A novel microduplication in INPP5A segregates with schizophrenia spectrum disorder in the family of a patient with both childhood onset schizophrenia and autism spectrum disorder.

Childhood-Onset Schizophrenia (COS) is a very rare and severe psychiatric disorder defined by adult schizophrenia symptoms occurring before the age of 13. We report a microduplication in the 10q26.3 region including part of the Inositol Polyphosphate-5-Phosphatase A (INPP5A) gene that segregates with Schizophrenia Spectrum Disorders (SSDs) in the family of a female patient affected by both COS and Autism Spectrum Disorder (ASD). Phenotyping and genotyping (including CGH-array) were performed for mother, healthy sister, and affected child according to the GenAuDiss protocol (NCT02565524). The duplication size is 324 kb and is present in a patient with COS and in her mother with SSD, but not in the patient's healthy sister. INPP5A encodes a membrane-associated 43 kDa type I inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. This protein is found both in mouse and human brains and we found that its Drosophila homologue 5PtaseI is specifically expressed in the central nervous system. Hydrolyzed products from InsP3 5-phosphatases mobilize intracellular calcium, which is relevant for dendritic spine morphogenesis in neurons and altered in both schizophrenia and ASD. These may constitute arguments in favor of this gene alteration in the pathophysiology of COS.

Reduced Functional Brain Activation and Connectivity During a Working Memory Task in Childhood-Onset Schizophrenia.

OBJECTIVE: Working memory (WM) deficits are consistently reported in schizophrenia and are related to poor functional outcomes. Functional magnetic resonance imaging studies of adult-onset schizophrenia have reported decreased functional activations and connectivity in the WM network, but no prior functional magnetic resonance imaging study has examined WM in childhood-onset schizophrenia (COS). The aim of this study was to examine the neural correlates of WM in COS. METHOD: Adult patients with COS (n = 32, 21.3 ± 1.1 years), nonpsychotic siblings of patients with COS (n = 30, 19.4 ± 0.8 years), and healthy controls (n = 39, 20.0 ± 0.7 years) completed 1- and 2-back WM tasks during 3-T functional magnetic resonance imaging. Functional activation and connectivity analyses were conducted. A separate group of 23 younger patients with COS (17.9 ± 7.4 years) could not perform the tasks after twice completing a standard training and are not included in this report. RESULTS: Patients with COS who were included scored significantly lower than controls on all tasks (p < .001). Patients with COS showed significantly lower activations in the dorsolateral prefrontal cortices, posterior parietal cortices, cerebellum, and caudate and decreased frontoparietal and corticostriatal functional connectivity compared with controls (p < .05, corrected). Siblings had functional activations and connectivity intermediate between those of patients and controls in a similar set of regions (p < .05, corrected). In patients, functional connectivity strength in the left frontoparietal network correlated positively with accuracy scores during the 1-back task (p = .0023, corrected). CONCLUSION: Decreased functional activation and connectivity in the WM network in COS supports pathophysiologic continuity with adult-onset schizophrenia. The low participation rate and accuracy of the patients highlights the disease severity of COS. Hypo-activations and hypo-connectivity were shared by siblings of patients with COS, suggesting COS as a potential endophenotype. CLINICAL TRIAL REGISTRATION INFORMATION: Evaluating Genetic Risk Factors for Childhood-Onset Schizophrenia; http://ClinicalTrials.gov;NCT00001198.

Comorbilidad del trastorno del espectro autista y el déficit de atención con hiperactividad. Estudio de revisión / omorbidity of autism spectrum disorder and attention deficit with hyperactivity. A review study

