RESUMEN
OBJECTIVES: To study the physical and neuropsychological development of children with Citrin deficiency (CD). METHODS: A total of 93 children, aged 1.9-59.8 months, who were diagnosed with CD by SLC25A13 gene analysis in the First Affiliated Hospital of Jinan University from August 2010 to August 2015, were enrolled as subjects. A retrospective analysis was performed for their birth condition and physical growth and neuropsychological development indices. Among these children, 7 underwent physical measurement and neuropsychological development assessment within 1 year old and after 1 year old, and therefore, a total of 100 cases were included for analysis. RESULTS: For the 93 children with CD, the incidence rate of failure to thrive was 25% (23 children) and the proportion of small for gestational age was 47% (44 children). For the 100 cases of CD, the incidence rates of growth retardation, underweight, emaciation, overweight, and microcephalus were 23% (23 cases), 14% (14 cases), 4% (4 cases), 8% (8 cases), and 9% (9 cases), respectively. The incidence rate of neuropsychological developmental delay was 25% (25 cases), and the incidence rates of development delay in the five domains of adaptability, gross motor, fine motor, language, and social ability were 7% (7 cases), 15% (15 cases), 7% (7 cases), 9% (9 cases), and 7% (7 cases), respectively. CONCLUSIONS: Physical and neuropsychological developmental delay can be observed in children with CD, and physical and neuropsychological development should be regularly assessed.
Asunto(s)
Desarrollo Infantil , Citrulinemia , Citrulinemia/fisiopatología , Humanos , Lactante , Proteínas de Transporte de Membrana Mitocondrial , Pruebas Neuropsicológicas , Estudios RetrospectivosRESUMEN
BACKGROUND: Little is known about the optimal dietary treatment for citrin deficiency. Our aim is to describe the management of UK citrin deficiency patients. METHODS: A longitudinal retrospective review was performed. Data were collected from medical records on presenting signs and symptoms, dietary management and clinical outcome. RESULTS: data were collected on 32 patients from 21 families. 50% were females (16/32). Median age at diagnosis was 4 y (5 days-35 y) with 12 patients diagnosed in the neonatal period with neonatal intrahepatic cholestasis (NICCD), eight later in childhood (FTTDCD) and 12 by family screening based on index cases from five families. No patient had adult-onset type II citrullinemia. The patient age at the time of data collection was a median of 11 y (1-44 y). 91% (29/32) of patients had normal physical and neurological development, 47% (15/32) experienced recurrent unexplained abdominal pain and 9% (3/32) episodes of hypoglycaemia. Siblings had different phenotypes (5 families had > 1 affected patient). Most patients preferred high protein foods, limiting sugar-containing foods. Only 41% (13/32) were prescribed a low CHO, high protein, high fat diet (restriction varied) and two used medium chain triglyceride (MCT) supplements. No patient was prescribed drug therapy. Twenty-five per cent (8/32) of patients were underweight and 41% (13/32) had height <-1 z-scores. CONCLUSIONS: patients presented with various phenotypes, symptoms and suboptimal growth. Symptoms and biochemical markers improved with age, but height remained low in some. More research is necessary to assess the effectiveness of dietary approaches in improving clinical outcomes and symptoms in citrin deficiency.
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Citrulinemia/dietoterapia , Dieta Alta en Grasa/métodos , Dieta Rica en Proteínas y Pobre en Hidratos de Carbono/métodos , Suplementos Dietéticos , Estado de Salud , Adolescente , Adulto , Biomarcadores/sangre , Niño , Preescolar , Citrulinemia/sangre , Citrulinemia/fisiopatología , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Fenotipo , Estudios Retrospectivos , Resultado del Tratamiento , Triglicéridos/administración & dosificación , Reino Unido , Adulto JovenRESUMEN
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) primarily manifests in neonates or infants with hepatomegaly, liver dysfunction, and hypoglycemia. This study investigated the functions of islet beta cells and their correlations with liver dysfunction in NICCD patients.We retrospectively analyzed clinical data on liver function and islet beta cell functions for 36 patients diagnosed with NICCD and 50 subjects as the control group. The NICCD group had significantly higher total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate amino transferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and alpha-fetoprotein (AFP) levels and albumin/globulin ratio (A/G) (Pâ<â.05), and lower ALB and GLB levels than the control group (Pâ<â.05). The differences in fasting blood glucose (FBG), fasting insulin, C-peptide (C-P), the homeostasis model of assessment for the insulin resistance index (HOMA-IR), fasting beta cell function (FBCI), and the HOMA beta cell function index (HBCI) between the NICCD and control groups were not significant (Pâ>â.05). A linear correlation was found between FBG and fasting insulin (Pâ<â.001) and between FBG and C-P in the NICCD patients (Pâ=â.001). Fasting insulin (Pâ=â.023), HOMA-IR (Pâ=â.023), FBCI (Pâ=â.049), and HBCI (Pâ=â.048) were positively correlated with increases in the ALT level. There was no difference in islet beta cell functions between the NICCD and control groups. The liver dysfunction may be correlated with islet beta cell functions in NICCD patients.
