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Specific Learning Disabilities (SLD) are often associated with emotional-behavioral problems. Many studies highlighted a greater psychopathological risk in SLD, describing both internalizing and externalizing problems. The aims of this study were to investigate the emotional-behavioral phenotype through the Child Behavior Checklist (CBCL), and evaluate the mediating role of background and cognitive characteristics on the relationship between CBCL profile and learning impairment in children and adolescents with SLD. One hundred and twenty-one SLD subjects (7–18 years) were recruited. Cognitive and academic skills were assessed, and parents completed the questionnaire CBCL 6–18. The results showed that about half of the subjects manifested emotional-behavioral problems with a prevalence of internalizing symptoms, such as anxiety and depression, over externalizing ones. Older children showed greater internalizing problems than younger ones. Males have greater externalizing problems compared to females. A mediation model analysis revealed that learning impairment is directly predicted by age and familiarity for neurodevelopmental disorders and indirectly via the mediation of the WISC-IV/WAIS-IV Working Memory Index (WMI) by the CBCL Rule-Breaking Behavior scale. This study stresses the need to combine the learning and neuropsychological assessment with a psychopathological evaluation of children and adolescents with SLD and provides new interpretative insights on the complex interaction between cognitive, learning, and emotional-behavioral phenotypes.

Developmental language disorder (DLD) is a neurodevelopmental condition, occurring in about 3% to 7% of preschoolers, that can impair communication and negatively impact educational and social attainments, in spite of adequate neurological, cognitive, emotional, social development, and educational opportunities for language learning. Significant risk factors for DLD are male sex, familial history of early language delay, low parental education, and various perinatal factors. A strong sex effect with a higher prevalence of language delay and DLD in males than in females has been consistently reported. Neurobiological and environmental risk factors, interacting with each other, are probably responsible for the phenotypic expression of DLD. The aim of this brief review is to further the knowledge of the role of sex in early language delay and DLD by analyzing the evidence from four significant sources: epidemiological studies, studies on twins, family aggregation studies, and studies on sex chromosome trisomies. Data pertaining only to sex differences (biological and physiological characteristics of females and males) will be analyzed. Studies on family aggregations and twins confirm the role of genetic factors and of sex in determining language abilities and disabilities, but genes alone do not determine outcomes. Sex chromosome trisomies represent a unique example of the relationship between a genetic alteration and a language disorder. Clarification of how sex acts in determining DLD could provide new information on early risk factors and, thus, contribute to improve diagnosis and clinical management.

Childhood apraxia of speech (CAS) is a motor speech disorder often co-occurring with language impairment and complex neurodevelopmental disorders. A cohort of 106 children with CAS associated to other neurodevelopmental disorders underwent a multidimensional investigation of speech and language profiles, chromosome microarray analysis and structural brain magnetic resonance (MR). Our aim was to compare the clinical profiles of children with CAS co-occurring with only language impairment with those who, in addition to language impairment, had other neurodevelopmental disorders. Expressive grammar was impaired in the majority of the sample in the context of similar alterations of speech, typical of the core symptoms of CAS. Moreover, children with complex comorbidities also showed more severe and persistent receptive language deficits. About 25% of the participants harbored copy number variations (CNVs) already described in association to neurodevelopmental disorders. CNVs occurred more frequently in children with complex comorbidities. MR structural/signal alterations were found in a small number of children and were of uncertain pathogenic significance. These results confirm that CAS needs multidimensional diagnostic and clinical management. The high frequency of language impairment has important implications for early care and demands a personalized treatment approach in which speech and language goals are consistently integrated.

