed to support the hypothesis that tests tapping WM manipulative processes heavily loading on DLFPC are quantitatively more impaired in relatives and, therefore, more sensitive to liability for schizophrenia. However, firm conclusions cannot be drawn until more studies assessing both maintenance and manipulative WM processes in relatives are available.

[Basic symptoms in schizophrenia, their clinical study and relevance in research]. / Síntomas básicos en la esquizofrenia, su estudio clínico y relevancia en investigación.

Basic symptoms consist of subtle sub-clinical disturbances subjectively experienced by schizophrenia patients. These are mainly related to drive, affect, thinking and language, perception, memory, motor action, central vegetative functions, control of cognitive processes, and stress tolerance. Initially described by Huber, from a phenomenological approach, basic symptoms are part of the earliest features of schizophrenia, and they can evolve along the course of the disorder. Their assessment during the prodromal phase of the disease (together with ultra-high risk criteria) is one of the 2 main approaches that allow the definition of states of clinical risk for the development of psychosis. The present review provides an updated view of the concept of basic symptoms, highlighting its potential value in establishing neurobiological correlates of interest in aetiopathogenic research.

Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning.

OBJECTIVES: Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the epistasis between NRN1 and BDNF. METHODS: The study was developed in a sample of 954 SSD/BPD patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one functional SNP in BDNF. RESULTS: The frequency of the haplotype C-C (rs645649-rs582262) was significantly increased in patients compared to controls (P = 0.0043), while the haplotype T-C-C-T-C-A (rs3763180-rs10484320-rs4960155-rs9379002-rs9405890-rs1475157) was more frequent in controls (P = 3.1 × 10(-5)). The variability at NRN1 was nominally related to changes in age at onset and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was significantly associated with the risk for SSD/BPD (P = 0.005). CONCLUSIONS: Results suggest that: (i) NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of BDNF.

Increased familiarity of intellectual deficits in early-onset schizophrenia spectrum disorders.

OBJECTIVES: Early-onset schizophrenia is considered to be neurobiologically similar to adult-onset forms, although it represents a more severe expression of the disorder. In the present study, we explored putative larger familial vulnerability of intellectual impairments in early-onset schizophrenia spectrum disorders (EOS) when compared to adult-onset (AOS) families. METHODS: A sample of 340 subjects including schizophrenia spectrum disorder patients, their first degree relatives and age-matched healthy controls was assessed on intelligence quotient (IQ). We used linear regression analysis and intraclass correlation coefficients (ICC) to explore familial aggregation of IQ across age at onset groups. RESULTS: The relationship between IQ level of patients and their first-degree relatives showed positive linear association (ß = 0.43, P < 0.01). High significant familial aggregation was found for intelligence quotient in EOS families (ICC = 0.618, P < 0.01), while AOS families responded to lower estimates (ICC = 0.204, P = 0.26; between ICC comparison z = 1.993, P < 0.05). CONCLUSIONS: High aggregation of intellectual performance in the EOS group suggests larger familial vulnerability in early-onset forms of the disease when cognitive functions are considered. Within a continuum of psychopathology in schizophrenia spectrum disorders, specific genetic effects are discussed for distinct onset forms that might be in line with a neurodevelopmental model of the disease.