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Citrulinemia/fisiopatología , Células Secretoras de Insulina/fisiología , Hígado/fisiopatología , Péptido C/sangre , Citrulinemia/genética , Femenino , Humanos , Lactante , Insulina/sangre , Masculino , Proteínas de Transporte de Membrana Mitocondrial/genética , Estudios RetrospectivosRESUMEN
Protein arginine methyltransferase 7 (PRMT7) catalyzes the introduction of monomethylation marks at the arginine residues of substrate proteins. PRMT7 plays important roles in the regulation of gene expression, splicing, DNA damage, paternal imprinting, cancer and metastasis. However, little is known about the interaction partners of PRMT7. To address this, we performed yeast two-hybrid screening of PRMT7 and identified argininosuccinate synthetase (ASS1) as a potential interaction partner of PRMT7. We confirmed that PRMT7 directly interacts with ASS1 using pull-down studies. ASS1 catalyzes the rate-limiting step of arginine synthesis in urea cycle and citrulline-nitric oxide cycle. We mapped the interface of PRMT7-ASS1 complex through computational approaches and validated the predicted interface in vivo by site-directed mutagenesis. Evolutionary analysis revealed that the ASS1 residues important for PRMT7-ASS1 interaction have co-evolved with PRMT7. We showed that ASS1 mutations linked to type I citrullinemia disrupt the ASS1-PRMT7 interaction, which might explain the molecular pathogenesis of the disease.
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Argininosuccinato Sintasa/genética , Argininosuccinato Sintasa/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Centrifugación , Citrulinemia/fisiopatología , Análisis Mutacional de ADN , Humanos , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Unión Proteica , Mapeo de Interacción de Proteínas , Técnicas del Sistema de Dos HíbridosRESUMEN
Citrin is a liver-type aspartate/glutamate carrier (AGC) encoded by the gene SLC25A13. Two phenotypes for human citrin deficiency have been described, namely the adult-onset citrullinemia type II (CTLN2) and the neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). However, citrin deficiency currently remains a perplexing and poorly recognized disorder. In particular, description of post-NICCD clinical presentations before CTLN2 onset is rather limited. Analysis of SLC25A13 mutations, identification of dysmorphic erythrocytes, hepatobiliary scintigraphic imaging and investigation of post-NICCD clinical presentations were performed in a citrin-deficient cohort comprised of 51 cases of children diagnosed with citrin deficiency in a Chinese pediatric center. Twelve SLC25A13 mutations were detected in this cohort, including the novel V411M and G283X mutations. Among the 51 citrin-deficient subjects, 7 cases had echinocytosis, which was associated with more severe biochemical abnormalities. Delayed hepatic discharge and bile duct/bowel visualization were common scintigraphic findings. Moreover, 9 of the 34 post-NICCD cases demonstrated concurrent failure to thrive and dyslipidemia, constituting a clinical phenotype different from NICCD and CTLN2. The novel mutations, echinocytosis, hepatobiliary scintigraphic features and the novel clinical phenotype in this study expanded the genotypic and phenotypic spectrum of citrin deficiency, and challenge the traditionally-assumed 'apparently healthy' period after the NICCD state for this disease entity.
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Proteínas de Transporte de Membrana Mitocondrial/genética , Pueblo Asiatico/genética , Conductos Biliares/diagnóstico por imagen , Citrulinemia/diagnóstico por imagen , Citrulinemia/genética , Citrulinemia/fisiopatología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Fenotipo , CintigrafíaRESUMEN
AIM: The aim of this study was to develop and apply a mutation screening protocol for the ASS1 gene in order to confirm the diagnosis of citrullinaemia type I in neonates with elevated citrulline on expanded newborn screening (E-NBS). METHODS: Three patients with an elevated citrulline level were identified via routine E-NBS between January and October 2008. Analysis of the ASS1 gene using a polymerase chain reaction and sequencing-based method was successfully applied to all three patients, together with a rapid mutation-specific detection method. Their clinical progress was followed for 16-22 months. RESULTS: All three patients were homozygous for a previously reported missense mutation, c.787G>A (p.Val263Met), associated with a mild or asymptomatic clinical course. CONCLUSIONS: As a consequence of E-NBS, an increasing number of neonates with elevated citrulline of uncertain clinical significance are being identified. Rapid sequence analysis of the ASS1 gene can be used to confirm citrullinaemia type I and, increasingly, to infer phenotypic severity. Homozygosity for the same mutation was found in all three patients despite non-consanguinity and variable Pacific Island origin. These data suggest that this mutation may be relatively prevalent in these ethnic groups and imply a possible founder effect.