Background In spite of the large literature on Late Talkers (LTs) it’s still unclear which factors predict outcome in children younger than 3 years old. Aims To identify the early language characteristics of LTs whose outcome was either a transient delay or a Developmental Language Disorder (DLD). Methods and procedures 50 LTs were assessed both by indirect and direct measures of expressive and receptive language at three time points between 2 and 4 years of age. Outcomes and results At the first evaluation, all LTs had an expressive language delay; 61% also had delayed early syntactic comprehension. Three different linguistic outcomes emerged: children who caught up with their peers (“Late Bloomers”) at age 3; children with slow language recovery (“Slow Learners”) at age 4 and children at risk of DLD. The linguistic measures that differentiated the groups changed with age. By 28 months, impaired syntactic comprehension differentiated children at risk of DLD at 4 years of age, from the other two groups. By 36 months, the discrepancy between vocabulary size and age was larger in children with persistent language difficulties compared to both “Late Bloomers” and “Slow Learners". Expressive grammar differentiated the groups significantly by age 3 with difficulties in this domain still persisting in children with DLD at age 4. Conclusions An early syntactic comprehension delay was a predictive index of DLD in LTs, suggesting the importance of evaluating this language component when assessing LT toddlers. Implications LTs with receptive-expressive language delay around 24–30 months could benefit from an early language intervention.

Childhood Apraxia of Speech is a severe and persistent clinical subtype of Speech Sound Disorder. Given the difficulties in the acquisition, programming and control of the movements underlying speech and the slowdown in a wide range of non-linguistic skills, the difficulty in implicit learning of sequential information could play a role in the disorder, contributing to understand its etiopathological mechanisms and behavioral manifestations.The present study was aimed at investigating implicit learning in children with Childhood Apraxia of Speech.Twenty-five children with Childhood Apraxia of Speech, aged between 4 and 12 years, were matched for IQ and age to a control group of 25 typically developing children. Implicit learning of participants was assessed by Serial Reaction Time Task.Children with Childhood Apraxia of Speech did not show implicit learning, as documented by the absence of differences between reaction times in the sequenced block and the random block, usually considered as a measure of implicit learning effect.Our results underline an implicit learning deficit in children with Childhood Apraxia of Speech, supporting the concept of a disorder not only confined to the speech domain, but also involving non-linguistic skills, in a composite and complex picture.

Aminoacylase 1 deficiency (ACY1D) is a rare inborn error of metabolism characterized by increased urinary excretion of N-acetylated amino acids. Clinical phenotypes of 15 known patients with ACY1 deficiency have been described up to now. Findings are greatly variable, ranging from normality to relevant neurological and psychiatric impairments, but clinical follow up has been rarely reported. To partially fill this gap, we present a detailed clinical description and the outcome four years post-diagnosis of a patient already described, with mild intellectual disability, language delay, autistic traits and compound heterozygous mutations in ACY1.

Background Arginine:glycine amidinotransferase deficiency (AGAT-d) is a very rare inborn error of creatine synthesis mainly characterized by absence of brain Creatine (Cr) peak, intellectual disability, severe language impairment and behavioural disorder and susceptible to supplementary Cr treatment per os. Serial examinations by magnetic resonance spectroscopy are required to evaluate Cr recovery in brain during treatment of high doses of Cr per os, which have been proved beneficial and effective in treating main clinical symptoms. A long term study with detailed reports on clinical, neurochemical and neuropsychological outcomes of the first Italian patients affected by AGAT-d here reported can represent a landmark in management of this disorder thus enhancing medical knowledge and clinical practice. Results We have evaluated the long term effects of Cr supplementation management in four Italian patients affected by AGAT-d, correlating specific treatments with serial clinical, biochemical and magnetic resonance spectroscopy examinations as well as the neuropsychological outcome by standardized developmental scales. Consecutive MRS examinations have confirmed that Cr depletion in AGAT-d patients is reversible under Cr supplementation. Cr treatment is considered safe and well tolerated but side effects, including weight gain and kidney stones, have been reported. Conclusions Early treatment prevents adverse developmental outcome, while patients diagnosed and treated at an older age showed partial but significant cognitive recovery with clear improvements in adaptive functioning.

