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PURPOSE: The BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex playing a critical role in gene regulation. Defects in the genes encoding the BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity. METHODS: We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach combining predicted genic constraints to propose candidate BAFopathy genes. RESULTS: We identified 127 patients carrying pathogenic, likely pathogenic variants or de novo variants of unknown clinical significance (VUS) in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed through ES reanalysis with new gene-disease evidence (N= 21) or variant re-classifications in known BAFopathy genes (N=13). We also identified de novo or predicted loss-of-function variants in four candidate BAFopathy genes, ACTL6A, BICRA (implicated in BAFopathy during this study), PBRM1, and SMARCC1. CONCLUSION: We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and a pathway-based reanalysis of ES data identified new evidence for candidate genes for BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.

Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.

The CAMTA1-associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome-based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N- and C- terminal functional domains. Clinical heterogeneity is observed, but 3'-terminal variants seem to associate with less pronounced cerebellar dysfunction.

Healthcare workers (HCW) are at high risk for suicide, yet little is known about the onset of suicidal thoughts and behaviors (STB) in this important segment of the population in conjunction with the COVID-19 pandemic. We conducted a multicenter, prospective cohort study of Spanish HCW active during the COVID-9 pandemic. A total of n = 4809 HCW participated at baseline (May-September 2020; i.e., just after the first wave of the pandemic) and at a four-month follow-up assessment (October-December 2020) using web-based surveys. Logistic regression assessed the individual- and population-level associations of separate proximal (pandemic) risk factors with four-month STB incidence (i.e., 30-day STB among HCW negative for 30-day STB at baseline), each time adjusting for distal (pre-pandemic) factors. STB incidence was estimated at 4.2% (SE = 0.5; n = 1 suicide attempt). Adjusted for distal factors, proximal risk factors most strongly associated with STB incidence were various sources of interpersonal stress (scaled 0-4; odds ratio [OR] range = 1.23-1.57) followed by personal health-related stress and stress related to the health of loved ones (scaled 0-4; OR range 1.30-1.32), and the perceived lack of healthcare center preparedness (scaled 0-4; OR = 1.34). Population-attributable risk proportions for these proximal risk factors were in the range 45.3-57.6%. Other significant risk factors were financial stressors (OR range 1.26-1.81), isolation/quarantine due to COVID-19 (OR = 1.53) and having changed to a specific COVID-19 related work location (OR = 1.72). Among other interventions, our findings call for healthcare systems to implement adequate conflict communication and resolution strategies and to improve family-work balance embedded in organizational justice strategies. This work was supported by grants from the Instituto de Salud Carlos III (ISCIII)/Ministerio de Ciencia e Innovación/FEDER, Spain (Jordi Alonso, grant number COV20/00711); ISCIII-FEDER, Spain (Jordi Alonso, grant number PI17/00521); ISCIII-FSE, Spain: Sara Borrell and Miguel Servet grants (Philippe Mortier, grant number CD18/00049 and CP21/00078); Generalitat de Catalunya, Spain (2017SGR452); and PERIS, Departament de Salut, Spain (Itxaso Alayo; SLT017/20/000009). Additional partial funding was received from the Gerencia Regional de Salud de Castilla y León (SACYL), Spain (José María Pelayo Terán, grant number GRS COVID 32/A/20). Sí

Mutations in the family of genes encoding the tubulin subunits of microtubules are associated with a spectrum of human brain malformations known as tubulinopathies. How these mutations impact tubulin activity to give rise to distinct developmental consequences is poorly understood. Here we report two patients exhibiting brain malformations characteristic of tubulinopathies and heterozygous T178M missense mutations in different β-tubulin genes, TUBB2A or TUBB3. RNAseq analysis indicates that both TUBB2A and TUBB3 are expressed in the brain during development, but only TUBB2A maintains high expression in neurons into adulthood. The T178 residue is highly conserved in β-tubulins and located in the exchangeable GTP-binding pocket of β-tubulin. To determine the impact of T178M on β-tubulin function we created an analogous mutation in the β-tubulin of budding yeast and show that the substitution acts dominantly to produce kinetically stabilized microtubules that assemble and disassemble slowly, with fewer transitions between these states. In vitro experiments with purified mutant tubulin demonstrate that T178M decreases the intrinsic assembly activity of β-tubulin and forms microtubules that rarely transition to disassembly. We provide evidence that the T178M substitution disrupts GTPase-dependent conformational changes in tubulin, providing a mechanistic explanation for kinetic stabilization. Our findings demonstrate the importance of tubulin’s GTPase activity during brain development, and indicate that tubulin isotypes play different, important roles during brain development.

