Correlations between Sleep Features and Iron Status in Children with Neurodevelopmental Disorders: A Cross-Sectional Study.

A high prevalence of sleep disturbances has been reported in children with neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID). The etiology of sleep disorders in these children is heterogeneous and, recently, iron deficiency has received increasing attention. This study aims to investigate sleep features in children with NDDs and to explore a possible correlation between serum iron status biomarkers and qualitative features of sleep. We included 4- to 12-year-old children with a diagnosis of ASD, ADHD, or ID and assessed their sleep features through the children's sleep habits questionnaire (CSHQ). Venous blood samples were collected to investigate ferritin, transferrin, and iron levels. The mean CSHQ total score exceeds the cut-off in all groups of children. In the ASD group, the Parasomnias subscale negatively correlated with serum ferritin levels (Rho = 0.354; p = 0.029). Our findings may suggest the existence of an association between iron status, sleep quality, and neurodevelopmental processes. In clinical practice, sleep assessment should be included in the routine assessment for patients with NDDs. Furthermore, a routine assessment of iron status biomarkers should be recommended for children with NDDs who have sleep disturbances.

Clinical characterization of a novel RAB39B nonstop mutation in a family with ASD and severe ID causing RAB39B downregulation and study of a Rab39b knock down mouse model.

Autism spectrum disorder (ASD) and intellectual disability (ID) often exist together in patients. The RAB39B gene has been reported to be mutated in ID patients with additional clinical features ranging from ASD, macrocephaly, seizures and/or early-onset parkinsonism. Here, we describe a novel RAB39B nonstop mutation [Xq28; c.640 T > C; p.(*214Glnext*21)] in a family with ASD, severe ID and poor motor coordination, and we assessed the pathogenicity of the mutation. A heterologous cell system and a Rab39b knockdown (KD) murine model, which mimic the nonstop mutation, were used to validate the deleterious effect of the RAB39B mutation. The mutation led to RAB39B protein instability, resulting in its increased degradation and consequent downregulation. Using a Rab39b KD mouse model, we demonstrated that the downregulation of RAB39B led to increased GluA2 lacking Ca2+-permeable AMPAR composition at the hippocampal neuronal surface and increased dendritic spine density that remained in an immature filopodia-like state. These phenotypes affected behavioural performance in a disease-specific manner. Rab39b KD mice revealed impaired social behaviour but intact social recognition. They also showed normal anxiety-like, exploratory and motivational behaviours but impaired working and associative memories. In conclusion, we found a novel RAB39B nonstop variant that segregated in a family with a clinical phenotype including ID, ASD and poor motor coordination. The pathogenicity of mutations causing the downregulation of RAB39B proteins, impacting AMPAR trafficking and dendritic spine morphogenesis, reinforced the idea that AMPAR modulation and dendritic spine assets could be considered hallmarks of neurodevelopmental disorders.

DRD1 and DRD2 Receptor Polymorphisms: Genetic Neuromodulation of the Dopaminergic System as a Risk Factor for ASD, ADHD and ASD/ADHD Overlap.

The dopaminergic system (DS) is one of the most important neuromodulator systems involved in complex functions that are compromised in both autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), conditions that frequently occur in overlap. This evidence suggests that both disorders might have common neurobiological pathways involving the DS. Therefore, the aim of this study was to examine the DRD1 and DRD2 dopamine receptor single nucleotide polymorphisms (SNPs) as potential risk factors for ASD, ADHD, and ASD/ADHD overlap. Genetic data were obtained from four groups: 75 ASD patients, 75 ADHD patients, 30 patients with ASD/ADHD overlap, and 75 healthy controls. All participants were between 2 and 17 years old. We compared the genotypic and allelic frequency of 18 SNPs among all of the study groups. Moreover, in the case of statistically significant differences, odds ratios (OR) were obtained to evaluate if the presence of SNPs might be a risk factor of developing a specific clinical phenotype. This study found that DRD1 and DRD2 receptors SNPs might be considered as potential risk factors for ASD and ADHD. However, only DRD2-12 (rs7131465) was significantly associated with a higher risk for the ASD/ADHD overlap. These data support the hypothesis of the genetic neuromodulation of the DS in the neurobiology of these conditions.

14q12q13.2 microdeletion syndrome: Clinical characterization of a new patient, review of the literature, and further evidence of a candidate region for CNS anomalies.

