Top PDF The developmental cognitive trajectory of the 22Q11 2 deletion

2.1.2 Standard scores versus raw scores in developmental trajectories A child’s raw score on the same test should increase with age. Therefore raw scores are not comparable across different age ranges or different tasks (Baron, 2004; Mervis & Klein-Tasman, 2004). Standard scores, however, are expected to remain relatively stable across an individual’s lifespan from the age of 4-years onwards (Sigelman & Rider, 2006; Weinert & Hany, 2003). Substantial changes in standard scores over time can reveal whether participants have deviated from the normative developmental cognitive trajectory. However, once a deviation is revealed, only raw scores can help explore the underlying cognitive pattern. For example, if standard scores showed that VCI declined over time, raw scores could reveal whether verbal intellectual functions had actually deteriorated with age or development had stagnated and reached a plateau. However,

Our final aim was to determine whether the development of attention subsystems was delayed in any or each NDD relative to the pattern seen in the TD sample. Studies of typical development consistently demonstrate improve- ments in the ability to perform increasingly difficult cog- nitive tests of attention with increasing age [46], generally followed by a period of stabilization [47,87]. For exam- ple, there is evidence that the ability to maintain alertness matures around the age of ten [88], while executive control mechanisms continue to develop throughout adolescence and into early adulthood (for a review see [46]). Using the ANT, the indices of the three attentional subsystems in typical development were found to be stable between the ages of six and ten [47]. For children with NDDs, it was not clear whether cognitive impairments stem from late but normal maturation of the requisite neurocognitive system or from a developmental trajectory that stabilizes at a similar rate but poorer level of achievement, despite exposure to relevant stimuli and ensuing practice to build the cognitive skill in question. If the former were the case, then we expected to uncover age-related improvements in performance akin to early stages of development found in younger TD girls. A lack of a significant age-effect in an attentional index implies that stabilization of the atten- tional index was similarly timed in TD girls and girls with a NDD.

In summary, we have described genetic conditions that can give rise to ASD or PD/LBD depending on their gene dosage, establishing precedence that there are potential converging mechanisms and pathways that play a role both in neurodevelopment and neurodegenerative processes. Partial PARK2 deletions/duplications cause early-onset PD when they lead to complete loss of protein in compound heterozygote or homozygote individuals, whereas heterozygote carriers are found in autism populations, which still express 50% of the Parkin protein, but in these cases lead to haploinsufficiency. On the contrary, expansions of the FMR1 gene >200 CGG repeats leads to a loss of FMRP protein and autism, but the premutation causes PD with the RNA found in foci in the brain of FXTAS cases [116]. The 22q11 deletion can lead to both ASD and PD as a continuous symptom spectrum similar to cases with trisomy 21 and the development of Alzheimer’s disease [136,137]. Lastly, deletions and partial duplications of SNCA gene pinpoint to new critical region for developmental delay and ASD on chromosome 4q22.1. We propose a new model for the SNCA multiplication/deletion region. While overexpression of the SNCA gene has been accepted as causative for PD and related neurodegenerative conditions, we proposed that deletions or partial duplications of the SNCA genomic regions lead to developmental delay and ASD and relevant models could shed light on this connection and mechanisms possible linked through synaptic function and neuronal development.

disadvantage compared to those with a known neuro-disability prior to entering education, although with increased early identification this might be avoided, particularly where parents might respond to differential diagnosis depending on the age at which diagnosis is confirmed (Hallberg et al 2010). As pointed out by Hallberg et al, where children are older at the time of diagnosis parents report a sense of relief and validation of there being an underlying explanation of their child’s developmental progress. This is in contrast to parents of children diagnosed at a younger age where their expectations of their child’s potential is altered.