The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like phenotype with a rare coding SUZ12 variant-the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver-like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre- and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly-affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically-recognizable syndromes emerge from different variant subtypes.

Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Contains fulltext : 234078.pdf (Publisher’s version ) (Open Access) Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

International audience; Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC.Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype–phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts.Conclusion: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.

COL4A1 mutations present with a spectrum of clinical phenotypes often involving the cerebrovascular and ophthalmic systems. We report 2 cases of COL4A1 mutations that presented with congenital cataracts and porencephaly. Both patients had posterior cortical cataracts and radiographically defined bilateral posterior lenticonus. Considering the long-term clinical implications of these mutations, posterior cortical cataracts, bilateral posterior lenticonus, and porencephaly should raise clinical suspicion for COL4A1 mutations.

Purpose:The pace of Mendelian gene discovery is slowed by the “n-of-1 problem” – the difficulty of establishing causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier but is often impeded by lack of a convenient or widely-available way to share data on candidate variants / genes among families, clinicians and researchers.Methods:Social networking among families, clinicians and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.Results:De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.Conclusion:Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with non-specific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP). Design and development of a web-based tool, MyGene2, that enables families, clinicians and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP is underway.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease.

Despite the large body of research on premorbid impairments in schizophrenia, studies comparing different early-onset psychoses are scarce.To examine premorbid impairments in first episodes of early-onset bipolar and schizophrenia disorders.We compared premorbid adjustment and other premorbid variables such as IQ and developmental abnormalities in a cohort of children and adolescents (N=69) with bipolar disorder (BP) or schizophrenia (SZ) experiencing their first psychotic episode and in a healthy control group (N=91).Schizophrenia patients showed more social impairment in childhood than bipolar patients (p0.05) and healthy controls (p0.001) and had higher rates of developmental abnormalities (p0.05) than healthy controls. Between childhood and early adolescence, schizophrenia and bipolar patients showed a greater decline in academic adjustment than healthy controls, more specifically in adaptation to school (p0.01).Early-onset schizophrenia patients show more early social impairment than early-onset bipolar patients. Intellectual premorbid abnormalities are less specific and probably more linked to early-onset psychosis.

The objective of this article is to review clinical differences between men and women with bipolar disorder. The secondary objective is to analyze the differences in adherence to medication between genders. Men usually present with manic episodes and have comorbid drug abuse, while women usually present with major depressive episode, the onset is often later, comorbidity of physical pathology is common and adherence to medication is greater than in men. In women who have an earlier onset of the illness and are single, the risk of nonadherence is higher than in other groups of women. There are two time periods that are very important in women: pregnancy and postpartum. Both are critical periods and a relapse or recurrence of symptoms at either stage can have serious consequences for the woman and/or her baby. In addition, the effect of medication on the fetus is unclear. In conclusion, there is a clear need for more studies on gender differences in bipolar disorder and how to improve adherence to treatment. Moreover, a better understanding of how to treat women with bipolar disorder during pregnancy and lactation will undoubtedly lead to improved outcomes for both the mother and her child.

