Missense variants in ATP1A3 and FXYD gene family are associated with childhood-onset schizophrenia.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia defined as onset before age of 13. Here we report on two unrelated cases diagnosed with both COS and alternating hemiplegia of childhood (AHC), and for whom two distinct pathogenic de novo variants were identified in the ATP1A3 gene. ATP1A3 encodes the α-subunit of a neuron-specific ATP-dependent transmembrane sodium-potassium pump. Using whole exome sequencing data derived from a cohort of 17 unrelated COS cases, we also examined ATP1A3 and all of its interactors known to be expressed in the brain to establish if variants could be identified. This led to the identification of a third case with a possibly damaging missense mutation in ATP1A3 and three others cases with predicted pathogenic missense variants in the FXYD gene family (FXYD1, FXYD6, and FXYD6-FXYD2 readthrough). FXYD genes encode proteins that modulate the ATP-dependant pump function. This report is the first to identify variants in the same pathway for COS. Our COS study illustrates the interest of stratifying a complex condition according to the age of onset for the identification of deleterious variants. Whereas ATP1A3 is a replicated gene in rare neuropediatric diseases, this gene has previously been linked with COS in only one case report. The association with rare variants in FXYD gene family is novel and highlights the interest of exploring these genes in COS as well as in pediatric neurodevelopmental disorders.

Treatment use in a prospective naturalistic cohort of children and adolescents with catatonia.

We aimed to (1) describe the treatment used in a large sample of young inpatients with catatonia, (2) determine which factors were associated with improvement and (3) benzodiazepine (BZD) efficacy. From 1993 to 2011, 66 patients between the ages of 9 and 19 years were consecutively hospitalized for a catatonic syndrome. We prospectively collected sociodemographic, clinical and treatment data. In total, 51 (77%) patients underwent a BZD trial. BZDs were effective in 33 (65%) patients, who were associated with significantly fewer severe adverse events (p = 0.013) and resulted in fewer referrals for electroconvulsive therapy (ECT) (p = 0.037). Other treatments included ECT (N = 12, 18%); antipsychotic medications, mostly in combination; and treatment of an underlying medical condition, when possible. For 10 patients, four different trials were needed to achieve clinical improvement. When all treatments were combined, there was a better clinical response in acute-onset catatonia (p = 0.032). In contrast, the response was lower in boys (p = 0.044) and when posturing (p = 0.04) and mannerisms (p = 0.008) were present as catatonic symptoms. The treatment response was independent of the underlying psychiatric or systemic medical condition. As in adults, BZDs should be the first-line symptomatic treatment for catatonia in young patients, and ECT should be a second option. Additionally, the absence of an association between the response to treatment and the underlying psychiatric condition suggests that catatonia should be considered as a syndrome.

Medical and developmental risk factors of catatonia in children and adolescents: a prospective case-control study.

CONTEXT: Rare diseases have been associated with more and more genetic and non genetic causes and risk factors. But this has not been systematically assessed in catatonia, one of the psychiatric syndromes, that is most frequently associated with medical condition. OBJECTIVE: We sought to assess the medical and developmental risk factors of catatonia in children and adolescents. METHODS: From 1993 to 2009, 58 youths aged 10 to 18 years were prospectively admitted for catatonia and were followed up after discharge. A multidisciplinary approach assessed patients' medical condition and developmental history. A causality assessment scored medical risk (maximum score=10; κ=0.91). We compared the prevalence of catatonia in these patients to that of 80 inpatients with bipolar I disorder admitted from 1993 to 2003 who were also followed up. RESULTS: We found that 13 (22.4%) patients had medical conditions and 18 (31%) had a history of developmental disorder in the catatonia group, whereas 1 (1.3%) and 17 (22.6%) patients had the same conditions in the bipolar group (p<0.001; p=0.17, respectively). Medical conditions associated with catatonia included auto-immune encephalitis (systemic lupus erythematosus [N=3] and anti-NMDA-receptor encephalitis [N=1]), seizures (N=1), ciclosporin encephalitis (N=1), post hypoglycaemic coma encephalitis (N=1), and genetic or metabolic conditions (chorea [N=2], 5HT cerebrospinal fluid deficit [N=1], storage disease [N=1], fatal familial insomnia [FFI; N=1], and PRODH mutations [N=1]). Six patients responded to a specific treatment approach related to their medical condition (e.g., plasma exchange in the case of auto-immune encephalitis). CONCLUSION: Catatonia in children and adolescents is associated with a high prevalence of medical conditions. This needs to be acknowledged as it may greatly delay the treatment of catatonia and the diagnosis of medically related catatonia. Tragically, this may deny patients treatment opportunities.

Association of adolescent catatonia with increased mortality and morbidity: evidence from a prospective follow-up study.