Met-hemizygosity in 22q11DS is associated with worse prefrontal cognitive functioning, possibly related to in- creased levels of tonic DA and decreased phasic DA re- lease [73, 74]. Alterations in DA function have previously also been implicated to play a role in reward-related dys- function and the development of psychotic symptoms in schizophrenia [3, 7, 75]. Moreover, lower striatal mean D2/3R binding has been found in Met hemizygotes, pos- sibly reflecting higher synaptic DA levels [76]. All in all, these findings may suggest that changes in dopamine function might explain the effect of COMT genotype on reward-related brain activity in frontal and striatal brain regions in 22q11DS. This explanation, however, remains speculative since the mechanism underlying COMT geno- type effects on extracellular DA levels is thought to be far more complex because of the different isoforms and the suggested intracellular location of COMT [14, 77–79] and our methods could not provide information on extracellu- lar DA levels.

A common variant of the human ACE gene provides a tool to determine if ACE activity does influence developmental progress after preterm birth. The presence (insertion, or 'I' allele) rather than the absence (deletion, or 'D' allele) of a 284-base-pair fragment in the human ACE gene is associ- ated with lower ACE activity in organs including both cir- culating inflammatory cells [11] and the circulation itself [12]. Given the likely causal association of pro-inflamma- tory responses, ischaemic-hypoxia, excitotoxic neuro- transmitters, and free radical attack with impaired neuro- outcome; and given the potential role of increased RAS activity in amplifying these effects, we might expect the DD genotype (encoding raised ACE activity) to be associ- ated with poorer neuro-developmental progress after pre- tem birth. Comparable findings have been described with respect to the deterioration of cognitive function in the elderly by some authors [13-15]. We have tested this hypothesis by studying the association of the ACE I/D pol- ymorphism with measures of neuro-developmental progress at 2 and 5 1/2 years of age in children who had participated in a neuro-developmental outcome study (The Avon Premature Infant Project, APIP [16]). All the patients were born at less than 33 weeks postmenstrual age (normal gestation is 37–40 weeks).

what the “true” prevalence of autism “really” is, given that there is no absolute agreement as to what exactly consti- tutes autism. There is superficial consensus that autism is a spectrum disorder (with severe and mild variants at endpoints of a continuum) but even that is contentious, as there are clearly several spectrum disorders within the so- called autism spectrum – at least in part related to the many different etiologies. For instance, some cases of autism are caused by 22q11 deletion syndrome and others are caused by Angelman syndrome, both with their own spectrum of problems within their “specific” phenotypes, and most cases of autism are caused by certain etiological factors, or combinations of etiological factors, all of which can be portrayed as being “spectrum problems.” Nevertheless, with the criteria of the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV), ASD (or “pervasive developmental disorder,” in the terminology of the DSM-IV), and with the implicit criterion that caseness will only be assigned in instances of clinical impairment (usually meaning need for intervention), cases of ASDs are identified in the general population of preschool children at about a rate of 0.6%–0.8%, 4,6,7 in school children and young adults at about

What this means is that the question of how language pathologies may inform the human language faculty in the light of Universal Grammar (UG) and vice versa receives a new twist—and it gives rise to interesting new questions (Tsimpli et al. 2017). Regardless of the outcome of these developments, UG viewed from the perspective of language pathology may open new windows into the human faculty of language as conceived today, independently of whether we assume a full-fledged faculty of language in the traditional sense (‘big UG’), a highly reduced one (‘small UG’), or the distinction between the faculty of language in the broad vs. narrow sense (Hauser et al. 2002)—windows that may not have been available in earlier stages of theoretically informed language re- search. As Tsimpli et al. (2017) put it (see also Grohmann 2017), one primary aim would be to obtain distinctive linguistic profiles regarding, say, lexical and gram- matical abilities and at the same time develop cognitive profiles across a range of genetically and non-genetically different populations who are monolingual, multilingual, or somewhere in between as well as populations with or without co-morbid linguistic and/or cognitive impairments as part of their genotype.