Background There is a need for comparisons of long-term outcomes in bipolar disorder patients with predominantly manic symptoms vs. predominantly depressive symptoms, especially the course of comorbid alcohol/substance abuse. Method A naturalistic sample of bipolar I patients ( n = 120) was followed prospectively for up to 10 years. At baseline, number and polarity of past episodes were used to classify patients as predominantly manic or predominantly depressive if there were more manic or more depressive episodes, respectively. 25 patients were excluded from the analyses. Outcomes including episodes, hospitalisations and suicide attempts were recorded at bimonthly visits. Mixed effects models compared the course of alcohol and other substance abuse in predominantly manic vs. depressive patients. Results Of the 95 patients analyzed, 44 (46.3%) had predominantly manic episodes and 51 (53.7%) had predominantly depressive episodes. At baseline, the predominantly depressive group had more history of suicide attempts (45.1% vs. 20.5%; p = 0.021) and more family history of affective disorders (64.7% vs. 38.6%; p = 0.020), but they had fewer previous hospitalisations than the manic group (mean 0.38 vs. 0.50; p = 0.025). During the 10-year follow-up, the predominantly depressive group was associated with more episodes ( p = 0.001), more hospitalisations ( p = 0.004) and more suicide attempts ( p = 0.002). At baseline, there were no differences between the manic and depressive groups in the frequency of alcohol abuse (43.2% and 35.3%, p = 0.565) or other substance abuse (13.6% and 9.8%, p = 0.794). During the 10-year follow-up, the frequency of alcohol and other substance abuse decreased significantly in the manic group only, after controlling by age at onset and civil (marital) status. Conclusion Long-term clinical outcomes differ between predominantly manic vs. depressive bipolar patients, with the predominantly depressive group having a worse prognosis and maintained alcohol and other substance abuse. These differences should be considered when designing treatment approaches for bipolar patients with comorbid alcohol/substance abuse.

BackgroundMindfulness-based cognitive therapy (MBCT) is a psychotherapeutic intervention that has been shown effective in several clinical conditions. Nevertheless, research is still needed on its effectiveness on cognition.ObjectiveTo analyze possible effects on cognition of the addition of MBCT intervention versus a brief structured group psycho-education to the standard treatment of subsyndromal bipolar depression. Our hypothesis was that MBCT could improve some aspects of cognitive function to a higher degree than psycho-education and treatment as usual (TAU).Methods/designA randomized, multicenter, prospective, versus active comparator, evaluator-blinded clinical trial was conducted. Forty patients with BD and subclinical or mild depressive symptoms were randomly allocated to:– MBCT added to psychopharmacological treatment (n = 16);– a brief structured group psycho-educational intervention added to psychopharmacological treatment (n = 17);– standard clinical management, including psychopharmacological treatment (n = 7).Assessments were conducted at screening, baseline, post-intervention (8 weeks) and 4-month follow-up.ResultsCognition results point to significant improvement in Stroop Color test as well as processing speed in TMT A test (P < 0.05) in the two psychological intervention groups versus TAU.ConclusionThese preliminary findings suggest that the addition of MBCT or psycho-education to usual treatment could improve some cognitive dimensions in subsyndromal bipolar depressive patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.

A 9-year-old girl was brought for consultation due to autism and a large head circumference. Her birth weight was 6 pounds after a 37-week gestation to a healthy G3P1SAb 2 mother. She had been a healthy child with the exception of the development of a lipomatous lesion on the left thigh, requiring surgical removal at age 3(1/2) years. Autism was diagnosed at age 5 yr by a developmental pediatrician. She did not have cognitive disabilities or a history of seizures. The family history was notable for maternal infertility with no history of developmental disabilities, large body or head size, or malignancy in close relatives.On physical examination, she was a mildly obese girl with a large head. Her weight was 50.4 kg (95%), height was 142 cm (90%), and head circumference was 60.3 cm (significantly95%; 4SDs above the mean). Examination of her skin was notable for a 2 x 6 cm scar on her left thigh and three café au lait macules on her trunk. She was Tanner Stage I. Mild hypotonia with normal deep tendon reflexes was observed; the remainder of the neurological examination was normal.Laboratory studies included high-resolution chromosomes, fragile X, metabolic screens, and methylation for Prader Willie Syndrome and Angelman Syndrome; all these studies were normal. Molecular testing of the PTEN gene (phosphatase and tensin homolog protein) revealed a R355X mutation, consistent with the diagnosis of Bannayan-Riley-Ruvalcaba Syndrome (BRRS). In parents and siblings, PTEN test results were negative for mutations.Endocrine evaluation revealed an abnormal thyroid nodule on ultrasound. Computed tomography and positron emission tomography scans raised suspicion of malignancy. She underwent a total thyroidectomy; the pathology report revealed a thyroid adenoma with Hurthle cells. She was treated with thyroid hormone replacement therapy.

