Early role for a Na+,K+-ATPase (ATP1A3) in brain development.

Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function catalyzed by the Na+,K+-ATPase α-subunit. Here, we describe ATP1A3 variants encoding dysfunctional α3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we built an ATP1A3 transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of ∼125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of ATP1A3 is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled ∼52,000 nuclei from four areas of an infant neocortex and show that ATP1A3 expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin interneurons in the frontal cortex. Finally, we discovered the heteromeric Na+,K+-ATPase pump complex may form nonredundant cell-type-specific α-ß isoform combinations, including α3-ß1 in excitatory neurons and α3-ß2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell ATP1A3 expression patterns point to a key role for α3 in human cortex development, as well as a cell-type basis for pre- and postnatal ATP1A3-associated diseases.

RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes.

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3'-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.

Burden Experienced by Primary Caregivers of Children With Psychotic Disorders and at Clinical High Risk for Psychosis.

BACKGROUND: Despite the existing research exploring caregiver burden in adult psychosis, few studies have examined the experience of providing care to children diagnosed with psychotic disorders (PDs) and those identified as having clinical high risk for psychosis (CHR-P). OBJECTIVE: This study measured the level of burden in caregivers of children with PD and CHR-P and examined associated risk factors, including social support, caregiver-child relationship, severity of illness, and frequency of psychiatric hospitalizations. METHODS: A total of 56 caregivers completed validated measures and provided demographic information. Measures included the Zarit Burden Interview, the Multidimensional Scale of Perceived Social Support, the Behavior Assessment System for Children, Third Edition, Parenting Relationship Questionnaire-Child and Adolescent Form (BASC-3 PRQ-CA), and the Clinical Global Impression-Severity scale. RESULTS: The majority of caregivers were women (86%), mothers (84%), White (63%), married (66%), working full-time (50%), college-educated (79%), and whose mean age was 45.7 years (SD = 8.09). Nearly half of the caregivers (45%) reported a high level of caregiver burden, 39% rated their burden in the mild to moderate range, and 16% reported little to no burden. There was no significant difference in mean burden between PD and CHR-P groups. Higher caregiver burden was associated with lower levels of social support (r = -.408, p = .002), lower levels of parenting confidence (r = -.514, p < .001), higher levels of relational frustration (r = .612, p < .001), and higher severity of illness (r = .316 p = .025). CONCLUSIONS: These findings underscore the critical unmet need for support for caregivers of children with PD and CHR-P. Applications to clinical practice are discussed.

Underrepresentation of Phenotypic Variability of 16p13.11 Microduplication Syndrome Assessed With an Online Self-Phenotyping Tool (Phenotypr): Cohort Study.

BACKGROUND: 16p13.11 microduplication syndrome has a variable presentation and is characterized primarily by neurodevelopmental and physical phenotypes resulting from copy number variation at chromosome 16p13.11. Given its variability, there may be features that have not yet been reported. The goal of this study was to use a patient "self-phenotyping" survey to collect data directly from patients to further characterize the phenotypes of 16p13.11 microduplication syndrome. OBJECTIVE: This study aimed to (1) discover self-identified phenotypes in 16p13.11 microduplication syndrome that have been underrepresented in the scientific literature and (2) demonstrate that self-phenotyping tools are valuable sources of data for the medical and scientific communities. METHODS: As part of a large study to compare and evaluate patient self-phenotyping surveys, an online survey tool, Phenotypr, was developed for patients with rare disorders to self-report phenotypes. Participants with 16p13.11 microduplication syndrome were recruited through the Boston Children's Hospital 16p13.11 Registry. Either the caregiver, parent, or legal guardian of an affected child or the affected person (if aged 18 years or above) completed the survey. Results were securely transferred to a Research Electronic Data Capture database and aggregated for analysis. RESULTS: A total of 19 participants enrolled in the study. Notably, among the 19 participants, aggression and anxiety were mentioned by 3 (16%) and 4 (21%) participants, respectively, which is an increase over the numbers in previously published literature. Additionally, among the 19 participants, 3 (16%) had asthma and 2 (11%) had other immunological disorders, both of which have not been previously described in the syndrome. CONCLUSIONS: Several phenotypes might be underrepresented in the previous 16p13.11 microduplication literature, and new possible phenotypes have been identified. Whenever possible, patients should continue to be referenced as a source of complete phenotyping data on their condition. Self-phenotyping may lead to a better understanding of the prevalence of phenotypes in genetic disorders and may identify previously unreported phenotypes.

De novo variant of TRRAP in a patient with very early onset psychosis in the context of non-verbal learning disability and obsessive-compulsive disorder: a case report.

BACKGROUND: TRRAP encodes a multidomain protein kinase that works as a genetic cofactor to influence DNA methylation patterns, DNA damage repair, and chromatin remodeling. TRRAP protein is vital to early neural developmental processes, and variants in this gene have been associated with schizophrenia and childhood disintegrative disorder. CASE PRESENTATION: Here, we report on a patient with a de novo nonsynonymous TRRAP single-nucleotide variant (EST00000355540.3:c.5957G > A, p.Arg1986Gln) and early onset major depression accompanied by a psychotic episode (before age 10) that occurred in the context of longer standing nonverbal learning disability and a past history of obsessions and compulsions. CONCLUSIONS: The de novo variant and presentation of very early onset psychosis indicate a rare Mendelian disorder inheritance model. The genotype and behavioral abnormalities of this patient are reviewed.

Suicidal behaviors and their relationship with psychotic-like symptoms in children and adolescents at clinical high risk for psychosis.

