Alessandro Pellicciari

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.

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 instrument: 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.

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.

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.

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: Is it a matter of GABA?

To the Editors: We have read with interest the latest advances regarding ZEB2 gene function in neuroembryology and its connections with epilepsy (McKinsey et al., 2013; Van den Berghe et al., 2013). Zinc finger E-box binding homeobox 2 (ZEB2, MIM#60580), also annotated as ZFHX1B and SIP1, is a member of the two-handed zinc finger/homeodomain transcription factors. Its role during development has been confirmed by invalidation in mice, which revealed arrest of embryonic development with severe neural plate and somatogenesis defects, as well as migratory failure of neural crest cells (Van de Putte et al., 2003). In humans, deletions or mutations of ZEB2 cause the Mowat-Wilson syndrome (MWS), which is characterized by a distinctive facial appearance, intellectual disability, and variable other features including agenesis of the corpus callosum and Hirschsprung disease (Mowat et al., 2003). Epilepsy is one of the main features of MWS, with a prevalence of about 70–75%. We recently delineated the electroclinical phenotype of epilepsy in MWS. In these patients, epilepsy is usually characterized by frontal lobe and atypical absence seizures, often preceded by fevertriggered seizures; in addition, we observed an age-dependent electroencephalography (EEG) pattern with frequent diffuse frontal dominant spike and wave discharges during the awake state and a near to continuous spike and wave activity during slow sleep (Cordelli et al., 2013). Some authors suggested that epilepsy in MWS could be the result of cerebral malformations (Engenheiro et al., 2008). Instead, we noticed that MRI did not disclose any cortical malformations clearly associated with epilepsy and that the electroclinical pattern (which was present irrespective of magnetic resonance imaging [MRI] findings) suggested an age-related disorder with a genetic, rather than a structural-malformative, etiology. Meanwhile, McKinsey and Van den Berghe et al. demonstrated the influence of ZEB2 on the neurogenesis of cortical c-aminobutyric acid (GABA)ergic interneurons. Their studies highlight that the lack of ZEB2 prevents the repression of NKX2-1 homeobox transcription factor, the expression of which provokes the differentiation of the progenitors in striatal interneurons rather than cortical ones. Deficit of GABAergic inhibition is supposed to underlie most forms of seizures, including focal and absence seizures (Yalc ın, 2012). However, results of GABAergic inhibition are brain-area and inhibitory-pathway specific. In fact, within one brain region, at a given time of life, some modifications in these circuitries will appear as proepileptic and others as antiepileptic (Bernard et al., 2000). Therefore, the switch between cortical and striatal GABAergic interneurons determined by mutations of ZEB2 could suggest a mechanism for the epilepsy observed in MWS, as proposed by McKinsey and Van den Berghe. From our point of view, that is the one of the clinicians, we strongly support this hypothesis, as the age-related electroclinical pattern we have detected in vivo is reminiscent of the idea of a genetic form of epilepsy and is scarcely influenced by brain macroanatomy. In conclusion, we feel that these observations could be of high importance in understanding how epilepsy is determined in patients with MWS. New interesting scenarios in terms of treatment are now opened.

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. McNemars 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.

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

PurposeMowat–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.MethodsIn 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.ResultsAll 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.ConclusionKnowledge 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.

Su1641 Audit of Gastrointestinal Symptoms and Psychopathological Traits in Patients With Eating Disorders: A Prospective Study

BACKGROUND: Esophago-gastrointestinal (EGI) symptoms are frequently reported by patients with eating disorders (ED), who tend to use somatic disturbances to justify modifications of alimentary behaviour. It is not clear if referred symptoms are real, whether they ameliorate after controlled diet or if there are related to psychopathogical traits. AIM: (i) to analyze the prevalence of moderate-severe EGI symptoms, either individual or pooled, and of Minnesota Multiphasic Personality Inventory (MMPI-2 or MMPI-A) scales in hospitalized ED patients and symptoms modifications after 6 months of follow-up; (ii) to correlate EGI symptoms and sds-body mass index (sdsBMI) changes with MMPI scales. METHODS: We enrolled 48 consecutive patients (41 F, median age 15) hospitalized with a diagnosis of ED. Thirty-nine patients (81%) were classified as AN and 9 (19%) as BN. At admission (T1) all patients completed MMPI-2 or MMPI-A and the italian version of a validated questionnaire on gastroesophageal (E) and gastrointestinal (GI) symptoms. EGI questionnaire was then completed at discharge (T2), at 1 month of follow up (T3) and after 6 months (T4). RESULTS: (i) the most frequently reported symptoms classified as moderate-severe were postprandial fullness (70%) and abdominal distention (57%). The most prevalent pychopathological trait with abnormal MMPI score (>55) was depression (67%). During observational period of 6 months (T1-T4), E and GI symptoms significantly decreased (IR 3-19 and 0.5-6.5, IR 1444 and 4-28, p<0.05 and p<0.0001, respectively), as well as sdsBMI (-3.4 -1.7 e -1.5 -0.4; p<0.001). Patients with abnormal scores of Hypochondriasis (HS) had significantly more severe abdominal distention and pooled GI symptoms than patients with normal HS scores (p<0.05 and p<0.005, respectively). (ii) sdsBMI change did not correlate with EGI symptoms improvement (p=NS). Normal HS, Hysteria (HY), Psychoastenia (PT), Schizophrenia (SC) scores were significantly correlated with reduction of postprandial fullness compared to abnormal scores (p<0.05). Abdominal distention improved in all patients, irrespectively of MMPI scores (p<0.05). Pooled E symptoms significantly diminished in patients with normal HY scores vs abnormal (p<0.05), whereas pooled GI symptoms improved irrespectively of high HS and HY scores (p<0.05). All patients showed a reduction in sdsBMI, irrespectively of MMPI scores (p<0.05). CONCLUSIONS: Postprandial fullness and abdominal distention are the most prevalent digestive complaints reported by ED patients. An improvement of sdsBMI is observed in controlled ED patients as well as EGI symptoms. Abnormal MMPI traits may interfere with amelioration of postprandial fullness, but has no influence on abdominal distention, nor on sdsBMI.

P02-131 - Reconsidering food avoidance emotional disorder through discussion of four cases

Objectives The Authors investigate the conceptualization of a group of patients with the same clinical and psychological patterns, affected by eating disturbances arisen during the age of latency. Methods Four cases are presented and discussed. Each subject was diagnosed as Food Avoidance Emotional Disorder (FAED). Results The described subjects present some of the typical features of eating disorders of adolescence. Moreover, regressive aspects, obligingness, dichotomyc behaviors and thoughts were noticed. The Authors observed that parental expectations and needs were transmitted to their sons. Conclusions Through the refusal of food the dochotomyc and fearful thoughts are crystallized. The child cannot comprehend the existence of a false Self built on the Others expectations. The Authors believe that FAED can be a precursor of Anorexia nervosa in the affected children, who show a less organized cognitive structure due to their young age.