Specific language impairment (SLI) diagnosed in the pre-school years is frequently associated with reading and writing difficulties at school age. The nature of this relationship is unclear, despite the availability of a large number of studies, mostly on English speaking children. Phonological processing deficits have been considered the prominent cause of both difficulties. However recent findings in both children with SLI and in children with reading difficulties are not easily accommodated within a single dimensional model explaining the relationship between oral and written language deficits. Our study focuses on the long-term reading and spelling outcome in relation to preschool oral language skills in a group of Italian adolescents with a documented history of SLI. Sixteen Italian adolescents diagnosed as SLI at our Hospital in the pre-school years and 32 normal controls were submitted to an extensive assessment of oral and written language skills. At a group level SLI adolescents had weak oral and written language skills in almost all tests. Results show that reading difficulties have some features in common with those of Italian developmental dyslexics but also have distinct characteristics, since reading accuracy and written comprehension, usually relatively spared in Italian developmental dyslexics, were impaired in adolescents with SLI. Longitudinal analyses showed that expressive morpho-syntactic and lexical abilities at pre-school age were the oral language skills that best predicted reading and spelling outcomes in adolescents with SLI. However, also children with severe phonological impairment in the absence of other oral language deficits showed later literacy difficulties, although less severe and mainly limited to reading accuracy. Our study supports the notion that there is a complex relationship between oral and written language difficulties which may change at different developmental time points, not captured by a single deficit model, but best conceptualized considering multiple interactions between language skills and literacy abilities.

The European Standards Committee on Oxidative DNA Damage (ESCODD) was set up to resolve the problems associated with the measurement of background levels of oxidative DNA damage (in particular 8-oxo-7,8-dihydroguanine, or 8-oxoGua) in human cells. A tendency for DNA oxidation to occur during sample preparation prior to chromatography has been recognized as the source of a very substantial artefact. To assess the success of attempts to eliminate the artefact, ESCODD has distributed to its members standard samples of pig liver and HeLa cells for analysis. Estimates of 8-oxoGua in pig liver, using chromatographic techniques, ranged from 2.23 to 441 per 10(6) guanines, with a median of 10.47 per 10(6) guanines. Chromatographic analysis of HeLa cell DNA gave a range of 1.84 to 214 per 10(6) guanines with a median of 5.23 per 10(6) guanines. HeLa cell DNA was also analysed by an enzymic approach, in which whole cell DNA was treated with formamidopyrimidine DNA glycosylase, which nicks DNA at sites of 8-oxoGua, and the breaks measured with the comet assay, alkaline unwinding or alkaline elution. Values with these methods ranged from 0.06 to 4.988-oxoGua per 10(6) guanines, with a median of 0.79 per 10(6) guanines. Although there are clearly still serious discrepancies between methods and laboratories, the lowest estimates by chromatography (arguably those in which the artefact was best controlled) are only 2.5 times higher than the median value obtained with the enzymic approach.

Children with Developmental Dyslexia (DD) are impaired in Rapid Automatized Naming (RAN) tasks, where subjects are asked to name arrays of high frequency items as quickly as possible. However the reasons why RAN speed discriminates DD from typical readers are not yet fully understood. Our study was aimed to identify some of the cognitive mechanisms underlying RAN-reading relationship by comparing one group of 32 children with DD with an age-matched control group of typical readers on a naming and a visual recognition task both using a discrete-trial methodology , in addition to a serial RAN task, all using the same stimuli (digits and colors). Results showed a significant slowness of DD children in both serial and discrete-trial naming tasks regardless of type of stimulus, but no difference between the two groups on the discrete-trial recognition task. Significant differences between DD and control participants in the RAN task disappeared when performance in the discrete-trial naming task was partialled out by covariance analysis for colors, but not for digits. The same pattern held in a subgroup of DD subjects with a history of early language delay (LD). By contrast, in a subsample of DD children without LD the RAN deficit was specific for digits and disappeared after slowness in discrete-trial naming was partialled out. Slowness in discrete-trial naming was more evident for LD than for noLD DD children. Overall, our results confirm previous evidence indicating a name-retrieval deficit as a cognitive impairment underlying RAN slowness in DD children. This deficit seems to be more marked in DD children with previous LD. Moreover, additional cognitive deficits specifically associated with serial RAN tasks have to be taken into account when explaining deficient RAN speed of these latter children. We suggest that partially different cognitive dysfunctions underpin superficially similar RAN impairments in different subgroups of DD subjects.