Introducción. La elevada presencia de trastorno por déficit de atención/hiperactividad (TDAH) en el trastorno del espectro autista (TEA) ha sido reconocida en el Manual diagnóstico y estadístico de los trastornos mentales, quinta edición, permitiendo el diagnóstico de ambos trastornos. Objetivo. Revisar las investigaciones publicadas entre 2010 y 2014 sobre las características cognitivas y sociales de la coocurrencia del TEA y el TDAH. Desarrollo. La revisión de los 33 estudios identificados evidencia una prevalencia de síntomas de TDAH en niños con TEA del 33-37%. La condición comórbida presenta más déficit en el control inhibitorio, la atención y la memoria de trabajo. Asimismo, en cognición social, la sintomatología del TDAH incrementa las dificultades en los casos de TEA. Además, el perfil clínico de TEA + TDAH muestra mayor gravedad que el de TDAH o TEA puros, y el retraso en el lenguaje y la intensidad/ frecuencia de rabietas son síntomas que ayudan a la identificación en edades tempranas. Conclusiones. Los hallazgos sugieren una superposición ‘aditiva’, y el TEA + TDAH comparte algunos déficits de ambos trastornos, lo cual tiene implicaciones para la evaluación y el diseño de tratamientos efectivos (AU)

Introduction. The high presence of attention deficit hyperactivity disorder (ADHD) in autism spectrum disorder (ASD) has been acknowledged in the Diagnostic and statistical manual of mental disorders, fifth edition, thus allowing the diagnosis of both disorders. Aims. The purpose of this study is to review the research published between 2010 and 2014 on the cognitive and social characteristics of the concurrence of ASD and ADHD. Development. A review of the 33 studies that were identified showed evidence that the prevalence of symptoms of ADHD in children with ASD was 33-37%. The comorbid condition presents a greater deficit in inhibitory control, attention and working memory. Likewise, in social cognition, the clinical features of ADHD increase the difficulties in cases of ASD. Moreover, the clinical profile of ASD + ADHD is seen to be more severe than that of pure ADHD or ASD, and delayed language development and the intensity/frequency of tantrums are symptoms that are a valuable aid in identification at early ages. Conclusions. Findings suggest an ‘additive’ overlapping and ASD + ADHD shares some of the deficits from both disorders, which has implications for the evaluation and design of effective treatments (AU)

At the boundary of the self: the insular cortex in patients with childhood-onset schizophrenia, their healthy siblings, and normal volunteers.

The insular cortex (insula), whose normal function involves delineating the boundary between self and non-self stimuli, has been implicated in the pathophysiology of the positive symptoms of schizophrenia, including hallucinations and delusions. Childhood-onset schizophrenia (COS), that includes the onset of psychosis before age 13, is a severe and continuous form of the illness which shows profound and global progressive cortical brain abnormalities during adolescence which merge in the adult pattern with age. Using prospectively acquired anatomic brain magnetic resonance imaging (MRI) scans, a matched sample of COS patients, their nonpsychotic full siblings and healthy volunteers, we measured insular volume using the FreeSurfer automated software. COS patients (n=98; 234 scans) had significantly lower right (p=0.003), left (p<0.001), and total (p<0.001) insular volumes than healthy volunteers (n=100; 248 scans). Right insular volume negatively correlated with positive symptoms as measured by the Scale for the Assessment of Positive Symptoms (SAPS) (p=0.02), while both left (p=0.01) and right (p=0.006) insula volumes were positively correlated with overall functioning, as measured by the Children's Global Assessment Scale (CGAS) scores. COS siblings (n=71; 153 scans), on the other hand, did not differ significantly from normal volunteers suggesting that the insular deficits are more related to the illness state than a familial endophenotype. These results also highlight the salience of the insula in positive symptoms of schizophrenia perhaps resulting from the inability to discriminate between self from the non-self in COS. Further work to connect insular deficits to other neurocircuitries is warranted.

Proton magnetic resonance spectroscopy and thought disorder in childhood schizophrenia.

OBJECTIVE: Although magnetic resonance spectroscopy has identified metabolic abnormalities in adult and childhood schizophrenia, no prior studies have investigated the relationship between neurometabolites and thought disorder. This study examined this association in language-related brain regions using proton magnetic resonance spectroscopic imaging ((1)H MRSI). METHOD: MRSI was acquired bilaterally from 28 youth with childhood-onset schizophrenia and 34 healthy control subjects in inferior frontal, middle frontal, and superior temporal gyri at 1.5T and short echo time (TR/TE = 1500/30 ms). CSF-corrected "total NAA" (tNAA; N-acetyl-aspartate + N-acetyl-aspartyl-glutamate), glutamate + glutamine (Glx), creatine + phosphocreatine (Cr + PCr), choline compounds (Cho), and myo-inositol (mI) were assayed in manually drawn regions-of-interest partitioned into gray matter, white matter, and CSF and then coregistered with MRSI. Speech samples of all subjects were coded for thought disorder. RESULTS: In the schizophrenia group, the severity of formal thought disorder correlated significantly with tNAA in the left inferior frontal and superior temporal gyri and with Cr + PCr in left superior temporal gyrus. CONCLUSIONS: Neurometabolite concentrations in language-related brain regions are associated with thought disorder in childhood-onset schizophrenia.