In secondary analyses that examined possible sources of lowered UPSIT scores among affected children, chro- nological age was considered. UPSIT norms are age cor- rected. If a given population is globally delayed with early impulsivity, then younger as compared with older affected children might be expected to perform espe- cially poorly as compared with same-age peers, and group differences might be attributable to markedly low- ered scores among only younger affected children. No age effects were found, however. Olfactory disorder in children with 22q11DS seems to be equally prevalent in younger and older children and therefore is not likely to reflect general developmental delay or impulsive re- sponding among younger children.

Figure 1 Neurodevelopmental model of schizophrenia, informed by new molecular genetic discoveries. One or more transmitted or de novo sequence or structural mutations, involving one or more genes, and acting individually or interactively, is proposed as the initial causal event. The pathway from genotype to phenotype is formulated as a dynamic process beginning at or before conception, and involving gene expression (including, but not limited to, protein activity) and interaction with normal brain development and neuronal plasticity mechanisms, and likely multiple other genetic and non-genetic factors. Different phenotypic endpoints are possible, and specific factors that dictate variable expression of ostensibly the same genetic loading are largely unknown and may be variant-specific. These resulting phenotypes could include clinically diagnosable schizophrenia, other psychiatric illnesses, other conditions including disorders of development, or no detectable expression. For example, a 22q11.2 deletion (yellow structural variant) may be expressed as schizophrenia and/or a related psychiatric disorder and/or another developmental disorder (yellow stars).

As aforementioned, the phenotype of the 22q11DS is highly variable and can affect multiple organs and tissue, but the severity is unrelated to the size of the deletion. However, data suggest that genes within the 1.5 Mb region are crucial for the etiology of the syndrome. It is possible that a small number of genes contribute most of the phenotypic effects, and one or few loci may have a greater phenotypic impact; however, at some level, some form of synergistic interaction between these elements is occurring to substantially increase disease risk. The variability of the cognitive and psychiatric phenotypes of the syndrome may also depend on the presence of additional trans- or cis-acting genetic modifiers. 5,28,58

criteria were the following: pervasive developmental disorder or intelligence quotient of⬍70 and medical disorders that may affect brain function (eg, uncontrolled seizures, head trauma, CNS tu- mor, and infection) or visual performance (eg, blindness). Partic- ipants with an intelligence quotient of ⬍ 70 were excluded to increase the reliability of the clinical data that focus on neuropsy- chiatric presentation and neurocognition. Furthermore, to enable comparison with participants without deletions with psychosis spectrum features, we excluded potential participants with signif- icant intellectual disability.

Recent studies also have focused on the specific contribution of social cogni- tive impairments to the presence of social difficulties in 22q11.2DS [12]. It is well established that both the affective ( i.e. emotion recognition and identification) and cognitive ( i.e. theory of mind (ToM) and perspective taking) dimensions of social cognition are impaired in the syndrome [6] [13]-[19], but see [20]. More- over, trouble recognizing faces and facial expressions have been linked to anomalies in visual form processing [18], as well as to the way patients visually scan faces [21] [22]. Individuals with 22q11.2DS were shown to look less at the eyes and more at the mouth when comparing faces [22] and when identifying facial emotions [21]. They also appear to be slower than typically developing in- dividuals at recognizing dynamic emotional expressions [20] during the phase when an emotion becomes more obvious [23]. These deficits represent impedi- ments to responding to others in a timely manner during interactions. However, despite the detection of these specific cognitive alterations, studies examining the relationship between social cognitive deficits and social functioning have not demonstrated a clear association between the two domains [6] [13] [14], making it difficult to isolate a putative cause of dysfunctional social behaviour.

