Loss of Christianson Syndrome Na+/H+ Exchanger 6 (NHE6) Causes Abnormal Endosome Maturation and Trafficking Underlying Lysosome Dysfunction in Neurons

Loss-of-function mutations in endosomal Na⁺/H⁺ exchanger 6 (NHE6) cause the X-linked neurologic disorder Christianson syndrome. Patients exhibit symptoms associated with both neurodevelopmental and neurodegenerative abnormalities. While loss of NHE6 has been shown to overacidify the endosome lumen, and is associated with endolysosome neuropathology, NHE6-mediated mechanisms in endosome trafficking and lysosome function have been understudied. Here, we show that NHE6-null mouse neurons demonstrate worsening lysosome function with time in culture, likely as a result of defective endosome trafficking. NHE6-null neurons exhibit overall reduced lysosomal proteolysis despite overacidification of the endosome and lysosome lumen. Akin to Nhx1 mutants in Saccharomyces cerevisiae, we observe decreased endosome-lysosome fusion in NHE6-null neurons. Also, we find premature activation of pH-dependent cathepsin D (CatD) in endosomes. While active CatD is increased in endosomes, CatD activation and CatD protein levels are reduced in the lysosome. Protein levels of another mannose 6-phosphate receptor (M6PR)-dependent enzyme, β-N-acetylglucosaminidase, were also decreased in lysosomes of NHE6-null neurons. M6PRs accumulate in late endosomes, suggesting defective M6PR recycling and retromer function in NHE6-null neurons. Finally, coincident with decreased endosome-lysosome fusion, using total internal reflection fluorescence, we also find a prominent increase in fusion between endosomal multivesicular bodies and the plasma membrane, indicating enhanced exosome secretion from NHE6-null neurons. In summary, in addition to overacidification of endosomes and lysosomes, loss of NHE6 leads to defects in endosome maturation and trafficking, including enhanced exosome release, contributing to lysosome deficiency and potentially leading to neurodegenerative disease.SIGNIFICANCE STATEMENT Loss-of-function mutations in the endosomal Na⁺/H⁺ exchanger 6 (NHE6) cause Christianson syndrome, an X-linked neurologic disorder. Loss of NHE6 has been shown to overacidify endosomes; however, endosome trafficking mechanisms have been understudied, and the mechanisms leading to neurodegeneration are largely unknown. In NHE6-null mouse neurons in vitro, we find worsening lysosome function with days in culture. Notably, pH-dependent lysosome enzymes, such as cathepsin D, have reduced activity in lysosomes yet increased, precocious activity in endosomes in NHE6-null neurons. Further, endosomes show reduced fusion to lysosomes, and increased fusion to the plasma membrane with increased exosome release. This study identifies new mechanisms involving defective endosome maturation and trafficking that impair lysosome function in Christianson syndrome, likely contributing to neurodegeneration.     

Cognitive phenotype of velocardiofacial syndrome: A review

The behavioural phenotype of velocardiofacial syndrome (VCFS), one of the most common human multiple anomaly syndromes, includes developmental disabilities, frequently including intellectual disability (ID) and high risk of diagnosis of psychotic disorders including schizophrenia. VCFS may offer a model of the relationship between ID and risk of major mental health difficulties. This paper reviews literature on the cognitive phenotype and its relationship with a polymorphism of the gene coding for catechol O-methyltransferase (COMT), a gene haploinsufficient in VCFS which modulates prefrontal dopamine levels. Principal features of the variable cognitive phenotype of VCFS in young people are ID, superiority of verbal over performance I.Q. and verbal over visuospatial memory, and difficulties with number and object magnitude comparisons, time perception and memory for serial order, and orienting of attention. Despite some improvements with age, problems with higher order attentional tasks involving planning persist, possibly modulated by COMT activity levels. Candidate cognitive endophenotypes include problems with retrieval of contextual information from memory and in executive control and focussing of attention. Longitudinal research using common core batteries of psychometric assessments, and experimental measures of cognitive function capable of direct translation for use with animal models, will further advance understanding of the developmental dynamics of VCFS.     

Development of the Children's Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP)

Whereas some scales exist for assessing aggression in typically developing children, they do not give a detailed analysis, and none is available for populations with developmental disabilities (DD). Parents of 365 children with DD completed the Children's Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP), which surveys the severity of aggressive and hostile behaviors (Problem Scale) in addition to their proactive or reactive qualities (the Provocation Scale). Factor analysis yielded a 5-factor solution: I. Verbal Aggression (12 items), II. Bullying (12 items), III. Covert Aggression (11 items), IV. Hostility (9 items), and V. Physical Aggression (8 items). Coefficient alpha ranged from moderate (0.74, Physical Aggression) to high (0.92, Verbal Aggression). General validity was supported by expected differences between age and gender groups. Preliminary normative data were presented. The C-SHARP appears to be a promising tool for assessing aggression and hostility in children with DD.     

SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder

Background: Posttraumatic stress disorder (PTSD) is a common and debilitating mental disorder that occurs following exposure to a traumatic event. However, most individuals do not develop PTSD following even a severe trauma, leading to a search for new variables, such as genetic and other molecular variation, associated with vulnerability and resilience in the face of trauma exposure. Method: We examined whether serotonin transporter (SLC6A4) promoter genotype and methylation status modified the association between number of traumatic events experienced and PTSD in a subset of 100 individuals from the Detroit Neighborhood Health Study. Results: Number of traumatic events was strongly associated with risk of PTSD. Neither SLC6A4 genotype nor methylation status was associated with PTSD in main effects models. However, SLC6A4 methylation levels modified the effect of the number of traumatic events on PTSD after controlling for SLC6A4 genotype. Persons with more traumatic events were at increased risk for PTSD, but only at lower methylation levels. At higher methylation levels, individuals with more traumatic events were protected from this disorder. This interaction was observed whether the outcome was PTSD diagnosis, symptom severity, or number of symptoms. Conclusions: Gene‐specific methylation patterns may offer potential molecular signatures of increased risk for and resilience to PTSD. Depression and Anxiety, 2011. © 2011 Wiley‐Liss, Inc.     

Screening for intellectual disabilities: a validation of the Hayes Ability Screening Index for in-patients with substance use disorder

Background: There is a reason to believe that many individuals with substance use disorder (SUD) in contact with services have an undiagnosed intellectual disability (ID). Assessing ID in persons with SUD can be challenging due to the influence of substances, time consumption, and specific requirements for the education of the assessor. On the other hand, an undiagnosed condition may lead to a lack of treatment adjustment and may result in drop-out from treatment or lack of treatment effect. There is a need for a time-saving, valid instrument to detect possible ID among people with SUD.

Aims: To validate the Hayes Ability Screening Index (HASI) as a screening instrument for identifying ID in a population of in-patients with SUD using all three ICD-10/DSM5 criteria in classifying ID as the validation criterion.

Methods: Eighty-four SUD in-patients aged 19–64 participated in this multicenter study. An ID was diagnosed according to the ICD-10 using WAIS-IV, Vineland II, and self-reported childhood learning difficulties.

Results: HASI correlated well with both the WAIS-IV and Vineland II. At the recommended cut-off score, the HASI had a sensitivity of 100% and a specificity of 65.4%. A large number of the false positives had IQ or both IQ and adaptive scores in the borderline range.

Conclusions: The HASI has good convergent, discriminant, and overall construct validity in detecting ID in in-patients with SUD.     

A process evaluation of the Friendships and Dating Program for adults with developmental disabilities: measuring the fidelity of program delivery

Adults with intellectual and developmental disabilities are frequently abused in dating and partnered relationships. The Friendships and Dating Program (FDP) was developed to prevent violence in dating and partnered relationships and to teach social skills needed to develop healthy, meaningful relationships among this population. A pilot study indicated the FDP resulted in a statistically significant increase in social network size and a significant decrease in instances of interpersonal violence. This study focused on utilizing a Process Evaluation Model (PEM) to document the level of treatment fidelity in the delivery of the 20 session FDP for adults with intellectual and developmental disabilities delivered by community agency personnel. The PEM also documented the amount of content delivered to the participants during each session. Results indicated that direct service personnel delivered the program with a high level of fidelity. Additionally, participants engaged at high rates over the course of the 10-week program. Further, the results indicated the FDP topics and methods of delivery were appropriate for adults with intellectual and developmental disabilities. Programs should use a Process Evaluation Model (PEM) and methods as a routine quality control mechanism to assess provision of salient participant procedures.     

Framework for assessing individuals with rare genetic disorders associated with profound intellectual and multiple disabilities (PIMD): the example of Phelan McDermid Syndrome

Abstract

Background: Specialized strategies are needed to understand the complex neuropsychological impairments reported in individuals with profound intellectual and multiple disabilities (PIMD) associated with rare genetic disorders. Methods: This narrative review focuses on assessment of individuals with Phelan-McDermid Syndrome (PMS) as a condition commonly associated with PIMD. Published case series and prospective studies were reviewed to evaluate approaches to cognitive, language, motor/sensory, and behavioral domains. This review is framed using general principles for neuropsychological evaluation in PIMD. Results: Neuropsychological assessment domains and tools varied across published reports. Adaptive behavior measures, out-of-range developmental assessments, and social-communication measures were commonly used. Available findings were used to shape a recommended framework with potential to improve measurement of clinical outcomes and advance scientific discovery. Conclusions: The recommended framework outlines an inter-disciplinary and multimodal neuropsychological assessment process relying on modified standardized assessments, functional assessments, and caregiver/informant reports when evaluating individuals with PIMD. Arrested development and skill variability/regression are also discussed as additional, important considerations in neuropsychological evaluation of individuals with PIMD and rare genetic disorders.     

Anxiety disorders in children with Williams syndrome, their mothers, and their siblings: Implications for the etiology of anxiety disorders

This study examines the prevalence of anxiety disorders in children with Williams syndrome (WS), their sibling closest in age, and their mothers as well as the predictors of anxiety in these groups. The prevalence of anxiety disorders was assessed and compared to that in the general population. Children with WS had a significantly higher prevalence of specific phobia, generalized anxiety disorder (GAD), and separation anxiety in comparison to children in the general population. While mothers had a higher prevalence of GAD than population controls, the excess was accounted for by mothers who had onset after the birth of their WS child. The siblings had rates similar to the general population. This pattern of findings suggests the presence of a gene in the WS region whose deletion predisposes to anxiety disorders. It is also worthwhile to investigate relations between genes deleted in WS and genes previously implicated in anxiety disorders.     

