Empirical tests of natural selection-based evolutionary accounts of ADHD : a systematic review

Objective ADHD is a prevalent and highly heritable mental disorder associated with significant impairment, morbidity and increased rates of mortality. This combination of high prevalence and high morbidity/mortality seen in ADHD and other mental disorders presents a challenge to natural selection-based models of human evolution. Several hypotheses have been proposed in an attempt to resolve this apparent paradox. The aim of this study was to review the evidence for these hypotheses. Methods We conducted a systematic review of the literature on empirical investigations of natural selection-based evolutionary accounts for ADHD in adherence with the PRISMA guideline. The PubMed, Embase, and PsycINFO databases were screened for relevant publications, by combining search terms covering evolution/selection with search terms covering ADHD. Results The search identified 790 records. Of these, 15 full-text articles were assessed for eligibility, and three were included in the review. Two of these reported on the evolution of the seven-repeat allele of the ADHD-associated dopamine receptor D4 gene, and one reported on the results of a simulation study of the effect of suggested ADHD-traits on group survival. The authors of the three studies interpreted their findings as favouring the notion that ADHD-traits may have been associated with increased fitness during human evolution. However, we argue that none of the three studies really tap into the core symptoms of ADHD, and that their conclusions therefore lack validity for the disorder. Conclusions This review indicates that the natural selection-based accounts of ADHD have not been subjected to empirical test and therefore remain hypothetical

A novel KIF11 mutation in a Turkish patient with microcephaly, lymphedema, and chorioretinal dysplasia from a consanguineous family.

Microcephaly–lymphedema–chorioretinal dysplasia (MLCRD) syndrome is a rare syndrome that was first described in 1992. Characteristic craniofacial features include severe microcephaly, upslanting palpebral fissures, prominent ears, a broad nose, and a long philtrum with a pointed chin. Recently, mutations in KIF11 have been demonstrated to cause dominantly inherited MLCRD syndrome. Herein, we present a patient with MLCRD syndrome whose parents were first cousins. The parents are unaffected, and thus a recessive mode of inheritance for the disorder was considered likely. However, the propositus carries a novel, de novo nonsense mutationinexon2 of KIF11. The patient also had midline cleft tongue which has not previously been described in this syndrome

The Quadratic Gaussian Rate-Distortion Function for Source Uncorrelated Distortions

We characterize the rate-distortion function for zero-mean stationary Gaussian sources under the MSE fidelity criterion and subject to the additional constraint that the distortion is uncorrelated to the input. The solution is given by two equations coupled through a single scalar parameter. This has a structure similar to the well known water-filling solution obtained without the uncorrelated distortion restriction. Our results fully characterize the unique statistics of the optimal distortion. We also show that, for all positive distortions, the minimum achievable rate subject to the uncorrelation constraint is strictly larger than that given by the un-constrained rate-distortion function. This gap increases with the distortion and tends to infinity and zero, respectively, as the distortion tends to zero and infinity.Comment: Revised version, to be presented at the Data Compression Conference 200

Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.

Background: Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George's Hospital. Methods: Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants. Results: Linkage analysis revealed cosegregation of a 16.1 Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. Whole exome sequencing in a single affected individual was undertaken, and the search for the causative variant was focused to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. NVL and GJC2 were sequenced in an additional cohort of individuals with a similar phenotype and non-synonymous variants were found in GJC2 in four additional families. Conclusion: This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery, and suggests that the phenotype produced by GJC2 mutations is predominantly one of 4 limb lymphoedema

Exclusive neuronal expression of SUCLA2 in the human brain

SUCLA2 encodes the ATP-forming subunit (A-SUCL-) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here we show that immunoreactivity of A-SUCL- in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL- immunoreactivity co-localized >99% with that of the d subunit of the mitochondrial F0-F1 ATP synthase. Specificity of the anti-A-SUCL- antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL- immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming subunit (G-SUCL-) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL- immunoreactivity that was however, not upregulated in samples obtained from diabetic versus non-diabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex

Symptom-based screening tool for asthma syndrome among young children in Uganda

Under-diagnosis of asthma in ‘under-fives’ may be alleviated by improved inquiry into disease history. We assessed a questionnaire-based screening tool for asthma among 614 ‘under-fives’ with severe respiratory illness in Uganda. The questionnaire responses were compared to post hoc consensus diagnoses by three pediatricians who were guided by study definitions that were based on medical history, physical examination findings, laboratory and radiological tests, and response to bronchodilators. Children with asthma or bronchiolitis were categorized as “asthma syndrome”. Using this approach, 253 (41.2%) had asthma syndrome. History of and present breathing difficulties and present cough and wheezing was the best performing combination of four questionnaire items [sensitivity 80.8% (95% CI 77.6–84.0); specificity 84.7% (95% CI 81.8–87.6)]. The screening tool for asthma syndrome in ‘under-fives’ may provide a simple, cheap and quick method of identifying children with possible asthma. The validity and reliability of this tool in primary care settings should be tested

Guidelines for initiation of anti-tumour necrosis factor therapy in rheumatoid arthritis: similarities and differences across Europe.

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