Background This study aimed to examine factors associated with treatment adherence in first-episode psychosis (FEP) patients followed up over 8 years, especially involuntary first admission and stopping cannabis use. Methods This prospective, longitudinal study of FEP patients collected data on symptoms, adherence, functioning, and substance use. Adherence to treatment was the main outcome variable and was categorized as ‘good’ or ‘bad’. Cannabis use during follow-up was stratified as continued use, stopped use, and never used. Bivariate and logistic regression models identified factors significantly associated with adherence and changes in adherence over the 8-year follow-up period. Results Of the 98 FEP patients analyzed at baseline, 57.1% had involuntary first admission, 74.4% bad adherence, and 52% cannabis use. Good adherence at baseline was associated with Global Assessment of Functioning score (p = 0.019), Hamilton Depression Rating Scale score (p = 0.017) and voluntary admission (p Conclusions The long-term association between treatment adherence and type of first admission and cannabis use in FEP patients suggest targets for intervention to improve clinical outcomes.

No prospective studies of first psychotic episodes have explored sex differences in smoking cessation. The aim of this study was to determine the influence of sex and substance abuse on smoking cessation during an 8-year follow-up of patients after a first psychotic episode. Logistic regression modeling was used to identify factors associated with smoking cessation by sex. To examine for sex variable interactions, the following two methods were used: 1) for other clinical variables, mixed analyses were calculated; and 2) for use of other substances, logistic regression models were performed only in the substance users. At baseline, 79% of men and 84% of women were current smokers. Lower smoking cessation after 8 years was associated with female sex (odds ratio, OR=0.30; 95% confidence intervals, CIs=0.12-0.75) and treatment with typical antipsychotics (OR=0.30, CIs=0.10-0.93). In a logistic regression model of alcohol users, those who used alcohol continuously were less likely to stop smoking (adjusted OR=0.22, CI=0.05-1.0). Among patients who continued using cannabis, female sex was associated with significant lower smoking cessation (adjusted OR=0.03, CI=0.001-0.77). Sex may act as a moderator in smoking cessation after a first psychotic episode. Smoking cessation interventions in these patients should consider sex differences and comorbidity with alcohol and cannabis use.

This patient presented on the first day of life with pronounced lactic acidosis with an elevated lactate/pyruvate ratio. Urine organic acids showed Krebs cycle metabolites and mildly elevated methylmalonate and methylcitrate. The acylcarnitine profile showed elevated propionylcarnitine and succinylcarnitine. Amino acids showed elevated glutamic acid, glutamine, proline, and alanine. From the age 2 of mo on, she had elevated transaminases and intermittent episodes of liver failure. Liver biopsy showed steatosis and a decrease of mitochondrial DNA to 50% of control. She had bilateral sensorineural hearing loss. Over the course of the first 2 y of life, she developed a progressively severe myopathy with pronounced muscle weakness eventually leading to respiratory failure, Leigh disease, and recurrent hepatic failure. The hepatic symptoms and the metabolic parameters temporarily improved on treatment with aspartate, but neither muscle symptoms nor brain lesions improved. Laboratory testing revealed a deficiency of succinyl-CoA ligase enzyme activity and protein in fibroblasts because of a novel homozygous mutation in the SUCLG1 gene: c.40A>T (p.M14L). Functional analysis suggests that this methionine is more likely to function as the translation initiator methionine, explaining the pathogenic nature of the mutation. Succinyl-CoA ligase deficiency due to an SUCLG1 mutation is a new cause for mitochondrial hepatoencephalomyopathy. (Pediatr Res 68: 159-164, 2010)

Liver failure in newborns can present formidable diagnostic challenges. The presentation of neonatal liver failure is variable and the initial assessment is crucial in the determination of potentially treatable causes. We present a case of neonatal hemochromatosis, review genetic and metabolic causes of neonatal liver failure, and outline an updated differential diagnosis of neonatal liver failure. In addition, we propose a comprehensive initial work-up of neonatal liver failure, and review current treatments for neonatal hemochromatosis.