The French version of the Reiss Screen for Maladaptive Behavior: Factor structure,point prevalence and associated factors

The main aims of the present study were to examine the factor structure and the internal consistency of the factors in the French version of the Reiss Screen of Maladaptive Behavior in a French-speaking European sample. The prevalence of psychopathology and the influence of associated factors were also examined. The Reiss Screen was administered to 467 adults (age range: 18–73) with intellectual disability living in the French-speaking regions of Switzerland and Belgium. A confirmatory factor analysis was performed to replicate the original factor structure. Internal consistency was examined by using Cronbach's alpha. Analyses of variance were computed to study the influence of gender, age and Down syndrome etiology. The original factor structure of the Reiss Screen was replicated. The overall rate of psychopathology in the sample was 37%. No linear relationship between age and psychopathology was found. However, adults aged less than 26 years had lower scores than older adults on several psychopathological domains. Males had higher scores than females on the Autism and the Avoidant Disorder subscales. Participants with Down syndrome had lower scores on all domains, with the exception of the Autism subscale. The results of this study suggest that the French version of the Reiss Screen can be a useful tool to detect psychopathology in adults with intellectual disability.     

Brief Report: High Frequency of Biochemical Markers for Mitochondrial Dysfunction in Autism: No Association with the Mitochondrial Aspartate/Glutamate Carrier SLC25A12 Gene

In the present study we confirm the previously reported high frequency of biochemical markers of mitochondrial dysfunction, namely hyperlactacidemia and increased lactate/pyruvate ratio, in a significant fraction of 210 autistic patients. We further examine the involvement of the mitochondrial aspartate/glutamate carrier gene (SLC25A12) in mitochondrial dysfunction associated with autism. We found no evidence of association of the SLC25A12 gene with lactate and lactate/pyruvate distributions or with autism in 241 nuclear families with one affected individual. We conclude that while mitochondrial dysfunction may be one of the most common medical conditions associated with autism, variation at the SLC25A12 gene does not explain the high frequency of mitochondrial dysfunction markers and is not associated with autism in this sample of autistic patients.     

Association of the STin2 polymorphism of the serotonin transporter gene with a neurocognitive endophenotype in major depressive disorder

BACKGROUND:: The aim of our study was to investigate the association of STin2 polymorphism and cognitive dysfunction in major depression. METHODS:: 71 patients with major depression and 99 controls were genotyped for STin2. All depressive subjects and 30 controls also completed tests measuring neurocognitive performance. RESULTS:: We found a significantly higher frequency of the STin2.10/Stin2.10 homozygous genotype in the depressed group compared to controls. In the depressed group subjects with at least one copy of the 10-repeat allele showed decreased interference threshold in Stroop III compared to patients without the 10-repeat allele. Average performance of the depressed group without the 12-repeat allele was significantly weaker in the Rey Auditory Verbal Learning Test working memory and recall tasks compared to patients having at least one copy of the 12-repeat allele. CONCLUSION:: Our results suggest that the presence of STin2.10 and absence of STin2.12 allele may be related to a possible genetic endophenotype for characteristic cognitive dysfunctions detected in MDD.     

Biomarkers for post thrombotic syndrome: A case-control study

Introduction

There is limited knowledge on the etiology of post thrombotic syndrome (PTS), although several mechanisms have been proposed.The objectives are to explore the role of different pathogenic mechanisms for PTS, through measurement of an elaborate panel of biomarkers in patients with and without PTS.

Materials and Methods

Patients with a history of deep vein thrombosis (DVT) with PTS (cases) and without PTS after minimal 2 years follow-up (controls), were selected from the outpatient clinic of two Dutch hospitals. As a reference to the normal population healthy individuals (HI) without a history of venous thromboembolism were invited to participate. The population consisted of: 26 cases, 27 controls, and 26 HI.A panel of predefined biomarkers was measured in venous blood.

Results

D-dimer showed a decreasing trend from cases to controls to HI; p = 0.010. Thrombin/antithrombin complex levels were significantly higher in cases than in controls; p = 0.032, and HI; p = 0.017. APC-ratio was significantly lower in cases compared to controls; p = 0.032, and HI; p = 0.011. A significant trend of increasing proTAFI from cases, to controls, and HI; p = 0.002 was found. There were no differences in inflammatory markers (CRP, Interleukin-6, Interleukin-8). Thrombomodulin, tissue-plasminogen activator, and von Willebrand factor were higher in patients compared to HI. There was a significant trend of decreasing sVCAM, from cases, to controls, and HI; p = 0.029.

Conclusions

Patients with PTS displayed increased coagulation activity, an altered pattern of fibrinolytic marker expression, and increased endothelial activation. We found no evidence of systemic inflammation in patients with PTS at 63 months since the last DVT.