Cognition and Behaviour in Sotos Syndrome: A Systematic Review

Background

Research investigating cognition and behaviour in Sotos syndrome has been sporadic and to date, there is no published overview of study findings.

Method

A systematic review of all published literature (1964–2015) presenting empirical data on cognition and behaviour in Sotos syndrome. Thirty four journal articles met inclusion criteria. Within this literature, data relating to cognition and/or behaviour in 247 individuals with a diagnosis of Sotos syndrome were reported. Ten papers reported group data on cognition and/or behaviour. The remaining papers employed a case study design.

Results

Intelligence quotient (IQ) scores were reported in twenty five studies. Intellectual disability (IQ < 70) or borderline intellectual functioning (IQ 70–84) was present in the vast majority of individuals with Sotos syndrome. Seven studies reported performance on subscales of intelligence tests. Data from these studies indicate that verbal IQ scores are consistently higher than performance IQ scores. Fourteen papers provided data on behavioural features of individuals with Sotos syndrome. Key themes that emerged in the behavioural literature were overlap with ASD, ADHD, anxiety and high prevalence of aggression/tantrums.

Conclusion

Although a range of studies have provided insight into cognition and behaviour in Sotos syndrome, specific profiles have not yet been fully specified. Recommendations for future research are provided.     

APLF (C2orf13) facilitates nonhomologous end-joining and undergoes ATM-dependent hyperphosphorylation following ionizing radiation

Nonhomologous end-joining (NHEJ) is the major mammalian DNA double-strand break (DSB) repair pathway of DSBs induced by DNA damaging agents. NHEJ is initiated by the recognition of DSBs by the DNA end-binding heterodimer, Ku, and the final step of DNA end-joining is accomplished by the XRCC4-DNA ligase IV complex. We demonstrate that Aprataxin and PNK-like factor (APLF), an endo/exonuclease with an FHA domain and unique zinc fingers (ZFs), interacts with both Ku and XRCC4-DNA ligase IV in human cells. The interaction of APLF with XRCC4-DNA ligase IV is FHA- and phospho-dependent, and is mediated by CK2 phosphorylation of XRCC4 in vitro. In contrast, APLF associates with Ku independently of the FHA and ZF domains, and APLF complexes with Ku at DNA ends. APLF undergoes ionizing radiation (IR) induced ATM-dependent hyperphosphorylation at serine residue 116, which is highly conserved across mammalian APLF homologues. We demonstrate further that depletion of APLF in human cells by siRNA is associated with impaired NHEJ. Collectively, these results suggest that APLF is an ATM target that is involved in NHEJ and facilitates DSB repair, likely via interactions with Ku and XRCC4-DNA ligase IV.     

Factors associated with elevated ALT in an international HIV/HBV co-infected cohort on long-term HAART

Background

Previous studies have demonstrated that hepatitis B virus (HBV) infection increases the risk for ALT elevations in HIV-HBV co-infected patients during the first year of HAART; however, there is limited data on the prevalence of ALT elevations with prolonged HAART in this patient group.

Methods/Principal findings

To identify factors associated with ALT elevations in an HIV-HBV co-infected cohort receiving prolonged HAART, data from 143 co-infected patients on HAART enrolled in an international HIV-HBV co-infected cohort where ALT measurements were obtained every 6 months was analysed. A person-visit analysis was used to determine frequency of ALT elevation (≥2.5×ULN) at each visit. Factors associated with ALT elevation were determined using multivariate logistic regression with generalized estimating equations to account for correlated data. The median time on HAART at the end of follow-up was 5.6 years (range 0.4–13.3) years. During follow-up, median ALT was 36 U/L with 10.6% of person-visits classified as having ALT elevation. Most ALT elevations were grade 2 (86.5%), with only 13.5% of all ALT elevations grade 3 or higher. Univariate associations with ALT elevation (p<0.05) included history of AIDS, HBV DNA ≥2,000 IU/ml, HBeAg positive, study visit CD4 <200 cells/ml and nadir CD4 <200 cells/ml. In the multivariate analysis, only study visit CD4 <200 cells/ml (OR 2.07, 95%CI 1.04–4.11, p = 0.04) and HBeAg positive status (OR 2.22, 95%CI 1.03–4.79, p = 0.04) were independently associated with ALT elevation.

Conclusions

In this HIV-HBV co-infected cohort, elevated ALT after >1 year of HAART was uncommon, and severe ALT elevations were rare. HIV-HBV co-infected patients on long-term HAART who are either HBeAg positive or have a CD4 count of <200 cells/ml are at increased risk for ALT elevations.     