BACKGROUND: Chromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare contiguous gene syndrome. Two regions of overlap (RO) of the 14q12q21.1 deletion have been identified: a proximal region (RO1), including FOXG1(*164874), NKX2-1(*600635), and PAX9(*167416) and a distal region (RO2), including NKX2-1 and PAX9. We report a 6-year-old boy with mild dysmorphic facial features, global developmental delay, and hypoplasia of the corpus callosum. METHODS AND RESULTS: Array-CGH analysis revealed a 14q12q13.2 microdeletion. We compared the phenotype of our patient with previously published cases in order to establish a genotype-phenotype correlation. CONCLUSION: The study hypothesizes the presence of a new RO, not including the previously reported candidate genes, and attempt to define the associated molecular and psychomotor/neurobehavioral phenotype. This region encompasses the distal breakpoint of RO1 and the proximal breakpoint of RO2, and seems to be associated with intellectual disability (ID), hypotonia, epilepsy, and corpus callosum abnormalities. Although more cases are needed, we speculated on SNX6(*606098) and BAZ1A(*605680) as potential candidate genes associated with the corpus callosum abnormalities.

Acute Disseminated Encephalomyelitis followed by Optic Neuritis: A Rare Syndrome of Uncertain Treatment and Prognosis.

AIM: Acute Disseminated Encephalomyelitis followed by optic neuritis (ADEM-ON), first described in 2013, is a rare demyelinating syndrome, typical of the pediatric age. We conducted a mini review of the existing literature, focusing on clinical, laboratory, radiological, therapeutic, and prognostic aspects in order to improve the identification of new cases. METHODS: We searched PubMed and Cochrane Library for studies on ADEM-ON between 2013 and 2018. RESULTS EXAMINATION: of the reported cases (three case reports and eight observational studies) established the following features. Time between ADEM and ON is highly variable. Almost all patients show antimyelin oligodendrocyte glycoprotein antibody (MOG-abs) seropositivity. High-dose intravenous steroid and plasmapheresis efficacy is reported for the acute phase; oral prednisone and other maintenance drugs may be useful in avoiding relapses. The clinical history may lead to a complete recovery but also to residual deficits. CONCLUSION: MOG-abs detection strongly supports ADEM-ON diagnosis, confirming this entity as part of MOG-abs spectrum disorder. Owing to the very small number of cases so far reported, predicting clinical evolution is very difficult.

Predictive validity for the clinical diagnosis of a new parent questionnaire, the CABI, compared with CBCL.

BACKGROUND: The questionnaires completed by the parents give a first general information on the behavioral problems of the child-adolescent, as a useful orientation to the clinical evaluation. The Child and Adolescent Behavior Inventory (CABI) is a 75-item parent questionnaire, which explores a large number of problem areas. The study of its predictive validity for the clinical diagnosis, in comparison with the Diagnostic and Statistical Manual of Mental Disorders (DSM)-oriented scales of the Child Behavior Checklist (CBCL), can assess whether its use may be advantageous. MATERIAL AND METHODS: Parents/caregivers of 462 children and adolescents responded to both CABI and CBCL as a preliminary routine investigation. The results were compared with those of diagnoses obtained after the completion of the usual clinical procedure. RESULTS: Accuracy values (probability of correct classification) resulted high for both instruments and significantly better for CABI anxiety and attention-deficit hyperactivity disorder (ADHD) scales, and for CBCL oppositional defiant disorder (ODD) and conduct disorder (CD) scales; no significant difference was found for depression scales. All the areas under the curve (AUC) of the receiver operating characteristic analysis reached excellent values, suggesting a very good predictive ability of the five scales of the two instruments. The comparison of AUC showed the CABI's anxiety and ADHD scales to give significantly higher values than those of CBCL, indicating that these two scales have a better predictive ability. CONCLUSION: The study indicates a very good comparative (vs CBCL) and predictive validity of the CABI, suggesting an advantage in the use of this shorter questionnaire, available for free use both for clinical practice and supposedly for screening and epidemiological evaluations.

Juvenile Fibromyalgia and Headache Comorbidity in Children and Adolescents: A Literature Review.