This paper examined outcomes among youth with catatonic syndrome and determined whether the characteristics suggesting the relevance of chronic catatonic schizophrenia (CCS) at index episode remained stable at follow-up. From 1993 to 2004, 35 individuals aged 12 to 18 years were prospectively admitted for management of catatonic syndrome and followed up after discharge. Mean duration from discharge to follow-up was 3.9 years (range 1-10). Four patients were lost to follow-up. Among the remaining 31 subjects (mean age=19.5 years, range 15-26), life-time diagnosis using the Diagnostic Interview for Genetic Studies was unchanged in 28 patients, and included schizophrenia (all subtypes; N=20), major depressive episode (N=5), bipolar disorder type I (N=4) and brief psychotic episode (N=2). Mortality (all-cause Standardized Mortality Ratio=6266; 95% CI=1181-18,547) and morbidity were severe, with 3 deaths (including 2 suicides), 6 patients presenting with a causal organic condition and 14 subjects needing continuous psychiatric care. All males in the study (N=8) who had chronic catatonic schizophrenia at the index episode still had chronic catatonic signs at follow-up. Catatonia is one of the most severe psychiatric syndromes in adolescents. It is associated with a 60-fold increased risk of premature death, including suicide, when compared to the general population of same sex and age. This increased risk of premature death remains higher than the one measured in former adolescent psychiatric patients (all-cause SMR=221; 95% CI=156-303; Engqvist and Rydelius, 2006), or in schizophrenia irrespective to age and subtype (all-cause SMR=157; 95% CI=153-160; Harris and Barraclough, 1998).

Association between sodium- and potassium-activated adenosine triphosphatase alpha isoforms and bipolar disorders.

BACKGROUND: The sodium- and potassium-activated adenosine triphosphatase (Na+, K+-ATPase) is a major plasma membrane transporter for sodium and potassium. We recently suggested that bipolar disorders (BD) may be associated with alterations in brain Na+, K+-ATPase. We further conjectured that the differences in Na+, K+-ATPase in BD patients could result partially from genetic variations in Na+, K+-ATPase alpha isoforms. METHODS: To test our hypothesis, we undertook a comprehensive study of 13 tagged single nucleotide polymorphisms (SNPs) across the three genes of the brain alpha isoforms of Na+, K+- ATPase (ATP1A1, ATP1A2, and ATP1A3, which encode the three alpha isoforms, alpha1, alpha2, and alpha3, respectively) identified using HapMap data and the Haploview algorithm. Altogether, 126 subjects diagnosed with BD from 118 families were genotyped (parents and affected siblings). Both individual SNPs and haplotypes were tested for association using family-based association tests as provided in the UNPHASED and PBAT set of programs. RESULTS: Significant nominal association with BD was observed for six single SNPs (alpha1: rs11805078; alpha2: rs2070704, rs1016732, rs2854248, and rs2295623; alpha3: rs919390) in the three genes of Na+, K+-ATPase alpha isoforms. Haplotype analysis of the alpha2 isoform (ATP1A2 gene) showed a significant association with two loci haplotypes with BD (rs2295623: rs2070704; global p value = .0198, following a permutation test). CONCLUSIONS: This study demonstrates for the first time that genetic variations in Na+, K+-ATPase are associated with BD, suggesting a role of this enzyme in the etiology of this disease.

Does catatonia influence the phenomenology of childhood onset schizophrenia beyond motor symptoms?

Childhood onset schizophrenia (COS) and catatonia (C) are rare and severe psychiatric disorders. The aim of this study was to compare the phenomenology of COS with and without catatonia. We examined 33 cases consecutively referred to two major public university hospitals in Paris. There were 18 cases of COS (age=15.9+/-0.8 years) and 15 of COS+C (age=15.4+/-1.4 years). Patients were referred over the course of 3 and 9 years, respectively. Psychiatric assessment included socio-demographic, clinical and psychometric variables: the Brief Psychiatric Rating Scale (BPRS), the Scales for the Assessment of Positive (SAPS) and Negative Symptoms (SANS), and a catatonia rating scale. Patients with COS+C appeared to be more severely ill at admission and discharge compared with COS in nearly all clinical scores. They also exhibited significantly longer episode duration (50.8 weeks+/-4.8 vs 20.6+/-19.5). On the basis of multivariate logistic regression, the only clinical measure which significantly predicted group membership was the SANS Affective Flattening score (odds ratio=1.24; 95% CI=1.06-1.43). Our findings strongly suggest that catatonic COS differs from COS in ways that extend beyond motor symptoms. The SANS and SAPS scales, commonly used in schizophrenia, are not detailed enough to accurately describe catatonia in COS. The use of a catatonia rating scale is recommended to enhance recognition of and research into COS with catatonia.

Direct profiling of the cerebellum by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry: A methodological study in postnatal and adult mouse.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI MS) can detect substantial changes in expression of proteins in tissues, such as cancer cells. A more challenging problem is detecting the smaller changes expected in normal development or complex diseases. Here we address methodological issues regarding the acquisition and analysis of MALDI MS data from tissue sections, in a study of mouse cerebellum at different stages of development. Sections of the cerebellar cortex were analyzed at the peak of granule neuron production [postnatal day (P) 7], during synapse formation (P14), and in adults. Data were acquired (Voyager-DEtrade mark STR Biospectrometry Workstation; seven acquisitions of 50 shots per section, 3.5-50 kDa), preprocessed (Data Explorer 4.3), and averaged. Among 846 peaks detected, in at least 50% of at least one group, 122 showed significant group differences (Kruskal-Wallis ANOVA) after Bonferroni correction. Factor analyses revealed two age-related factors, possibly reflecting gradients of expression during development. Predictive analysis of microarrays generated a model from half of the sample that correctly predicted developmental groups for the second half. Intraclass correlation coefficients, measuring within-mouse consistency of peak heights from three tissue sections, were acceptable at lower m/z and for larger peaks at higher m/z. Low mass was the best predictor of significant group differences. The analysis demonstrates that MALDI MS of normal tissue sections at different ages can detect consistent, significant group differences. Further work is needed to increase the sensitivity of the methods and to apply them reliably to brain regions and to subproteomes with relevance to diverse brain functions and diseases.