Objective: Predictors of poor response to treatments in youths with disruptive behavior disorders (DBDs), including conduct disorder (CD) and oppositional defiant disorder (ODD), are under-studied. Multimodal psychosocial interventions are the best option, but a significant portion of patients needs adjunctive pharmacotherapy. The concept of “psychopathy”, and namely, the callous (lack of empathy and guilt) and unemotional (shallow emotions) trait, has been considered a possible specifier indicating a more severe subgroup of patients. We explored whether the callous–unemotional trait (CU) may affect the response to multimodal treatment in referred youths with DBDs. Method: 118 youths (102 males, age range 6–14 years, mean age 11.1 ± 2.5 years) completed a 12-month multimodal intervention, 48 of whom (41%) needed an associated pharmacotherapy. The patients were assessed according to psychopathological profile (Child Behavior Checklist, CBCL), severity and improvement (Clinical Global Impression-Severity and Improvement scores, CGI-S and CGI-I), functional impairment (Children-Global Assessment Scale, C-GAS), and psychopathic dimension (Antisocial Process Screening Device, APSD), including CU dimension. Results: 58 patients (49.2%) were non-responders. They had more frequently a diagnosis of CD than ODD, presented a comorbid mood disorder, higher CBCL scores in rule-breaking behavior, and higher APSD (“psychopathic”) scores. Subjects with higher or lower CU differed only according to the rate of responders (35% vs. 60%, p

A crucial issue in youths with disruptive behavior disorders, including oppositional defiant disorder and conduct disorder, is the refractoriness to treatments. A multimodal approach with individual therapy to improve social skills and self-control and family and school interventions is the best psychosocial treatment. Predictors of poor response to psychosocial treatment remain understudied. We aimed at exploring whether callous (lack of empathy and guilt) and unemotional (shallow emotions) (CU) trait and type of aggression (predatory vs. affective) can affect response to psychosocial treatment in referred youths with disruptive behavior disorders.The sample consisted of 38 youths (28 boys and 10 girls, age range: 6-14 years, mean age: 13.1 ± 2.6 years) diagnosed as having oppositional defiant disorder or conduct disorder according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria and a clinical interview (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version), who completed a 6-month therapeutic program at our hospital. Patients were assessed according to severity and improvement (Clinical Global Impressions-Severity score [CGI-S] and CGI-Improvement score), functional impairment (Children's Global Assessment Scale [C-GAS]), type of aggression, predatory versus affective (Aggression Questionnaire), and CU dimension (Antisocial Process Screening Device and the Inventory of CU Traits).Among the 38 patients, 21 (55.3%) were responders and 17 (44.7%) were nonresponders, according to CGI-Improvement score and CGI-S. Nonresponders were more impaired at the baseline according to CGI-S and C-GAS. Nonresponders presented higher scores of predatory aggression, whereas affective aggression did not differ between groups. Nonresponders presented higher scores in CU trait of Antisocial Process Screening Device and in Inventory of CU total score (callous trait), but these differences did not survive Bonferroni correction.Severity at the baseline and predatory aggression are negative predictors of psychosocial treatment, but the role of the callous trait needs more exploration in larger samples. Further research may increase our diagnostic and prognostic capacities, thus improving our treatment strategies.