Juvenile fibromyalgia (JFM) is a chronic pain syndrome with onset in developmental age, characterized by widespread musculoskeletal pain associated with other neurological or nonneurological symptoms. Headache is one of the most frequent comorbid conditions with JFM, but this association is still poorly studied in the juvenile population. The literature review was conducted searching through PubMed, Scopus, and Web of Science with a combination of the following free-text terms: "fibromyalgia," "juvenile fibromyalgia," "headache," "primary headache," "migraine," "children," "adolescents," and "comorbidity." The research resulted only in two specific studies regarding comorbidity JFM + Juvenile Headache (JH). From each study, we extracted data about sample features, clinical characteristics of both JFM and PH, and assessment tools. The clinical approach to JFM and JH should include a complete examination of the main causes of comorbid diseases, thus improving the therapeutic approach to the patient in developmental age.

Sex-Gender Comparisons in Comorbidities of Children and Adolescents With High-Functioning Autism Spectrum Disorder.

Over the last few years, new studies focused their attention on the gender-related features in high-functioning autism spectrum disorder (HFA), often leading to controversial results. Another interesting aspect of these subtype of patients is linked to the complexity of clinical presentation, where besides core symptoms, other co-occurrence disorders may complicate the diagnostic evaluation. Therefore, we retrospectively studied 159 HFA patients, male and female, investigating their comorbidities and to find any gender difference. For each patient, were evaluated the presence/absence, type and gender distribution of psychopathological comorbidities, according to DSM-5 diagnostic criteria. The total sample was divided in 100 male and 59 female patients, age and intelligence quotient matched. In our sample, the psychiatric comorbidities observed were Attention Deficit Hyperactivity Disorder, Anxiety Disorders, Depressive Disorders, Bipolar Disorder, Obsessive-Compulsive Disorder, and Anorexia Nervosa. No statistical significant differences were found between male and female HFA patients comorbidities except for Anorexia Nervosa. In both male and female patients, attention deficit and hyperactivity disorder and anxiety disorders were found in high percentage. In conclusion, our investigation showed that a statistical significant difference of comorbidity between male and female HFA patients was found only for AN diagnosis. However, the question about the distinction between female and male HFA patients remains quite interesting and an open area of research for future studies.

Neurodevelopmental and emotional-behavioral outcomes in late-preterm infants: an observational descriptive case study.

BACKGROUND: Over the last decade, several studies investigated the outcomes in children born very preterm. Only recently there has been an increasing interest in the late preterm infants (born between 34 + 0 and 36 + 6 weeks). This population is at high risk of morbidity and mortality in the first years of life. Other studies reported that they are also at risk of long-term developmental problem. Therefore, the aim of this study is to describe the neurodevelopmental and emotional-behavioral outcome in a sample of late preterm patients. METHODS: The study included late preterm children and adolescents who had neuropsychiatric and/or neurological symptoms. They underwent a general, neurocognitive and an emotional-behavioral assessment. Exclusion criteria included: patients affected by Central Nervous System congenital abnormalities, neurodegenerative diseases, genetic disorders, epilepsy, or in pharmacological treatment, or adopted children. A descriptive statistics analysis was performed to describe the sociodemographic and clinical characteristics of patients. Risk factors related to late preterm birth, prevalence of neurodevelopmental disorders, and cognitive functioning were recorded and analyzed. RESULTS: The sample included 68 LPI (45 males and 23 females) aged from 2 to 16.3 years (mean age 7,5 years), who were affected by one or more neurodevelopmental disorder, including Language Disorder, Attention Deficit Hyperactivity Disorder, Specific Learning Disorder, Developmental Coordination Disorder, Intellectual Disability and Autism Spectrum Disorder. Moreover, in 30.8% of patients, internalizing problems (affective and social skills problem) were detected. CONCLUSIONS: Our results support the importance of a long-term surveillance of late preterm and the great need for more longitudinal large population studies in order to collect data on the neurodevelopmental outcomes of this population.

Hyperprolactinemia and insulin resistance in drug naive patients with early onset first episode psychosis.