BACKGROUND: Previous research has demonstrated elevated rates of suicide attempts and ideation in individuals with psychosis. This study investigated rates and severity of suicidal behavior in youth with and at clinical high risk for psychosis, and examined the positive, negative, and disorganized symptoms associated with suicidal behaviors among the clinical high risk group. METHODS: Eighty-six youth ages 7-18 (n=21 non-clinical controls [NCC], n=40 clinical high risk [CHR], n=25 diagnosed psychotic disorder [PD]) were recruited. CHR and PD participants were identified using the Structured Interview for Prodromal Symptoms (SIPS) and Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (KSADS-PL). All participants completed the Suicide Behaviors Questionnaire-Revised (SBQ-R). RESULTS: Findings indicated significantly higher levels of suicidal behavior among CHR and PD relative to NCC participants (F=7.64, p=0.001). 17.5% of CHR participants had previously attempted suicide. Dysphoric Mood and Odd Behavior or Appearance were significantly correlated with suicidal behavior severity among CHR youth. CONCLUSION: Suicidal behavior was observed with greater frequency and severity in the CHR and PD groups than in the NCC group. CHR suicidal behavior severity was correlated most strongly with Dysphoric Mood and Odd Behavior or Appearance, a relationship which warrants further investigation.

Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis.

N100 Repetition Suppression Indexes Neuroplastic Defects in Clinical High Risk and Psychotic Youth.

Highly penetrant mutations leading to schizophrenia are enriched for genes coding for N-methyl-D-aspartate receptor signaling complex (NMDAR-SC), implicating plasticity defects in the disease's pathogenesis. The importance of plasticity in neurodevelopment implies a role for therapies that target these mechanisms in early life to prevent schizophrenia. Testing such therapies requires noninvasive methods that can assess engagement of target mechanisms. The auditory N100 is an obligatory cortical response whose amplitude decreases with tone repetition. This adaptation may index the health of plasticity mechanisms required for normal development. We exposed participants aged 5 to 17 years with psychosis (n = 22), at clinical high risk (CHR) for psychosis (n = 29), and healthy controls (n = 17) to an auditory tone repeated 450 times and measured N100 adaptation (mean amplitude during first 150 tones - mean amplitude during last 150 tones). N100 adaptation was reduced in CHR and psychosis, particularly among participants <13 years old. Initial N100 blunting partially accounted for differences. Decreased change in the N100 amplitude with tone repetition may be a useful marker of defects in neuroplastic mechanisms measurable early in life.

Neurophysiological differences between patients clinically at high risk for schizophrenia and neurotypical controls--first steps in development of a biomarker.

BACKGROUND: Schizophrenia is a severe, disabling and prevalent mental disorder without cure and with a variable, incomplete pharmacotherapeutic response. Prior to onset in adolescence or young adulthood a prodromal period of abnormal symptoms lasting weeks to years has been identified and operationalized as clinically high risk (CHR) for schizophrenia. However, only a minority of subjects prospectively identified with CHR convert to schizophrenia, thereby limiting enthusiasm for early intervention(s). This study utilized objective resting electroencephalogram (EEG) quantification to determine whether CHR constitutes a cohesive entity and an evoked potential to assess CHR cortical auditory processing. METHODS: This study constitutes an EEG-based quantitative neurophysiological comparison between two unmedicated subject groups: 35 neurotypical controls (CON) and 22 CHR patients. After artifact management, principal component analysis (PCA) identified EEG spectral and spectral coherence factors described by associated loading patterns. Discriminant function analysis (DFA) determined factors' discrimination success between subjects in the CON and CHR groups. Loading patterns on DFA-selected factors described CHR-specific spectral and coherence differences when compared to controls. The frequency modulated auditory evoked response (FMAER) explored functional CON-CHR differences within the superior temporal gyri. RESULTS: Variable reduction by PCA identified 40 coherence-based factors explaining 77.8% of the total variance and 40 spectral factors explaining 95.9% of the variance. DFA demonstrated significant CON-CHR group difference (P <0.00001) and successful jackknifed subject classification (CON, 85.7%; CHR, 86.4% correct). The population distribution plotted along the canonical discriminant variable was clearly bimodal. Coherence factors delineated loading patterns of altered connectivity primarily involving the bilateral posterior temporal electrodes. However, FMAER analysis showed no CON-CHR group differences. CONCLUSIONS: CHR subjects form a cohesive group, significantly separable from CON subjects by EEG-derived indices. Symptoms of CHR may relate to altered connectivity with the posterior temporal regions but not to primary auditory processing abnormalities within these regions.

Comparing stimulant effects in youth with ADHD symptoms and epilepsy.

To retrospectively examine response to stimulant treatment in patients with epilepsy and ADHD symptoms as predicted by seizure freedom for six months, use of methylphenidate (MPH) versus amphetamine (AMP) preparations, cognitive level, and medical records were searched for patients under the age of 18 with epilepsy and ADHD symptoms treated with MPH or AMP (n=36, age=10.4 ± 3.5; male=67%). "Responders" had a CGI-improvement score of ≤ 2 and did not stop medication because of adverse effects. "Worsened" patients discontinued medication because of agitation/emotional lability. Seizure freedom did not predict treatment response. Lower cognitive level was associated with increased rate of worsening (p=0.048). No patients who were seizure-free at the start of the medication trial experienced an increase in seizures. Of the patients having seizures at the start of trial, one patient on MPH and two patients on AMP had increased seizures during the trial. Seizures returned to baseline frequency or less after stimulant discontinuation or anticonvulsant adjustment. Methylphenidate was associated with a higher response rate, with 12 of 19 given MPH (0.62 ± 0.28 mg/kg/day) compared with 4 of 17 given AMP (0.37 ± 0.26 mg/kg/day) responding (p=0.03). Methylphenidate treatment and higher cognitive level were associated with improved treatment outcome, while seizure freedom had no clear effect. Confidence in these findings is limited by the study's small, open-label, and uncontrolled design.