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Citrulinemia/clasificación , Citrulinemia/diagnóstico , Mutación/genética , Argininosuccinato Sintasa/genética , Argininosuccinato Sintasa/aislamiento & purificación , Citrulina/sangre , Citrulinemia/genética , Citrulinemia/fisiopatología , Efecto Fundador , Pruebas Genéticas , Humanos , Recién Nacido , Masculino , Islas del PacíficoRESUMEN
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) shows diverse metabolic abnormalities such as urea cycle dysfunction together with citrullinemia, galactosemia, and suppressed gluconeogenesis. Such abnormalities apparently resolve during the first year of life. However, metabolic profiles of the silent period remain unknown. We analyzed oxidative stress markers and profiles of amino acids, carbohydrates, and lipids in 20 asymptomatic children with aspartate/glutamate carrier isoform 2-citrin-deficiency aged 1-10 years, for whom tests showed normal liver function. Despite normal plasma ammonia levels, the affected children showed higher blood levels of ornithine (p<0.001) and citrulline (p<0.01)--amino acids involved in the urea cycle--than healthy children. Blood levels of nitrite/nitrate, metabolites of nitric oxide (NO), and asymmetric dimethylarginine inhibiting NO production from arginine were not different between these two groups. Blood glucose, galactose, pyruvate, and lactate levels after 4-5h fasting were not different between these groups, but the affected group showed a significantly higher lactate to pyruvate ratio. Low-density and high-density lipoprotein cholesterol levels in the affected group were 1.5 times higher than those in the controls. Plasma oxidized low-density lipoprotein apparently increased in the affected children; their levels of urinary oxidative stress markers such as 8-hydroxy-2'-deoxyguanosine and acrolein-lysine were significantly higher than those in the controls. Results of this study showed, even during the silent period, sustained hypercitrullinemia, hypercholesterolemia, and augmented oxidative stress in children with citrin deficiency.
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Pueblo Asiatico , Citrulinemia/complicaciones , Hipercolesterolemia/complicaciones , Proteínas de Transporte de Membrana/deficiencia , Proteínas Mitocondriales/deficiencia , Estrés Oxidativo , Aminoácidos/sangre , Apolipoproteínas/sangre , Biomarcadores/orina , Carbohidratos/sangre , Niño , Preescolar , Citrulinemia/sangre , Citrulinemia/fisiopatología , Ayuno/sangre , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/fisiopatología , Lactante , Japón , Metabolismo de los Lípidos , Hígado/patología , Hígado/fisiopatología , Pruebas de Función Hepática , Masculino , Proteínas de Transporte de Membrana Mitocondrial , Óxido Nítrico/metabolismo , Urea/metabolismo , Vitamina E/sangreRESUMEN
BACKGROUND: Adult-onset type II citrullinemia is an inborn error of urea cycle metabolism that can lead to hyperammonemic encephalopathy and coma. However, type II citrullinemia is rare outside Japan, and diagnosis and treatment can be delayed. Magnetic resonance spectroscopy may be a useful adjunct to magnetic resonance imaging, and has been applied to noninvasively study chemical metabolism in the human brain. PATIENTS: We describe 2 patients with type II citrullinemia who presented with episodic postprandial somnolence and coma. Diffusion-weighted magnetic resonance imaging showed bilaterally symmetrical signal abnormalities of the insular cortex and cingulate gyrus. On magnetic resonance spectroscopy, glutamine and glutamate levels were elevated, and choline and myo-inositol levels were decreased. The diagnosis of citrullinemia was confirmed based on elevated plasma ammonia and citrulline levels. CONCLUSION: Characteristic features found at the time of magnetic resonance imaging and magnetic resonance spectroscopy may be helpful for early diagnosis of type II citrullinemia in adult patients who present with hyperammonemic encephalopathy and coma.