BACKGROUND: Hyperprolactinemia and glucose and lipid metabolism abnormalities are often found in patients with schizophrenia and are generally considered secondary to the use of antipsychotic drugs. More recent studies have shown these same neuroendocrine and metabolic abnormalities in antipsychotic naïve patients with first episode psychosis (FEP), rising the hypothesis that schizophrenia itself may be related to an abnormal regulation of prolactin secretion and to impaired glucose tolerance. The aim of this study was to compare prolactin levels, glycometabolism parameters and lipid profile between a sample of 31 drug-naive adolescents in the acute phase of FEP and a control group of 23 subjects at clinical high risk (CHR) of developing psychosis. METHODS: The assessment involved anthropometric data (weight, height, BMI index, pubertal stage) and blood tests (levels of glucose, glycated hemoglobin, serum insulin, triglycerides, total and fractionated cholesterol, prolactin). Insulin resistance (IR) was calculated through the homeostatic model of assessment (HOMA-IR), assuming a cut-off point of 3.16 for adolescent population. FEP patients and CHR controls were compared by using Student's t-distribution (t-test) for parametric data. P < 0.05 was considered significant. RESULTS: Significant higher level of prolactin was found in FEP group than in CHR group (mean = 28.93 ± 27.16 vs 14.29 ± 7.86, P = 0.009), suggesting a condition of hyperprolactinemia (HPRL). Patients with FEP were more insulin resistant compared to patients at CHR, as assessed by HOMA-IR (mean = 3.07 ± 1.76 vs 2.11 ± 1.11, P = 0.043). Differences of fasting glucose (FEP = 4.82 ± 0.71, CHR = 4.35 ± 0.62, P = 0.016) and HbA1c (FEP = 25.86 ± 13.31, CHR = 33.00 ± 2.95, P = 0.013), were not clinically significant as the mean values were within normal range for both groups. No significant differences were found for lipid profile. A BMI value within the range of normal weight was found for both groups, with no significant differences. CONCLUSION: We suggested that HPRL, increase in HOMA-IR, and psychotic symptoms may be considered different manifestations of the acute onset of schizophrenia spectrum psychosis, with a common neurobiological vulnerability emerging since adolescence. The influence of age and gender on clinical manifestations of psychotic onset should be considered for early prevention and treatment of both schizophrenia spectrum psychosis and neuroendocrine-metabolic dysfunctions.

Frontal lobe metabolic alterations in autism spectrum disorder: a 1H-magnetic resonance spectroscopy study.

PURPOSE: Recently, neuroimaging studies were performed using 1H-magnetic resonance spectroscopy (1H-MRS), revealing a quantitative alteration of neurochemicals (such as neurotransmitters and metabolites) in several brain regions of patients with autism spectrum disorder (ASD). The involvement of the frontal lobe in the neurobiology of ASD has long been documented in the literature. Therefore, the aim of this study was to analyze the alterations of N-acetylaspartate/creatine (NAA/Cr) and choline/Cr (Cho/Cr) ratios in the frontal lobe subcortical white matter (WM) in ASD patients, in order to reveal any alteration of metabolites that might be the expression of specific clinical features of the disorder. PATIENTS AND METHODS: An 1H-MRS study of the frontal lobe subcortical WM was performed in 75 children with ASD and in 50 age-matched controls to evaluate the functional activity of this brain region. RESULTS: NAA/Cr and Cho/Cr ratios were significantly altered in ASD, compared to control subjects. Moreover, in the ASD group, NAA/Cr was significantly lower in patients with a cognitive impairment. CONCLUSION: Results from this study confirm the existence of brain metabolites' alterations in frontal lobe WM in children with ASD, supporting the relevance of this brain region in the clinical expressions of this disorder, including its role in the cognitive impairment. Further 1H-MRS investigations will allow to comprehensively explain the relationship between metabolic alteration in a specific brain region and specific clinical features of ASD.

Parenting Stress and Emotional/Behavioral Problems in Adolescents with Primary Headache.

Primary headache is a frequent and disabling disorder, common among children and adolescents, and it is a painful syndrome often accompanied by functional impairment and associated with emotional and behavior problems. The aim of this study was to investigate parenting stress and emotional/behavioral problems in adolescents affected by primary headache compared with healthy adolescents. The study population consisted of 35 adolescents and a control group of 23 healthy subjects. The assessment included the administration of clinical standardized scales such as Parent Stress Index-Short Form, Pediatric Migraine Disability Assessment Score Questionnaire, and Child Behavior Checklist (CBCL). Headache group and control group did not differ in terms of parenting stress (p = 0.29). On the contrary, headache group showed more internalizing problems (p = 0.023), affective problems (p = 0.01), anxious (p = 0.001), and somatic complaints (p < 0.001) compared with control group. In addition, we found a significant correlation between PSI domains and specific CBCL subscales in the headache group. The findings emphasize the need for expanded intervention in the clinical treatment of pediatric headache, a treatment that may also include the family members. Further research is needed.