Clinical practice of rTMS reveals a functional dissociation between agency and hallucinations in schizophrenia.

We report here the case of a hospitalized 11 year-old boy (YP) with a positive diagnosis of 'Childhood Onset Schizophrenia'. YP experienced verbal-auditory hallucinations, a delusion of alien control and hetero-aggressive behaviour. Antipsychotic drugs were unsuccessful and furthermore provoked severe acute dystonia. fMRI-guided rTMS applied over several cortical regions provided the means to reveal for the first time a functional dissociation between auditory-verbal hallucinations and agency. These results demonstrate the efficacy of rTMS for young patients suffering from drug-resistant hallucinations but they furthermore question the physiopathology of the hallucinatory process by suggesting that agency and hallucinations may be sub-served by different neural networks.

Abnormal development of the anterior cingulate in childhood-onset schizophrenia: a preliminary quantitative MRI study.

The anterior cingulate is a key component of neural networks subserving attention and emotion regulation, functions often impaired in patients with psychosis. The study aimed to examine anterior cingulate volumes and sulcal morphology in a group of patients with childhood-onset schizophrenia (COS) compared with controls. Brain magnetic resonance imaging (MRI) scans were obtained in 13 COS and 18 matched control children, ages 6-17 years. Volume measures for the anterior cingulate gyrus (ACG) were obtained through manual labeling. A determination of cingulate sulcal pattern (single or double) was made for each hemisphere. The COS group had a reduced leftward skew of the double cingulate sulcal pattern, and absence of the normal left>right ACG volume asymmetry. The right ACG was larger in the COS than in controls. The schizophrenic children showed decreases in all ACG volumes with age, while the controls showed increases or no change. The data suggest that significant cingulate abnormalities may result from deviations in progressive neurodevelopmental processes, beginning before birth and continuing through childhood and adolescence, in persons who develop schizophrenia. These structural differences may relate to the well-described cognitive deficits these children display, and to the cardinal symptoms of schizophrenia.

Childhood-onset schizophrenia: smooth pursuit eye-tracking dysfunction in family members.

BACKGROUND: Childhood-onset schizophrenia (COS), a severe form of the disorder, is of interest for etiologic studies. Smooth pursuit eye-tracking dysfunction (ETD) is a biological marker for schizophrenia. AIMS: To compare familial eye-tracking abnormalities for COS and adult-onset schizophrenia (AOS). METHOD: Eye-tracking performance for 70 COS parents, 64 AOS parents and 20 COS siblings was compared to their respective age-matched control groups. RESULTS: COS and AOS parents had higher rate of dichotomously rated eye-tracking dysfunction than their respective controls (16% vs. 1% and 22% vs. 4%, respectively). COS parents and siblings also differed from controls on several continuous measures. However, scores for COS, AOS and control groups overlapped extensively. CONCLUSIONS: Genetic factors underlying eye-tracking dysfunction appear more salient for COS. However, eye-tracking measures have to be used with caution for endophenotypic definition due to low predictive power. DECLARATION OF INTEREST: The study was done at the National Institutes of Health.

Clozapine-induced neutropenia in children: management with lithium carbonate.