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Encéfalo/metabolismo , Encéfalo/fisiopatología , Citrulinemia/metabolismo , Citrulinemia/fisiopatología , Glutamina/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Adulto , Amoníaco/sangre , Biomarcadores/análisis , Biomarcadores/metabolismo , Mapeo Encefálico , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Colina/metabolismo , Citrulina/sangre , Citrulinemia/diagnóstico , Coma/etiología , Coma/metabolismo , Coma/fisiopatología , Imagen de Difusión por Resonancia Magnética , Progresión de la Enfermedad , Diagnóstico Precoz , Resultado Fatal , Ácido Glutámico/metabolismo , Giro del Cíngulo/metabolismo , Giro del Cíngulo/fisiopatología , Humanos , Hiperamonemia/sangre , Hiperamonemia/diagnóstico , Hiperamonemia/fisiopatología , Inositol/metabolismo , Espectroscopía de Resonancia Magnética/normas , Masculino , Valor Predictivo de las PruebasAsunto(s)
Proteínas de Unión al Calcio/deficiencia , Transportadores de Anión Orgánico/deficiencia , Ácido Aspártico/metabolismo , Calcio/metabolismo , Proteínas de Unión al Calcio/fisiología , Colestasis Intrahepática/etiología , Mapeo Cromosómico/métodos , Citrulinemia/clasificación , Citrulinemia/genética , Citrulinemia/fisiopatología , Frecuencia de los Genes , Homocigoto , Humanos , Recién Nacido , Maleatos/metabolismo , Proteínas de Transporte de Membrana/genética , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial , Proteínas Mitocondriales/genética , Mutación , NAD/metabolismo , Transportadores de Anión Orgánico/fisiologíaRESUMEN
INTRODUCTION: Citrullinemia is an autosomal recessive disease, which is caused by a deficiency of the argininosuccinate synthetase. The neonatal forms are serious and many times are associated with a high level of mortality. CASE REPORT: A newborn that came in again on her third day of life due to a apneic episodes which required mechanical ventilation. Previously, she rejected feeding, had poor suction, lethargy and remarkable hypoactivity. During the following hours, she showed serious neurologycal deterioration with multifocal convulsions and coma, passing away 20 hours after admission due to endocraneal hypertension. The metabolic evaluation confirmed very significant hyperammonemia, with important increase of citrullin and glutamin, and arginine in the low limits of normality. She was treated with sodium benzoate and arginine and she also needed exanguinotransfusion. It was not possible to put her on hemodyalisis. The findings of the autopsy confirmed massive cerebral edema and characteristic hystological changes in the liver. The determination of the enzymatical activity in liver tissue showed a partial deficiency, with a residual activity of 25% of the average control. CONCLUSIONS: This is a case of fulminant neonatal citrullinemia that we considered of interest in order to draw the attention of the clinical on this type of diseases. The prognosis depends on early diagnosis, witch is based on clinical suspicion and analytical determination of ammonia in every newborn with unexplained vomiting, lethargy or other symptoms of encephalopathy.
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Citrulinemia/fisiopatología , Adulto , Amoníaco/sangre , Niño , Citrulina/sangre , Citrulinemia/sangre , Citrulinemia/diagnóstico , Resultado Fatal , Femenino , Glutamina/sangre , Humanos , Lactante , Recién Nacido , Hígado/enzimología , PronósticoRESUMEN
UNLABELLED: Adult-onset type 2 citrullinaemia (CTLN2) is caused by a deficiency of the citrin protein encoded by the SLC25A13 gene. Citrin, an aspartate glutamate carrier in mitochondria, is an essential component of the malate-aspartate NADH shuttle. Recently, citrin deficiency has been reported to manifest as neonatal intrahepatic cholestasis. We report here five cases with neonatal intrahepatic cholestasis caused by citrin deficiency. Genetic diagnosis revealed compound heterozygotes of 851del4/IVS11 + 1G-->A in two patients, IVS11 + 1G-->A/E601X, and IVS11 + 1G-->A/unknown in each one patient and homozygote for S225X in one patient. All cases revealed high levels of alpha-fetoprotein, which are not observed in CTLN2 patients. The condition was self-limiting and spontaneously disappeared after 5-7 months of age in four patients. However, one patient developed hepatic dysfunction from the age of 6 months and required a living-related liver transplantation at the age of 10 months. The patient showed complete recovery after transplantation, and now at the age of 3 years, shows normal growth and mental development. CONCLUSION: we report the first case of neonatal intrahepatic cholestasis caused by citrin deficiency with severe hepatic dysfunction requiring a living-related liver transplantation. Patients with this disorder should be followed up carefully, even during infancy.
