Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care.

PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.

PURPOSE: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined. METHODS: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations. RESULTS: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis. CONCLUSION: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.

Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype.

Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS.

Psychometric evaluation of SAFA P test for eating disorders in adolescents: comparative validation with EDI-2.

OBJECTIVE: This study evaluates the psychometric properties of self-administered psychiatric scale for children and adolescents with psychogenic eating disorders (SAFA P)--a brief self-report designed to screen and assess eating disorders (ED) in children and adolescents. Although SAFA P belongs to a broad battery of tests (SAFA) that explores different psychiatric conditions, it has not undergone appropriate validation until now. METHOD: We administered SAFA P and Eating Disorder Inventory 2 (EDI-2) to 87 ED patients, with an average age of 15.4 ± 1.6 years. RESULTS: The internal reliability of SAFA P is good (Cronbach α = .776). Convergent validity with EDI-2 was assessed: both SAFA P subscale P1 (p < .005) and EDI-2 subscale bulimia (p < .001) showed a statistically significant difference among the three diagnostic categories (anorexia nervosa, bulimia nervosa and eating disorder not otherwise specified). Sensibility and specificity range from 62 to 91%, depending on the subscales. McNemar's test did not reveal statistically significant differences in assessing the concordance of the two measures. Statistically significant correlations were found between specific couples of subscales (p < .001). CONCLUSIONS: Cross-validation with EDI-2 showed good results. SAFA P may be an alternative, useful and reliable instrument for assessing cursory ED in childhood and adolescence.

Drama therapy and eating disorders: a historical perspective and an overview of a Bolognese project for adolescents.

OBJECTIVES: The authors present a description of a theater workshop ("Metamorphosis Project"), developed at the Bologna Eating Disorders Center. DESIGN: The workshops are aimed at young, hospitalized patients, and are largely based on the principles of drama therapy. In this article, this therapeutic modality is introduced by a discussion of the theoretical basis for the use of theater in psychiatry from the points of view of several preeminent psychiatrists, including Freud, Winnicott, Klein, and Moreno. RESULTS: Three (3) clinical reports are presented. The satisfaction rate among the first groups of participants was 93%. CONCLUSIONS: It is suggested that theater can be useful in decreasing defense mechanisms, allowing a patient-focused approach, mitigating specific symptoms, and improving the quality of life during the hospital stay.

The relationship between alexithymia, shame, trauma, and body image disorders: investigation over a large clinical sample.

BACKGROUND: The connections between eating disorders (EDs) and alexithymia have not been fully clarified. This study aims to define alexithymia's connections with shame, trauma, dissociation, and body image disorders. METHODS: We administered the Dissociative Experience Scale-II, Trauma Symptom Inventory, Experience of Shame Scale, Toronto Alexithymia Scale-20, and Body Uneasiness Test questionnaires to 143 ED subjects. Extensive statistical analyses were performed. RESULTS: The subjects showed higher scores on alexithymia, shame, dissociation, and traumatic feelings scales than the nonclinical population. These aspects are linked with each other in a statistically significant way. Partial correlations highlighted that feelings of shame are correlated to body dissatisfaction, irrespective of trauma or depressed mood. Multiple regression analysis demonstrates that shame (anorexic patients) and perceived traumatic conditions (bulimic and ED not otherwise specified) are associated with adverse image disorders. CONCLUSION: Shame seems to hold a central role in the perception of an adverse self-image. Alexithymia may be interpreted as being a consequence of previous unelaborated traumatic experiences and feelings of shame, and it could therefore be conceptualized as a maladaptive-reactive construct.

Audit of digestive complaints and psychopathological traits in patients with eating disorders: a prospective study.

BACKGROUND: Esophago-gastrointestinal symptoms are frequently reported by patients with eating disorders. Scanty data exist on the relationship between psychopathological traits and digestive complaints. AIMS: To prospectively analyze (i) prevalence of digestive symptoms; (ii) psychopathological traits; (iii) relationship between symptom scores and psychopathological profiles. METHODS: Psychopathological and digestive symptom questionnaires were completed at baseline, at discharge, at 1 and 6 months' follow-up in 48 consecutive patients (85.4% female, median age, 15 years) hospitalized for eating disorders. RESULTS: The most frequently reported symptoms were postprandial fullness (96%) and abdominal distention (90%). Pooled esophageal (4; IQR 0-14) and gastrointestinal (34; IQR 19-53) symptoms significantly decreased at 6 months' follow-up (1; IQR 0-3 and 10; IQR 4-34; p<0.0001 and p<0.005, respectively). Pooled gastrointestinal symptoms significantly correlated with hypochondriasis (r=0.42, p<0.01). Both esophageal and gastrointestinal symptoms improved in patients with normal values of hypochondriasis and hysteria scales (p<0.05 and p<0.005, respectively) compared to those with pathological traits. CONCLUSIONS: Digestive symptoms are frequently reported by patients with eating disorders with their expression and outcome being influenced by psychopathological profiles. Hypochondriasis and hysteria traits are predictive factors for symptomatic improvement.