There is a need for comparisons of long-term outcomes in bipolar disorder patients with predominantly manic symptoms vs. predominantly depressive symptoms, especially the course of comorbid alcohol/substance abuse.A naturalistic sample of bipolar I patients (n=120) was followed prospectively for up to 10years. At baseline, number and polarity of past episodes were used to classify patients as predominantly manic or predominantly depressive if there were more manic or more depressive episodes, respectively. 25 patients were excluded from the analyses. Outcomes including episodes, hospitalisations and suicide attempts were recorded at bimonthly visits. Mixed effects models compared the course of alcohol and other substance abuse in predominantly manic vs. depressive patients.Of the 95 patients analyzed, 44 (46.3%) had predominantly manic episodes and 51 (53.7%) had predominantly depressive episodes. At baseline, the predominantly depressive group had more history of suicide attempts (45.1% vs. 20.5%; p=0.021) and more family history of affective disorders (64.7% vs. 38.6%; p=0.020), but they had fewer previous hospitalisations than the manic group (mean 0.38 vs. 0.50; p=0.025). During the 10-year follow-up, the predominantly depressive group was associated with more episodes (p=0.001), more hospitalisations (p=0.004) and more suicide attempts (p=0.002). At baseline, there were no differences between the manic and depressive groups in the frequency of alcohol abuse (43.2% and 35.3%, p=0.565) or other substance abuse (13.6% and 9.8%, p=0.794). During the 10-year follow-up, the frequency of alcohol and other substance abuse decreased significantly in the manic group only, after controlling by age at onset and civil (marital) status.Long-term clinical outcomes differ between predominantly manic vs. depressive bipolar patients, with the predominantly depressive group having a worse prognosis and maintained alcohol and other substance abuse. These differences should be considered when designing treatment approaches for bipolar patients with comorbid alcohol/substance abuse.

Introduction Brain-derived neurotrophic factor (BDNF) promotes growth and maintenance of connections and participates in plasticity mechanisms.The cognition an the functioning of patients with a first episode of psychotic (FEP) is altered. Objectives We analyze the relation between the BDNF, the cognitive performance and prognosis in patients with FEP. Design and Methods 45 patients with a FEP from the Basque Country, diagnosed using the SCID-I and DSM-IV. Plasma BDNF levels were measured using the BDNF Sandwich ELISA Kit. All patients were assessed clinically three times over a year using PANSS, GAF and Strauss Carpenter scales. Battery of cognitive tests (Wechsler Memory Scale and WAIS-III) was applied six months after the acute episode. Results Positive correlation between BDNF levels after six months of treatment and five cognitive domains: abstract verbal reasoning (r = 0.468), motor and processing speed (r = 0.397), learning capacity (r = 0.559), immediate memory (r = 0.409) and delayed memory (r = 0.382). Also, the patients with lower BDNF plasma levels at baseline, at 6 months follow-up had worse social activity (0.61 vs. 0.89; p = 0.041) and functioning (0.69 vs. 0.93; p = 0.044).The BDNF levels increased along the follow up, after the pharmacological treatment (basal-1 month: Z = −2.88; p ≤ 0.004 and 1–6 months: Z = −2.23; p ≤ 0.05). Conclusions Our results suggest that BDNF is associated with cognitive impairment seen after a FEP and their prognosis. After the pharmacological treatment, the BDNF levels increase significantly and at 6 moths of treatment there were normal levels. Further investigations of the role of this neurotrophin in the symptoms associated with onset of psychosis are warranted.