The neurocognitive profile of 22q11DS is also highly variable, both among individuals and throughout its development. Almost all individuals with 22q11DS cope with the resulting cognitive deficits. Borderline intellectual function (an IQ of 70–75) is the most common intellectual disability in these patients. The mathematic ability is usually weak, but their memory is good. Attention difficulties, visual spatial abnormalities, and impaired executive function are also common. Most children with 22q11DS achieve higher scores in verbal tasks than in non-verbal tasks. In addition, learning difficulties are very common during the preschool and in primary school-aged children. Psychiatric problems related to 22q11DS have also been described in children and adolescents, including attention-deficit/hyperactivity disorders, anxiety disorders, depression, and autism spectrum disorders. 43–46

A chromosome 22q11 deletion was found in 12 (10%) of the 125 patients. The frequency of a chro- mosome 22q11 deletion did not differ significantly between patients with different types of VSD (Table 1). Among the various cardiovascular features ana- lyzed as independent variables, the only ones found to be significantly associated with a chromosome 22q11 deletion after adjustment for multiple compar- isons were abnormal arch laterality (a right aortic arch or double aortic arch) (RR: 7.1; 95% CI: 3.2–16), abnormal aortic arch branching (RR: 13.3; 95% CI: 5.2–34.0), and the inclusive category of aortic arch and/or branch pulmonary artery anomalies (RR: 6.9; 95% CI: 3.6 –13) (Table 2). Of 20 patients with an abnormal aortic arch and/or discontinuous pulmo- nary arteries, 9 (45%) had a chromosome 22q11 de- letion compared with only 3 of the 92 patients (3%) with normal sidedness and branching of the aortic arch and continuous branch pulmonary arteries (arch data were incomplete for the remaining 13 patients).

In all 29 patients, the intracardiac anatomy was normal by echocardiographic or MRI imaging (Fig 2). In 18 patients, the anatomy of the thoracic vessels was also normal (left-sided aortic arch with a normal branching pattern and a single right-sided superior vena cava). In the remaining 11 patients (38%), anomalies of the thoracic vessels were detected. One of these patients was found to have a left-sided su- perior vena cava draining to the coronary sinus, and 10 were diagnosed with congenital anomalies of the aortic arch system (Fig 2, Table 2). A vascular ring (right aortic arch with an aberrant retroesophageal left subclavian artery and left-sided ligamentum ar- teriosum to the left pulmonary artery) was diag- nosed in 3 of the 10 patients with aortic arch anom- alies. These 3 patients had evidence of tracheal compression on MRI. The remaining 7 patients with arch anomalies did not have a vascular ring but had either a right aortic arch with mirror-image branch- ing of the brachiocephalic arteries (N ⫽ 3) or a left aortic arch with an aberrant retroesophageal right subclavian artery (N ⫽ 4). Two of these patients also had a small patent ductus arteriosus not identified previously (1 right-sided and 1 left-sided).

There have been few studies directly examining the properties of the BBB in ASD but a number of studies have recently pointed to alterations in BBB function in these conditions. Genetic screening has identified multiple barrier-related functions for known autism-associated genes, indicating that some autism-associated genes are regulating the BBB to some degree [142]. Soluble forms of endothelial cell markers such as PECAM are lower in children and adults with ASD [143–145]. A subset of children with ASD showed signi fi cantly higher levels of auto- antibodies against brain endothelial cells in their sera compared to neurotypical controls (27% versus 2% respectively), indicating that there may be increased permeability of the BBB in some ASD in- dividuals [146]. The evidence for whether BBB disruption is present in ASD based on molecular markers of increased BBB permeability such as S100B, GFAP, neuron-specific enolase (NSE), myelin basic protein (MBP), and creatine kinase brain isoenzyme (CK-BB) is mixed. One recent study found that S100B, GFAP, and NSE did not differ between ASD and control children but did find that GFAP levels were sig- ni fi cantly higher in ASD individuals and GFAP levels positively corre- lated with scores on the Childhood Autism Rating Scale [147]. Other studies did find significantly increased levels of S100β in serum [148] and in plasma [149] for children with ASD and that this correlated with increased levels of the cytokine tumour necrosis factor-alpha (TNF- α ) [149]. In a neonatal population, there were significantly higher levels Table 1

