A genetic linkage study in Brazil identifies a new locus for persistent developmental stuttering on chromosome 10

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Visuomotor processing and hand force coordination in dyslexic children during a visually guided manipulation task

Developmental Dyslexia negatively affects children's reading and writing ability and, in most cases, performance in sensorimotor tasks. These deficits have been associated with structural and functional alterations in the cerebellum and the posterior parietal cortex (PPC). Both neural structures are active during visually guided force control and in the coordination of load force (LF) and grip force (GF) during manipulation tasks. Surprisingly, both phenomena have not been investigated in dyslexic children. Therefore, the aim of this study was to compare dyslexic and non-dyslexic children regarding their visuomotor processing ability and GF-LF coordination during a static manipulation task. Thirteen dyslexic (8-14YO) and 13 age- and sex-matched non-dyslexic (control) children participated in the study. They were asked to grasp a fixed instrumented handle using the tip of all digits and pull the handle upward exerting isometric force to match a ramp-and-hold force profile displayed in a computer monitor. Task performance (i.e., visuomotor coordination) was assessed by RMSE calculated in both ramp and hold phases. GF-LF coordination was assessed by the ratio between GF and LF (GF/LF) calculated at both phases and the maximum value of a cross-correlation function (r(max)) and its respective time lag calculated at ramp phase. The results revealed that the RMSE at both phases was larger in dyslexic than in control children. However, we found that GF/LF, rmax, and time lags were similar between groups. Those findings indicate that dyslexic children have a mild deficit in visuomotor processing but preserved GF-LF coordination. Altogether, these findings suggested that dyslexic children could present mild structural and functional alterations in specific PPC or cerebellum areas that are directly related to visuomotor processing. (C) 2014 Elsevier Ltd. All rights reserved.

The phonological and visual basis of developmental dyslexia in Brazilian Portuguese reading children

Evidence from opaque languages suggests that visual attention processing abilities in addition to phonological skills may act as cognitive underpinnings of developmental dyslexia. We explored the role of these two cognitive abilities on reading fluency in Brazilian Portuguese, a more transparent orthography than French or English. Sixty-six children with developmental dyslexia and normal Brazilian Portuguese children participated. They were administered three tasks of phonological skills (phoneme identification, phoneme, and syllable blending) and three visual tasks (a letter global report task and two non-verbal tasks of visual closure and visual constancy). Results show that Brazilian Portuguese children with developmental dyslexia are impaired not only in phonological processing but further in visual processing. The phonological and visual processing abilities significantly and independently contribute to reading fluency in the whole population. Last, different cognitively homogeneous subtypes can be identified in the Brazilian Portuguese population of children with developmental dyslexia. Two subsets of children with developmental dyslexia were identified as having a single cognitive disorder, phonological or visual; another group exhibited a double deficit and a few children showed no visual or phonological disorder. Thus the current findings extend previous data from more opaque orthographies as French and English, in showing the importance of investigating visual processing skills in addition to phonological skills in children with developmental dyslexia whatever their language orthography transparency.

Autism spectrum disorder in a girl with a de novo x;19 balanced translocation

Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with a de novo X;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed a de novo balanced translocation, with the karyotype 46,X,t(X;19)(p21.2;q13.4). Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY). Although abnormal phenotypes associated with de novo balanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process.

Investigation of auditory processing disorder and language impairment using the speech-evoked auditory brainstem response