IntroductionThere are manic disorders with depressive symptoms in mixed mania that do not reach the threshold for the diagnosis of mixed episode.Mania and hypomania are evaluated with scales that do not detect the depressive symptoms of patients in manic episode.ObjectivesTo determine the usefulness of HAMD-5 and MES depression scales in patients with bipolar disorder type I and II who have a manic or hypomanic episode with depressive symptoms. These scales were compared with the HAMD-21 and the MADRS scales respectively.Methods100 subjects between 18 and 65 years old were included. All patients met the DSM-IV-TR criteria for bipolar disorder with manic or hypomanic symptoms and major depression.All patients were evaluated at baseline and at 3 and 4 weeks during the follow-up.ResultsAt baseline the HAMD-5 and the MES had high reliability (α = 0.88 and α = 0,74 respectively)The test-retest reliability between the 3rd and the 4th week was great for both scales (HAMD-5: r = 0,89; p < 0,001; MES: r = 0,77; p < 0,001).The convergent validity had an acceptable level for the HAMD-5 (HAMD-21/HAMD-5 = 0,73; 95% CI 0,599–0,873) and for the MES (MADRS/MES = 0,79; 95% CI 0,766–0,894)Regarding the discriminant validity, the values for the HAMD-5 and MES were higher than for the HAMD-21 and MADRS respectively (HAM-5: AUC = 0,92, 95% CI: 0,892–0,980; MES: AUC = 0,86, 95% CI: 0,786–0,934).ConclusionsBoth scales showed an adequate correlation with the HAMD-21 and MADRS and a high capacity of detection of mixed, pure and other symptoms as their remission.

IntroductionMixed Bipolar patients are those who have co-existing depressive symptoms during mania. These patients are supposed to have a worse evolution.ObjectiveThe objective of this study was to compare the long-term outcomes of patients who had at least one mixed episode with those who experienced only pure manic episodes.Methods169 outpatients diagnosed of Bipolar I disorder and treated at least during two years were included. 120 patients (71%) complited the follow-up over 10 years. Baseline demographic and clinical variables were included.ResultsThe patients with mixed episodes (37%) had a significantly younger mean age at onset comparing with those with manic episodes (25.3 years vs. 30.8 years; p=0.025) they also had more previous mood- incongruent psychotic symptoms χ2= 6.77, p=0.034), more number of hospitalizations (OR= 1.36, 95% CI = 1.14; -1.63; p< 0.001), and more number of episodes (OR= 1.21, 95% CI = 1.10-1.31; p< 0.001). There were no significant differences relating to depressive episodes, alcohol use, drug abuse, suicidal behaviour and suicide attempts.DiscussionAge at onset differed significantly between the mixed episode and pure mania groups, with mixed episode patients having a younger age of onset. This is interesting as one of the major results of the study we have found that age at onset mediates some of the factors classically related to outcome in mixed episodes like alcohol abuse and suicide attempts. However, independently of age at onset, these patients represent a especially severe type of bipolar disorder.

The presence of depressive subsyndromal symptoms (SS) in bipolar disorder (BD) increases the risk of affective relapse and worsens social, cognitive functioning, and quality of life. Nonetheless, there are limited data on how to optimize the treatment of subthreshold depressive symptoms in BD. Mindfulness-Based Cognitive Therapy (MBCT) is a psychotherapeutic intervention that has been shown effective in unipolar depression. The assessment of its clinical effectiveness and its impact on biomarkers in bipolar disorder patients with subsyndromal depressive symptoms and psychopharmacological treatment is needed. A randomized, multicenter, prospective, versus active comparator, evaluator-blinded clinical trial is proposed. Patients with BD and subclinical or mild depressive symptoms will be randomly allocated to: 1) MBCT added to psychopharmacological treatment; 2) a brief structured group psychoeducational intervention added to psychopharmacological treatment; 3) standard clinical management, including psychopharmacological treatment. Assessments will be conducted at screening, baseline, post-intervention (8 weeks) and 4 month follow-up post-intervention. The aim is to compare MBCT intervention versus a brief structured group psychoeducation. Our hypothesis is that MBCT will be more effective in reducing the subsyndromal depressive symptoms and will improve cognitive performance to a higher degree than the psychoeducational treatment. It is also hypothesized that a significant increase of BDNF levels will be found after the MBCT intervention. This is the first randomized controlled trial to evaluate the effects of MBCT compared to an active control group on depressive subthreshold depressive symptoms in patients with bipolar disorder. ClinicalTrials.gov: NCT02133170 . Registered 04/30/2014.