Organoids generated from iPSCs derived from microcephaly patients with mutations in mitosis-associated genes show dysregulation of the cell division plane, resulting in early depletion of NPCs and smaller organoids (Gabriel et al., 2016; Lancaster et al., 2013; Li et al., 2017a). Deletion of the tumor- suppressor gene PTEN in hPSCs results in over-proliferation and delayed neurogenesis of NPCs in organoids, resulting in abnormally large organoids reminiscent of macrocephalic brains (Li et al., 2017b). In addition to genetic conditions, neurotrophic pathogens affecting brain development can be modeled using brain organoids. For example, exposure of brain organoids to Zika virus results in preferential infection of NPCs, which suppresses proliferation and causes an increase in cell death, ultimately leading to drastically reduced organoid size (Cugola et al., 2016; Dang et al., 2016; Garcez et al., 2016; Qian et al., 2017, 2016). Moreover, such infected cortical organoids display a series of characteristics identified in congenital Zika syndrome, including thinning of the neuronal layer, disruption of apical surface adherens junctions and dilation of the ventricular lumen, offering direct evidence for the causal relationship between embryonic Zika exposure and neurological disorders (Ming et al., 2016; Nguyen et al., 2016; Qian et al., 2017, 2016; Rasmussen et al., 2016; Wen et al., 2017; Zhang et al., 2016). Subsequently, brain organoids have been used as platforms for validating results of compound screening in search of anti-viral drug candidates (Watanabe et al., 2017; Xu et al., 2016; Zhou et al., 2017).

Growth and patterning along the Antero-Posterior (AP) axis appear to be tightly coordinated with the development of the Proximal- Distal (PD) axis, in a process mediated by specific interactions between the AP organizer (the Zone of Polarizing Activity) and the controller of limb outgrowth (the Apical Ectodermal Ridge). Some genes involved in AP patterning have been described but mecha- nisms regarding the molecular and cellular mechanisms that control limb patterning remain to be understood. In order to study AP patterning during limb development we have made a cDNA microarray containing 4.608 genes from a chicken limb library (stages HH20 to HH24). We have hybridized microarray using fluorescence-labeled cDNAs reverse transcribed from mRNAs isolated from anterior and posterior part of limb buds. We have found clones that present statistically different fluorescence inten- sities. By whole mount in situ hybridization we have tested if those genes that are differentially detected in the microarray are differen- tially expressed along the AP axis of the limb bud. The sequence of one of the clones analyzed corresponds to the VEGF-D, that had not been described in chicken before, and is expressed in the posterior part of the limb bud from HH18 to stage 25 and later on is localized in different domains: proximal, distal and posterior. Sonic hedgehog (Shh) gene, located in the posterior limb bud, and retinoic acid (RA) are able to induce limb duplication if misplaced in the anterior part limb bud. RA and Shh beads misplaced in the anterior part of the limb bud induced ectopic expression of VEGF- D in the anterior part of the limb bud suggesting that VEGF-D is downstream of RA and Shh. In order to elucidate VEGF-D function during limb development in situ hybridizations of VEGF receptors types 2 and 3 are being performed. As it has been shown recently in mouse embryos, VEGF-D seems to be very important in lymphangiogenesis.

Detailed analyses of Eph and ephrin gene expression have been performed in zebrafish, Xenopus, mouse, rat and chicken embryos. Just as structure and function is highly conserved, expression is very similar for each homologue, consistent with their role in controlling specific developmental events. Our laboratory has had a long-term interest in EphA3, having isolated human EphA3 from a pre B cell leukaemia (Wicks et al., 1992). Using a human EphA3 probe we isolated a near full length zebrafish EphA3 cDNA. The inferred amino acid sequence of the ligand binding domain is shown in Fig. 1 compared with the same region in human, mouse and chicken. Strikingly, all four sequences are identical at 219/238 residues and the zebrafish sequence shows 94% identity with the human sequence. This sequence similarity, taken together with evidence of functional equivalence in studies of the binding of EphA3 to human and zebrafish ephrin A5 (Oates et al., 1999), imply a critical role for EphA3 during evolution.