This study investigated whether there are differences in the Speech-Evoked Auditory Brainstem Response among children with Typical Development (TD), (Central) Auditory Processing Disorder (C) APD, and Language Impairment (LI). The speech-evoked Auditory Brainstem Response was tested in 57 children (ages 6-12). The children were placed into three groups: TD (n = 18), (C)APD (n = 18) and LI (n = 21). Speech-evoked ABR were elicited using the five-formant syllable/da/. Three dimensions were defined for analysis, including timing, harmonics, and pitch. A comparative analysis of the responses between the typical development children and children with (C)APD and LI revealed abnormal encoding of the speech acoustic features that are characteristics of speech perception in children with (C)APD and LI, although the two groups differed in their abnormalities. While the children with (C)APD might had a greater difficulty distinguishing stimuli based on timing cues, the children with LI had the additional difficulty of distinguishing speech harmonics, which are important to the identification of speech sounds. These data suggested that an inefficient representation of crucial components of speech sounds may contribute to the difficulties with language processing found in children with LI. Furthermore, these findings may indicate that the neural processes mediated by the auditory brainstem differ among children with auditory processing and speech-language disorders. (C) 2012 Elsevier B.V. All rights reserved.

A complex chromosomal rearrangement involving chromosomes 2, 5, and X in autism spectrum disorder

Here, we describe a female patient with autism spectrum disorder and dysmorphic features that harbors a complex genetic alteration, involving a de novo balanced translocation t(2;X)(q11;q24), a 5q11 segmental trisomy and a maternally inherited isodisomy on chromosome 5. All the possibly damaging genetic effects of such alterations are discussed. In light of recent findings on ASD genetic causes, the hypothesis that all these alterations might be acting in orchestration and contributing to the phenotype is also considered. (C) 2012 Wiley Periodicals, Inc.

Analysis of Copy Number Variants identifies new candidate genes for Autism Spectrum Disorder and Intellectual Disability

Autism spectrum disorder (ASD) and Intellectual Disability (ID) are complex neuropsychiatric disorders characterized by extensive clinical and genetic heterogeneity and with overlapping risk factors. The aim of my project was to further investigate the role of Copy Numbers Variants (CNVs), identified through genome-wide studies performed by the Autism Geome Project (AGP) and the CHERISH consortium in large cohorts of ASD and ID cases, respectively. Specifically, I focused on four rare genic CNVs, selected on the basis of their impact on interesting ASD/ID candidate genes: a) a compound heterozygous deletion involving CTNNA3, predicted to cause the lack of functional protein; b) a 15q13.3 duplication containing CHRNA7; c) a 2q31.1 microdeletion encompassing KLHL23, SSB and METTL5; d) Lastly, I investigated the putative imprinting regulation of the CADPS2 gene, disrupted by a maternal deletion in two siblings with ASD and ID. This study provides further evidence for the role of CTNNA3, CHRNA7, KLHL23 and CADPS2 as ASD and/or ID susceptibility genes, and highlights that rare genetic variation contributes to disease risk in different ways: some rare mutations, such as those impacting CTNNA3, act in a recessive mode of inheritance, while other CNVs, such as those occurring in the 15q13.3 region, are implicated in multiple developmental and/or neurological disorders possibly interacting with other susceptibility variants elsewhere in the genome. On the other hand, the discovery of a tissue-specific monoallelic expression for the CADPS2 gene, implicates the involvement of epigenetic regulatory mechanisms as risk factors conferring susceptibility to ASD/ID.

Examining The Genetic, Social-Cognitive, And Neural Correlates Of Autism Spectrum Disorder Behaviors In Typically Developing Chi