In this study we investigated the effects of long-term memory (LTM) verbal knowledge on short-term memory (STM) verbal recall in a sample of Italian children affected by different subtypes of specific language impairment (SLI). The aim of the study was to evaluate if phonological working memory (PWM) abilities of SLI children can be supported by LTM linguistic representations and if PWM performances can be differently affected in the various subtypes of SLI. We tested a sample of 54 children affected by Mixed Receptive-Expressive (RE), Expressive (Ex) and Phonological (Ph) SLI (DSM-IV - American Psychiatric Association, 1994) by means of a repetition task of words (W) and non-words (NW) differing in morphemic structure [morphological non-words (MNW), consisting of combinations of roots and affixes - and simple non-words - with no morphological constituency]. We evaluated the effects of lexical and morpho-lexical LTM representations on STM recall by comparing the repetition accuracy across the three types of stimuli. Results indicated that although SLI children, as a group, showed lower repetition scores than controls, their performance was affected similarly to controls by the type of stimulus and the experimental manipulation of the non-words (better repetition of W than MNW and NW, and of MNW than NW), confirming the recourse to LTM verbal representations to support STM recall. The influence of LTM verbal knowledge on STM recall in SLI improved with age and did not differ among the three types of SLI. However, the three types of SLI differed in the accuracy of their repetition performances (PMW abilities), with the Phonological group showing the best scores. The implications for SLI theory and practice are discussed.

The aim of the study was to investigate whether children with Specific Language Impairment (SLI) show reduced left hemisphere specialization for language and, if so, whether it is associated with a deficit in phonological encoding and a specific type of SLI (Mixed Receptive-Expressive, Expressive, Phonological). We adopted two dichotic listening paradigms, which differed in the phonological similarity of the presented words (Fused and Non-Fused dichotic words tests), as well as a phonological working memory test. Participants included 34 pre-school and school age children affected by SLI. On the dichotic tests, as a group the children with SLI showed a reduced pattern of left hemisphere specialization for language compared to age-matched normal children, with significant differences only in the Fused condition. However, the pattern of hemispheric specialization varied depending on the type of SLI, with reduced left hemisphere specialization in the Expressive type and, to a lesser extent, in the Phonological type of SLI, but not in the Receptive-Expressive type. The three subgroups also differed in phonological processing abilities and the incidence of a positive family history for language disorders: the Receptive-Expressive group performed worse on the working memory and dichotic tests and the Expressive and Phonological groups presented high frequency for familial language disorder. These results suggest that different subtypes of SLI are not different manifestations of the same underlying disorder, but represent pathological conditions that have distinct markers both at the behavioral and neurofunctional level.

A dissociation between short- and long-term memory (LTM) and between the episodic and the semantic component of LTM is reported in a young girl who became amnesic at the age of 6 after an episode of acute encephalopathy resulting in bilateral frontal, insular, thalamic, ponto-mesencephalic, hippocampal and temporal lesions, as documented by MRI. The girl became amnesic a few months after starting school. A follow-up investigation showed that she was able to learn to read, write and acquire number facts and procedures and to improve her semantic knowledge. Our results show that the features of adult amnesia can also be found in children and that new semantic knowledge can be acquired in spite of an anterograde memory deficit. This dissociation does not agree with theories viewing long-term declarative memory as a unitary process mediated by the hippocampal system, but supports recent hypotheses that the acquisition of semantic knowledge is independent from episodic memory processes, and takes place through spared cortical regions subjacent to the hippocampi (Vargha-Khadem et al., 1997).

The evidence presented in this chapter demonstrates that hippocampal sclerosis is a substrate for TLE also in children.

We report a 9-year-old girl who presented from an early age a severe and specific verbal memory disorder, in the absence of a definite etiology. The results of an extensive neuropsychological assessment showed a dissociation between normal visuo-spatial memory abilities and a marked short-term and long-term verbal memory impairment. We argue that our case is affected by “developmental dysmnesia”, a condition so far described in two cases only (De Renzi and Lucchelli, 1990, and Temple, 1997). The disorder affected episodic as well as semantic verbal memory. The long term effects on learning and cognition of a memory deficit occurring early in childhood are discussed.