Proteomic analysis of lipid raft-enriched membranes isolated from internal organelles

The mitochondria-associated membrane (MAM) is a sub-region of the endoplasmic reticulum (ER) that facilitates crosstalk between the ER and mitochondria. The MAM actively influences vital cellular processes including Ca²⁺ signaling and protein folding. Detergent-resistant microdomains (DRMs) may localize proteins to the mitochondria/MAM interface to coordinate these events. However, the protein composition of DRMs isolated from this region is not known. Lipid-raft enriched DRMs were isolated from a combined mitochondria/MAM sample and analyzed using two-dimensional reversed-phased tandem mass spectrometry. Strict post-acquisition filtering of the acquired data led to the confident identification 250 DRM proteins. The majority (58%) of the identified proteins are bona fide mitochondrial or ER proteins according to Gene Ontology annotation. Additionally, 74% of the proteins have previously been noted as MAM-resident or -associated proteins. Furthermore, ∼20% of the identified proteins have a documented association with lipid rafts. Most importantly, known internal LR marker proteins (inositol 1,4,5-trisphosphate receptor type 3, erlin-2, and voltage-dependent anion channel 1) were detected as well as most of the components of the mitochondrial/MAM-localized Ca²⁺ signaling complex. Our study provides the basis for future work probing how the protein activities at the mitochondrion/MAM interface are dependent upon the integrity of these internal lipid-raft-like domains.     

FANCM-associated proteins MHF1 and MHF2, but not the other Fanconi anemia factors,limit meiotic crossovers

Genetic recombination is important for generating diversity and to ensure faithful segregation of chromosomes at meiosis. However, few crossovers (COs) are formed per meiosis despite an excess of DNA double-strand break precursors. This reflects the existence of active mechanisms that limit CO formation. We previously showed that AtFANCM is a meiotic anti-CO factor. The same genetic screen now identified AtMHF2 as another player of the same anti-CO pathway. FANCM and MHF2 are both Fanconi Anemia (FA) associated proteins, prompting us to test the other FA genes conserved in Arabidopsis for a role in CO control at meiosis. This revealed that among the FA proteins tested, only FANCM and its two DNA-binding co-factors MHF1 and MHF2 limit CO formation at meiosis.     

The p38 Pathway Regulates Oxidative Stress Tolerance by Phosphorylation of Mitochondrial Protein IscU

The p38 pathway is an evolutionarily conserved signaling pathway that responds to a variety of stresses. However, the underlying mechanisms are largely unknown. In the present study, we demonstrate that p38b is a major p38 MAPK involved in the regulation of oxidative stress tolerance in addition to p38a and p38c in Drosophila. We further show the importance of MK2 as a p38-activated downstream kinase in resistance to oxidative stresses. Furthermore, we identified the iron-sulfur cluster scaffold protein IscU as a new substrate of MK2 both in Drosophila cells and in mammalian cells. These results imply a new mechanistic connection between the p38 pathway and mitochondria iron-sulfur clusters.     

Determinants of Mortality and Loss to Follow-Up among Adults Enrolled in HIV Care Services in Rwanda

Background

Antiretroviral therapy (ART) improves morbidity and mortality in patients with HIV, however high rates of loss to follow-up (LTF) and mortality have been documented in HIV care and treatment programs.

Methods

We analyzed routinely-collected data on HIV-infected patients ≥15 years enrolled at 41 healthcare facilities in Rwanda from 2005 to 2010. LTF was defined as not attending clinic in the last 12 months for pre-ART patients and 6 months for ART patients. For the pre-ART period, sub-distribution hazards models were constructed to estimate LTF and death to account for competing risks. Kaplan-Meier (KM) and Cox proportional hazards models were used for patients on ART.

Results

31,033 ART-naïve adults were included, 64% were female and 75% were WHO stage I or II at enrollment. 17,569 (56%) patients initiated ART. Pre-ART competing risk estimates of LTF at 2 years was 11.2% (95%CI, 10.9–11.6%) and 2.9% for death (95%CI 2.7–3.1%). Among pre-ART patients, male gender was associated with higher LTF (adjusted sub-hazard ratio (aSHR) 1.3, 95%CI 1.1–1.5) and death (aSHR 1.7, 95%CI 1.4–2.1). Low CD4 count (CD4<100 vs. ≥350 aSHR 0.2, 95%CI 0.1–0.3) and higher WHO stage (WHO stage IV vs. stage I aSHR 0.4, 95%CI 0.2–0.6) were protective against pre-ART LTF. KM estimates for LTF and death in ART patients at 2 years were 4.4% (95%CI 4.4–4.5%) and 6.3% (95%CI 6.2–6.4%). In patients on ART, male gender was associated with LTF (adjusted hazard ratio (AHR) 1.4, 95%CI 1.2–1.7) and death (AHR1.3, 95%CI 1.2–1.5). Mortality was higher for ART patients ≥40 years and in those with lower CD4 count at ART initiation.

Conclusions

Low rates of LTF and death were founds among pre-ART and ART patients in Rwanda but greater efforts are needed to retain patients in care prior to ART initiation, particularly among those who are healthy at enrollment.