Autism spectrum disorders (ASD) are pervasive developmental disorders that affect approximately 1 in 50 children (Blumberg et al., 2013). Due to the social nature of the deficits that characterize the disorders, many have classified them as disorders of social cognition, which is the process that individuals use in order to successfully interact with members of their own species (Frith & Frith, 2007). Previous research has typically neglected the spectrum nature of ASD in favor of a more categorical approach of ¿autistic¿ versus ¿non-autistic,¿ but the spectrum requires a more continuous approach. Thus, the present study sought to examine the genetic, social-cognitive, and neural correlates of ASD-like traits as well as the relationship between these dimensions in typically developing children. Parents and children completed several quantitative measures examining several areas of social-cognitive functioning, including theory of mind and social functioning, restricted/repetitive behaviors and interests, and adaptive/maladaptive functioning. Children were also asked to undergo an EEG and both parents and children contributed a saliva sample that was used to sequence four single nucleotide polymorphisms (SNPs) of the OXTR gene, rs1042778, rs53576, rs2254298, and rs237897. We successfully demonstrated a significant relationship between behavioral measures of social-cognition and differences in face perception via the N170. However, the directionality of these relationships varied based on the behavioral measure and particular N170 difference scores. We also found support for the associations between the G_G allelic combination of rs1042778 and the A_A and A_G allelic combinations of rs2254298 and increased ASD-like behavior with decreased social-cognitive functioning. In contrast, our results contradict previous findings with rs237897 and imply that individuals with the A_A and A_G genotypes are less similar to those with ASD and have higher social cognitive functioning than those with the G_G genotype. In conclusion, we have demonstrated the existence of ASD-like traits in typically developing children and have shown a link between behavioral, genetic, and neural correlates of social-cognition. These findings demonstrate the importance of considering autism as a spectrum disorder and provide support for the move to a more continuous approach to neurodevelopmental disorders.

Oculopharyngeal muscular dystrophy - an under-diagnosed disorder?

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant muscle disorder, usually of late onset. OPMD is among the few triplet repeat diseases/ polyalanine (poly(A)) expansion diseases for which the function of the mutated gene is quite well established. The disease is characterised by slowly progressive bilateral ptosis, dysphagia and proximal limb weakness, appearing after the age of 40 years. Prevalence and incidence of OPMD are low, but the disease occurs all over the world. The pedigrees of two Swiss kindred have been previously reported in Switzerland. In the last 2 years, accumulation of newly diagnosed cases in North-West Switzerland have been observed, which suggests that OPMD may be more prevalent than previously thought. Primary care providers, opthalmologists and neurologists that are alert for the almost specific combination of clinical signs, together with the availability of reliable genetic testing may help to recognise currently undiagnosed patients. They can advance knowledge and the characterisation of the OPMD population in Switzerland. Since the number of disorders linked to poly(A) expansions is growing rapidly, the study of OPMD may contribute to the understanding of a large group of other developmental and degenerative diseases. On the basis of a patient with "classical" OPMD, this review summarises the clinical, therapeutic, epidemiological, pathomechanistic and genetic aspects of OPMD, provides practical information about the differential diagnosis of OPMD, and presents a survey of different investigational methods.

A Drosophila XPD model links cell cycle coordination with neuro-development and suggests links to cancer

XPD functions in transcription, DNA repair and in cell cycle control. Mutations in human XPD (also known as ERCC2) mainly cause three clinical phenotypes: xeroderma pigmentosum (XP), Cockayne syndrome (XP/CS) and trichothiodystrophy (TTD), and only XP patients have a high predisposition to developing cancer. Hence, we developed a fly model to obtain novel insights into the defects caused by individual hypomorphic alleles identified in human XP-D patients. This model revealed that the mutations that displayed the greatest in vivo UV sensitivity in Drosophila did not correlate with those that led to tumor formation in humans. Immunoprecipitations followed by targeted quantitative MS/MS analysis showed how different xpd mutations affected the formation or stability of different transcription factor IIH (TFIIH) subcomplexes. The XP mutants most clearly linked to high cancer risk, Xpd R683W and R601L, showed a reduced interaction with the core TFIIH and also an abnormal interaction with the Cdk-activating kinase (CAK) complex. Interestingly, these two XP alleles additionally displayed high levels of chromatin loss and free centrosomes during the rapid nuclear division phase of the Drosophila embryo. Finally, the xpd mutations showing defects in the coordination of cell cycle timing during the Drosophila embryonic divisions correlated with those human mutations that cause the neurodevelopmental abnormalities and developmental growth defects observed in XP/CS and TTD patients.

Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination

BACKGROUND L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood-brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. METHODS AND RESULTS Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4, the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. CONCLUSIONS The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

A Functionalist Perspective on Social Anxiety and Avoidant Personality Disorder

A developmental-evolutionary perspective is used to synthesize basic research from the neurosciences, ethology, genetics, and developmental psychology into a unified framework for understanding the nature and origins of social anxiety and avoidant personality disorder. Evidence is presented that social anxiety disorder (social phobia) and avoidant personality disorder may be alternate conceptualizations of the same disorder because they have virtually the same symptoms and genetic basis, and respond to the same pharmacologic and psychotherapeutic interventions. A functionalist perspective on social anxiety is formulated to (a) explain the origins of normative states of anxiety, (b) outline developmental pathways in the transition from normative anxiety to social anxiety and avoidant personality disorders, and (c) account for the processes leading to gender-differentiated patterns of anxiety-related disorders after puberty.

Elevated pCO2 causes developmental delay in early larval Pacific oysters, Crassostrea gigas

Increasing atmospheric CO2 equilibrates with surface seawater, elevating the concentration of aqueous hydrogen ions. This process, ocean acidification, is a future and contemporary concern for aquatic organisms, causing failures in Pacific oyster (Crassostrea gigas) aquaculture. This experiment determines the effect of elevated pCO2 on the early development of C. gigas larvae from a wild Pacific Northwest population. Adults were collected from Friday Harbor, Washington, USA (48°31.7' N, 12°1.1' W) and spawned in July 2011. Larvae were exposed to Ambient (400 µatm CO2), MidCO2 (700 µatm), or HighCO2 (1,000 µatm). After 24 h, a greater proportion of larvae in the HighCO2 treatment were calcified as compared to Ambient. This unexpected observation is attributed to increased metabolic rate coupled with sufficient energy resources. Oyster larvae raised at HighCO2 showed evidence of a developmental delay by 3 days post-fertilization, which resulted in smaller larvae that were less calcified.

Delineating developmental and metabolic pathways in vivo by expression profiling using the RIKEN set of 18,816 full-length enriched mouse cDNA arrays

We have systematically characterized gene expression patterns in 49 adult and embryonic mouse tissues by using cDNA microarrays with 18,816 mouse cDNAs. Cluster analysis defined sets of genes that were expressed ubiquitously or in similar groups of tissues such as digestive organs and muscle. Clustering of expression profiles was observed in embryonic brain, postnatal cerebellum, and adult olfactory bulb, reflecting similarities in neurogenesis and remodeling. Finally, clustering genes coding for known enzymes into 78 metabolic pathways revealed a surprising coordination of expression within each pathway among different tissues. On the other hand, a more detailed examination of glycolysis revealed tissue-specific differences in profiles of key regulatory enzymes. Thus, by surveying global gene expression by using microarrays with a large number of elements, we provide insights into the commonality and diversity of pathways responsible for the development and maintenance of the mammalian body plan.

Comorbidity Between Major Depression and Alcohol Use Disorder From Adolescence to Adulthood

Background—Limited information exists regarding the long-term development of comorbidity between Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD; abuse/dependence). Using a representative prospective study, we examine multiple aspects pertaining to MDD+AUD comorbidity, with a focus on the relation between disorders across periods (adolescence, early adulthood, adulthood) and cumulative impairments by age 30. Method—816 participants were diagnostically interviewed at ages 16, 17, 24, and 30. Results—Rates of comorbid MDD+AUD were low in adolescence (2%), but increased in early adulthood (10%) and adulthood (7%). Rates of cumulative comorbidity were elevated (21%). Most individuals with a history of MDD or AUD had the other disorder, except for women with MDD. Prospectively, adolescent AUD predicted early adult MDD, while early adult MDD predicted adult AUD. Compared to pure disorders, MDD+AUD was associated with higher risk of alcohol dependence, suicide attempt, lower global functioning, and life dissatisfaction. Conclusions—Lifetime rates of comorbid MDD+AUD were considerably higher than in crosssectional studies. Comorbidity was partly explained by bidirectional and developmentally-specific associations and predicted selected rather than generalized impairments. Clinically, our findings emphasize the need to always carefully assess comorbidity in patients with MDD or AUD, taking into account concurrency and developmental timing.