Summary: Purpose: To describe an 11-year-old girl with symptomatic localization-related epilepsy and normal intelligence who developed reversible mental deterioration and pseudoatrophic brain changes while receiving valproate (VPA). Methods: Assessment of mental function using Wechsler Intelligence Scale for Children-III (WISC) and Raven's Progressive Matrices (PM), EEG recordings while awake and asleep, and brain magnetic resonance imaging (MRI), were performed at the beginning of VPA therapy, after 2 years and 8 months of treatment and following VPA discontinuation. Results: After 2 years and 6 months on VPA (≤26 mg/kg/day) the girl insidiously developed mental deterioration (loss of 18 IQ points and drop in age-adjusted PM score from the 95th to the 50th percentile) associated with MRI-documented pseudoatrophy of the brain. Onset of severe cognitive impairment coincided with serum VPA concentrations near 100 μg/ml. There were no other manifestations of drug toxicity or hyperammonemia. Background EEG activity was normal. Reduction of VPA dosage and subsequent discontinuation 4 months later resulted in disappearance of clinical symptoms with a 20-point improvement at IQ testing and recovery of previous PM score. Repeat MRI showed disappearance of pseudoatrophic changes. Conclusions: The striking cognitive improvement and reversal of pseudoatrophic brain changes following VPA discontinuation strongly suggest a drug-induced condition. Based on this and previous reports, the syndrome of VPA-associated mental deterioration and pseudoatrophy of the brain appears to encompass different but possibly related clinical entities, which include parkinsonism with cognitive deterioration, mental deterioration with signs of VPA-toxicity, and isolated mental deterioration, as seen in our patient. A drug-induced effect should be considered whenever cognitive deterioration and imaging findings of brain atrophy occur in VPA-treated patients.

In simple visuomotor reaction time tasks, the difference between reaction time (RT) in the uncrossed hand/hemifield condition from RT in the crossed hand/hemifield, known as CUD (crossed-uncrossed difference), has been interpreted as reflecting interhemispheric transmission time (IHTT). Several studies in normal adults have found a CUD of a few milliseconds (3–4), while an abnormally long CUD has been reported in patients who underwent a surgical section of the corpus callosum or in congential acallosal subjects. The corpus callosum, which is the most important structure for interhemispheric transfer of information, completes its myelination approximately by age ten. It has been hypothesized that the functional maturity of the corpus callosum concides with the termination of the myelination cycle. No developmental study has focused on the development of IHTT, in relation to callosal maturation. The purpose of our study has been to investigate the development of interhemispheric transfer of visuomotor information in children aged seven to eleven, using a simple RT task with lateralized visual stimuli. The results indicate an age-related decrease of CUD, which we interpret as reflecting the maturation of the corpus callosum during childhood years.

Childhood apraxia of speech (CAS) is a subtype of motor speech disorder usually co-occurring with language impairment. A supramodal processing difficulty, involving executive functions (EFs), might contribute to the cognitive endophenotypes and behavioral manifestations. The present study aimed to profile the EFs in CAS, investigating the relationship between EFs, speech and language severity, and the connectivity of the frontal aslant tract (FAT), a white matter tract involved in both speech and EFs. A total of 30 preschool children with CAS underwent speech, language, and EF assessments and brain MRIs. Their FAT connectivity metrics were compared to those of 30 children without other neurodevelopmental disorders (NoNDs), who also underwent brain MRIs. Alterations in some basic EF components were found. Inhibition and working memory correlated with speech and language severity. Compared to NoND children, a weak, significant reduction in fractional anisotropy (FA) in the left presupplementary motor area (preSMA) FAT component was found. Only speech severity correlated and predicted FA values along with the FAT in both of its components, and visual-spatial working memory moderated the relationship between speech severity and FA in the left SMA. Our study supports the conceptualization of a composite and complex picture of CAS, not limited to the speech core deficit, but also involving high-order cognitive skills.