Generalized tonic-clonic seizure secondary to duloxetine poisoning: a short report with favorable out come.

Duloxetine is a potent and selective inhibitor of serotonin and norepinephrine reuptake (SNRI) with a weak activity over dopamine reuptake used in the treatment of major depressive disorder. Daily doses of 60 mg are effective in treatment of major depression. There are few cases of isolated duloxetine overdose in humans. We think this is the first report of a generalized tonic-clonic seizure following isolated duloxetine poisoning with a very high dosage.

Epilepsy and trimethylaminuria: A new case report and literature review.

Trimethylaminuria is a metabolic disorder characterized by the excessive excretion of trimethylamine in bodily secretions, which confers a very unpleasant odour resembling that of dead fish. Literature reports only two cases affected by trimethylaminuria and epilepsy. We describe a third patient who, from the age of seven, was affected by temporal focal seizures with nocturnal episodes of nausea, vomiting, anxiety and autonomic activation followed by headache. EEG showed focal paroxysmal abnormalities prevailing on the right temporo-parieto-occipital regions. We began administering levetiracetam and seizures stopped. Our patient also showed learning disabilities despite a normal intelligence quotient (IQ), while another described patient had an IQ varying from borderline to mild mental retardation. We discuss the association between trimethylaminuria and epilepsy, and formulate some hypotheses on the relationship between trimethylamine convulsive effect and the anticonvulsive role of levetiracetam.

Emergent factors in eating disorders in childhood and preadolescence.

We have reviewed the literature related to the current advances in comprehension of Eating Disorders (ED) in childhood and preadolescence. The state of art regarding the psychodynamic models concerning the onset of ED are explained. DSM-IV and ICD-10 criteria are discussed, pointing out their little value in the characterization of early eating difficulties. Historic and new diagnostic classifications are displayed in detail. We provided a clearer description of subclinical patterns. Finally we focus on the key role of the paediatrician in detecting and managing parental concerns regarding feeding.

SAFA: A new measure to evaluate psychiatric symptoms detected in a sample of children and adolescents affected by eating disorders. Correlations with risk factors.

In order to evaluate the psychiatric symptoms associated with a diagnosis of eating disorders (ED) we have administered a new psychometric instument: the Self Administrated Psychiatric Scales for Children and Adolescents (SAFA) test. SAFA was administered to a cohort of 97 patients, aged from 8.8 to 18, with an ED diagnosis. Age, body mass index (BMI) and BMI standard deviation score were analyzed. Furthermore, while looking for linkable risk factors, we evaluated other data that took an influence over the SAFA profile, like parental separation and family components' number. Compared to the range of statistical normality (based on Italian population), patients with bulimia nervosa or binge-eating disorder showed higher and pathologic values in specific subscales. When analyzing sex, males showed more pathologic values in most anxiety-related, obsessiveness-compulsiveness-related and insecurity subscales. A correlation among age, BMI and specific subscales (low self esteem, psychological aspects) emerged in participants with anorexia nervosa. In order to plan more appropriate diagnostic and therapeutic approaches in children or adolescents suffering from ED, the SAFA test can be an important instrument to evaluate psychiatric symptoms. Therefore, we propose to include this useful, simple self-administered test as a new screening tool for ED diagnosis.

Prospective study on long-term treatment with oxcarbazepine in pediatric epilepsy.

Following a previous preliminary report on a group of children suffering from partial epilepsies, we present the final considerations on the same group in order to evaluate the long-term efficacy, tolerability and safety of oxcarbazepine (OXC). We enrolled 36 patients (mean age 8.5), between January 2003 and December 2004, with new diagnosis of partial epilepsy: 25 patients were affected by idiopathic partial epilepsy, eight by symptomatic epilepsy and three by cryptogenic epilepsy. Each patient was scheduled to attend the center four times after the initial examination: 3 months (T1), 12 months (T2), 24 (T3) months and 36 (T4) months after the beginning of OXC-monotherapy (T0). At the end of our study, 20 patients were seizure free (SF): nine stopped OXC because of SF for at least 2 years, 11 were still on therapy. One patient showed a reduction of seizure frequency >or=50%, three were non responders (but still on therapy), nine stopped OXC due to a non-responder condition during follow-up before T4 and one because of adverse effects. At the end of the study no EEG focal abnormalities became generalized because of treatment. Normalization of EEG was observed in ten patients. Our preliminary findings have been confirmed. OXC can be considered an effective and well tolerated first line drug for long-term monotherapy in children with epilepsy, both for idiopathic and symptomatic/cryptogenic forms.