Clozapine, an atypical antipsychotic, is the most effective medication for treatment-resistant schizophrenia, but its use is limited by the high risk of neutropenia and agranulocytosis. In children, the rate of clozapine-induced neutropenia is even higher than in adults. We report two cases of children 7- and 12-years old diagnosed with very early onset schizophrenia, who developed neutropenia when treated with clozapine. In both cases addition of lithium carbonate elevated the white blood count (WBC) allowing clozapine rechallenge. WBC and total neutrophil count remained stable long-term with coadministration of clozapine (400-425 mg per day) and lithium with the blood level of 0.8-1.1 microg/mL. This report supports the use of adjunct lithium for clozapine-induced neutropenia as a safe and successful strategy in children.

[Prodromal symptoms of schizophrenics syndrome in children and adolescent]. / Objawy prodromalne zespolów schizofrenicznych u dzieci i mlodziezy.

This presentation concentrates on modality and frequency analysis of prodromal schizophrenic symptoms of the children and adolescent. A sample (n-50) of children between 8 and 19 years was tested by structural interview. There were observed the signs resembling following symptoms: negative symptoms (74%), anxiety disorders (42%) and obsessive-compulsive disorders (20%).

Brain imaging in childhood- and adolescence-onset schizophrenia associated with obsessive-compulsive symptoms.

OBJECTIVE: Childhood- and adolescence-onset schizophrenic patients with obsessive-compulsive symptoms (OCS) constitute a specific subgroup of schizophrenia. We performed magnetic resonance imaging in this group seeking evidence of neurodevelopmental insults. METHOD: Thirty-two schizophrenic patients were compared with 19 controls. Schizophrenic subjects were divided into 15 patients with OCS (SOCS+ group; onset at 15.5 +/- 1.6 years) and 17 without OCS (SOCS- group; onset at 15.3 +/- 1.3 years). Areas of the hippocampus, frontal lobe, corpus callosum and putamen were analysed morphometrically. RESULTS: The left hippocampus was significantly smaller in the SOCS+ group than in the SOCS- and control groups. CONCLUSION: Reduced size of the left hippocampus in the SOCS+ group supports a neurodevelopmental etiology in this subgroup.

Velocardiofacial syndrome in childhood-onset schizophrenia.

OBJECTIVES: Deletion of chromosome 22q11 (velocardiofacial syndrome) is associated with early neurodevelopmental abnormalities and with schizophrenia in adults. The rate of 22q11 deletions was examined in a series of patients with childhood-onset schizophrenia (COS), in whom early premorbid developmental and cognitive impairments are more pronounced than in adult-onset cases. METHOD: Through extensive recruiting and screening, a cohort of 47 patients was enrolled in a comprehensive study of very-early-onset schizophrenia. All were tested with fluorescence in situ hybridization for deletions on chromosome 22q11. RESULTS: Three (6.4%) of 47 patients were found to have a 22q11 deletion. All 3 COS patients with 22q11 deletions had premorbid impairments of language, motor, and social development, although their physical characteristics varied. Brain magnetic resonance imaging revealed increased midbody corpus callosum area and ventricular volume in relation both to healthy controls and to other COS patients. CONCLUSIONS: The rate of 22q11 deletions in COS is higher than in the general population (0.025%, p < .001) and may be higher than reported for adult-onset schizophrenia (2.0%, p = .09). These results suggest that 22q11 deletions may be associated with an earlier age of onset of schizophrenia, possibly mediated by a more salient neurodevelopmental disruption.

Blink rate in pediatric complex partial seizure disorder.

This study examined spontaneous blink rate, a putative measure of dopamine function, in 30 children with complex partial epilepsy and 61 normal children. The children with epilepsy had significantly lower blink rates than the normal children in a conversation and a verbal recall task, particularly if they had a schizophrenia-like psychosis, EEG evidence for left focal epileptic activity, illogical thinking, discourse deficits, and distractibility. They modulated their blink rates across a listening, a conversation, and a verbal recall task like the normal children. Given previously reported low blink rates in schizophrenic children, these findings suggest that children with complex partial epilepsy or schizophrenia might have similar biological features.

Formal thought disorder and psychopathology in pediatric primary generalized and complex partial epilepsy.