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Proteínas de Unión al Calcio/deficiencia , Colestasis Intrahepática/etiología , Colestasis Intrahepática/cirugía , Citrulinemia/fisiopatología , Trasplante de Hígado , Transportadores de Anión Orgánico/deficiencia , Colestasis Intrahepática/congénito , Femenino , Humanos , Lactante , Recién Nacido , Donadores Vivos , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana Mitocondrial , Proteínas Mitocondriales/genética , Mutación , Remisión EspontáneaRESUMEN
By using homozygosity mapping and positional cloning, we have shown that adult-onset type II citrullinemia (CTLN2) is caused by mutations of the SLC25A13 gene, which is localized on chromosome 7q21.3 and encodes a mitochondrial solute carrier protein named citrin. So far, we have reported nine mutations, most of which cause loss of citrin, and we have established several methods for DNA diagnosis. These methods have shown that more than 90% of the patients diagnosed as suffering from CTLN2 by enzymatic analysis carry SLC25A13 mutations in both alleles, indicating that CTLN2 is caused by citrin deficiency. Furthermore, by using the same DNA diagnosis methods, we discovered that 70 neonates or infants suffering from a particular type of neonatal hepatitis carry the same SLC25A13 mutations. Since the symptoms of the neonates are different from those of the more severe CTLN2 and usually ameliorate without special treatment, we designated the neonatal disease neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). We conclude that citrin deficiency causes NICCD in neonates and CTLN2 in adults through the additional effects of genetic or environmental modifiers. Since the function of citrin, together with that of an isoform, aralar, was found to be as a mitochondrial aspartate glutamate carrier, the various symptoms of NICCD and CTLN2 may be understood as caused by defective aspartate export from the mitochondria to the cytosol and defects in the malate aspartate shuttle. It is, however, still difficult to understand the cause of the hepatic deficiency of argininosuccinate synthetase protein in CTLN2.
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Citrulinemia/etiología , Hepatitis/etiología , Proteínas de Transporte de Membrana/deficiencia , Mitocondrias/metabolismo , Proteínas Mitocondriales/deficiencia , Adolescente , Adulto , Anciano , Argininosuccinato Sintasa/genética , Argininosuccinato Sintasa/metabolismo , Niño , Colestasis Intrahepática/etiología , Citrulinemia/genética , Citrulinemia/fisiopatología , Citrulinemia/terapia , Frecuencia de los Genes , Hepatitis/genética , Hepatitis/terapia , Humanos , Hígado/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Persona de Mediana Edad , Mitocondrias/genética , Proteínas de Transporte de Membrana Mitocondrial , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismoRESUMEN
Type II citrullinaemia (CTLN2) is an adult- or late childhood-onset liver disease characterized by a liver-specific defect in argininosuccinate synthetase protein. The enzyme abnormality is caused by deficiency of the protein citrin, which is encoded by the SLC25A 13 gene. Until now, however, few cases with SLC25A13 mutations have been reported in children with liver disease. We describe an infant who presented with neonatal hepatitis in association with hypergalactosaemia detected by neonatal mass screening. DNA analysis of SLC25A13 revealed that the patient was homozygous for a IVS11+1G>A mutation. This case suggests that SLC25A13 mutant should be suspected in neonatal patients with hypergalactosaemia of unknown cause.
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Citrulinemia/genética , Galactosemias/genética , Proteínas de Transporte de Membrana/genética , Proteínas Mitocondriales/genética , Citrulinemia/sangre , Citrulinemia/complicaciones , Citrulinemia/fisiopatología , Femenino , Galactosa/sangre , Galactosemias/sangre , Galactosemias/complicaciones , Humanos , Recién Nacido , Tamizaje Masivo , Proteínas de Transporte de Membrana MitocondrialAsunto(s)
Proteínas de Unión al Calcio/genética , Citrulina/sangre , Citrulina/genética , Citrulinemia/genética , Proteínas de Transporte de Membrana , Mitocondrias Hepáticas/metabolismo , Proteínas Mitocondriales , Mutación/genética , Proteínas de Unión al Calcio/metabolismo , Citrulinemia/sangre , Citrulinemia/fisiopatología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Exones/genética , Eliminación de Gen , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias Hepáticas/patología , Proteínas de Transporte de Membrana MitocondrialRESUMEN
We describe a 64-year-old man with 'citrullinemia type II' whose serum citrulline levels fluctuated between normal and abnormally high during episodic manifesting periods. Elevations of the serum threonine/serine ratio and pancreatic secretory trypsin inhibitor level are very useful diagnostic markers. Our patient's cerebrospinal fluid citrulline level was also elevated, and T1-weighted magnetic resonance images revealed high-intensity signals at the bilateral internal capsule and the cerebral peduncles. Single-photon emission computed tomography of his brain showed reduced bilateral temporal lobar blood flow. Even if the serum citrulline level is within the normal range, citrullinemia should be considered in adult patients without primary liver dysfunction who show episodic consciousness disturbance, psychotic symptoms or both.