OBJECTIVE: To examine whether formal thought disorder and psychopathology occurred in children with complex partial seizures (CPS) rather than children with primary generalized epilepsy with absences (PGE) or nonepileptic children. METHOD: Formal thought disorder was coded in 30 children with CPS, 24 children with PGE, and 61 nonepileptic children, and structured interview-based psychiatric diagnoses were obtained for the epileptic subjects. RESULTS: The CPS subjects had significantly more illogical thinking than the PGE and nonepileptic children. The severity of their illogical thinking was related to global cognitive dysfunction and a schizophrenia-like psychosis. Age of onset and seizure control, however, were significantly associated with the severity of illogical thinking in the PGE group. One or more psychiatric diagnoses were found in 63% of the CPS and 54% of the PGE patients, particularly if they had global cognitive deficits. CONCLUSION: Illogical thinking, associated with cognitive dysfunction or schizophrenia-like symptoms, might be a feature of pediatric CPS. Psychopathology might be related to global cognitive dysfunction in pediatric CPS and PGE.

Pubertal development and onset of psychosis in childhood onset schizophrenia.

In this study, pubertal development was examined for a sample of children and adolescents with childhood onset schizophrenia (COS) defined as psychosis by age 12. Developmental and psychiatric histories were obtained for 28 adolescents (mean age 14.5 +/- 2.3 years) with severe, treatment refractory COS (14 males, 14 females). Age of onset of psychosis was also examined in relation to menarche and development of secondary sex characteristics. Girls had a trend towards developing secondary sex characteristics earlier than boys (P = 0.06), consistent with North American norms. Males (N = 14) and females (N = 14) had similar age of onset of psychosis. The age of development of secondary sex characteristics was associated with onset of psychosis for girls, but this finding was driven by one outlier. There was no significant correlation between development of psychosis and menarche. Neither male nor female probands differed significantly from their well siblings or from North American norms in their age of onset of pubertal development. There was no evidence of early onset of secondary sex characteristics for this sample. Finally, there was an absence of a clear relationship between onset of psychosis and indices of sexual development for these very early onset cases.

[On schizophrenic cases which present neurosis-like symptoms from early childhood--in relation to the prodromal signs and childhood schizophrenia].

The concept of "childhood schizophrenia" is ambiguous because of problems on the diagnostic level, especially in regard to symptomatology and prognosis. After studies which produced the description of "early infantile autism", childhood schizophrenia studies were even more confused. One reason for this was that there were not sufficient follow-up studies about the schizophrenia-like psychoses during occurring childhood, on the one hand, and the retrospective-anamnestic research was limited in the field of adult psychiatry, on the other hand. The author has focused on two points of view in order to discuss the problem of childhood schizophrenia. One is the non outbreak of childhood psychoses in children from 6 to 8 years old which was demonstrated by a couple of epidemiological research studies. The other is the concept of "Knick" (in Germany) which usually accompanies classical German theories of schizophrenia. "Knick" means that, at some point in the patient's history, there is an incident that is the indication of the onset of schizophrenia. The subjects were selected from the author's own cases. They continuously and insidiously developed schizophrenic symptoms during pre-puberty and puberty, presenting behavioral abnormalities or neurosis-like signs from early childhood. The diagnostic criteria for schizophrenia corresponds to DSM-III and with the German theory of Bleuler and Schneider. All cases have been treated for more than ten years. The acute onset cases, the mentally retarded cases (DSM-III .318) and the cases with suspected organic brain disorders were excluded because of the diagnostic problems. The author could differentiate these subjects into three groups based on the development in the infantile stage. The first was autistic group and the second mentally subnormal (DSM-III .317) or borderline group. Psychiatric problems of these two groups were already obvious in early childhood. The third group developed normally until they were 3-5 years old. After that they presented neurotic symptoms having some kind of intra-familiar problems. The author could confirm that these three groups manifested various kinds of neurosis-like symptoms, mainly obsessive-compulsive ones, from 3-5 years old. The so-called latent time, which is thought to be a non-outbreak time of childhood psychoses, may correspond to the prodromal stage of schizophrenia in these cases. This research is based on study of 31 children. An in-depth study has been done by the author of 6 of these children, 2 in each of the 3 categories described above. The "Knick"-points were not identifiable in these cases.(ABSTRACT TRUNCATED AT 400 WORDS)