Schizophrene Psychosen sind schwerwiegende psychische Erkrankungen mit einer Prävalenz von etwa 1 %, die alle Facetten des Lebens Betroffener und ihrer Angehörigen beeinträchtigen können. Die Genese dieser Erkrankungen wird oft unter Verwendung des Vulnerabilitäts-Stress-Modells veranschaulicht. Hierbei entsteht durch genetische Faktoren eine Prädisposition und der Ausbruch der Krankheit kann durch verschiedene Umweltfaktoren getriggert beziehungsweise ausgelöst werden. Diese genetische Komponente wird heute mit 60 – 80 % beziffert. Die molekulargenetische Erforschung der psychischen Erkrankungen nahm in letzten Jahrzehnten rapide zu. Deren Ergebnisse helfen uns diese Erkrankungen zu verstehen, sie effektiver zu behandeln und potentiell auch Vorsorgemaßnahmen zu ergreifen. Ein Beispiel solcher prädisponierenden genetischen Faktoren ist das 22q11.2-Mikrodeletionssyndrom (22q11-MDS), dass das höchste bekannte Risiko für die Entstehung schizophrener Psychosen mit sich bringt. In unserer Studie untersuchten wir mit Hilfe quantitativer Real-Time-PCR genetisches Material von Patient*innen mit schizophrenen Psychosen auf Vorliegen einer 22q11.2-Mikrodeletion. Eine Klassifikation der Subtypen erfolgte nach ICD-10 sowie nach der „Aufteilung der endogenen Psychosen“ nach Karl Leonhard. Insgesamt wurden hierzu 1177 Patient*innen untersucht, bei sechs von ihnen konnte ein 22q11-MDS identifiziert werden. Das entspricht 0,51 % der Stichprobe. Somit konnten wir die unterschiedlich durch zahlreiche Kollegen angegebene erhöhte Prävalenz des 22q11-MDS bei Patienten mit schizophrenen Psychosen korrigieren. Da wir bis heute die derart größte Stichprobe untersuchten, gelang es uns die bisherigen Angaben zu präzisieren – laut unserer Daten ist die Prävalenz des 22q11-MDS bei Patient*innen mit schizophrenen Psychosen um das 10- bis 20-fache höher als die der Allgemeinbevölkerung. Dabei ergab sich ein um 10- bis 20-fach erhöhtes relatives Risiko für Entwicklung einer schizophrenen Psychose bei diesen Patient*innen. Wir konnten zudem eine Häufung des 22q11-MDS in Fällen mit einer affektvollen Paraphrenie feststellen. Vier Patient*innen mit einer solchen Diagnose wiesen eine 22q11.2-Mikrodeletion auf, was 2,7 % dieser Subgruppe der schizophrenen Psychosen entspricht. Somit konnten wir die Beobachtungen von Karl Leonhard bestätigen. Er konnte bei der affektvollen Paraphrenie eine hohe familiäre Häufung feststellen und von einer starken genetischen Komponente dieser Subgruppe ausging. Unter dem Aspekt der ICD-10-Klassifikation konnten wir hingegen keinen besonderen Phänotyp feststellen. Wir fanden die gleiche stark erhöhte Prävalenz des 22q11-MDS sowohl bei Patienten mit schizophrenen Psychosen als auch mit schizoaffektiven Störungen, beiden Hauptgruppen des Schizophreniespektrums. Daher können wir unseren zahlreichen Kollegen zustimmen, die das 22q11-MDS als das genetische Model der schizophrenen Psychosen ansehen. Theoretisch ist es denkbar, die Träger*innen der 22q11.2-Mikrodeletion bereits im frühen Alter zu identifizieren. Sie und ihre Angehörigen könnten auf diese Weise über die Erkrankungen aufgeklärt und bezüglich der möglichen negativen Umweltfaktoren und der diversen Trigger wie z.B. Drogen geschult werden. Solche Maßnahmen könnten vielen Betroffenen helfen, durch die Erkennung der eventuellen Prodromi sich einer rechts-zeitigen Therapie zu unterziehen. Das könnte einen prognostischen Vorteil für die Patient*innen bedeuten und ihnen eine höhere Lebensqualität bitten. / Schizophrenic psychoses are severe mental Illnesses with a prevalence of 1 % that can impair all facets of the lives of the patients and their families. The genesis of this group of diseases is often illustrated using the vulnerability-stress model. In this model, a predisposition result through genetic factors and the outbreak of the disease can be triggered or initiated by various environmental factors. The genetic component is currently estimated at 60 – 80 %. In recent decades the molecular-genetic research of mental illnesses has rapidly increased and help us to understand schizophrenic psychoses, to treat these more effectively and potentially take preventive strategies. One example of such predisposing genetic factors is the 22q11.2-Deletion Syndrome (22q11-DS), which carries the highest known risk for developing a schizophrenic psychosis. In our study we used quantitative real-time PCR to examine genetic material from patients with schizophrenic psychoses for the 22q11-DS. We used the classification according to ICD-10 and the “classification of endogenous psychoses” formulated by Karl Leonhard. In total we examined 1177 patients and identified a 22q11-DS in six of them. This corresponds to 0.51 % of the samples. This allowed us to correct varying prevalence of the 22q11-DS in patients with schizophrenic psychoses that had been reported. Using the largest sample of this design to date we were able to refine the previous information – according to our data the prevalence of 22q1-DS in patients with schizophrenic psychoses is 10 – 20 times higher than in the general population. This revealed a 10 – 20-fold increased relative risk for developing a schizophrenic psychosis. We also identify a clustering of 22q11-DS in patients with affect-laden paraphrenia – four patients, which corresponds to 2.7 % of this subgroup of schizophrenic psychoses. So, we can confirm the observation of Karl Leonhard, who identified a high familial clustering in affect-laden paraphrenia and suspected a strong genetic component in this subgroup. Considering the ICD-10 classification we could not identify any special phenotype. We found the same strongly increased prevalence of 22q11-MDS in patients with schizophrenic psychoses as well as schizoaffective disorders, both major groups of the schizophrenia spectrum. Therefore, we can agree with our numerous colleagues who consider 22q11-MDS to be the genetic model of schizophrenic psychoses. Theoretically, the carriers of the 22q11.2 microdeletion could be identified at an early age. In this way, they and their relatives could be informed about the disease and educated about the possible negative environmental factors and the various triggers such as drugs. Such measures could help many affected people to earlier undergo treatment by recognizing possible prodromes. This could mean a prognostic advantage for the patients and offer them a higher quality of life.

Objetivos: estudar indivíduos com (G1) e sem (G2) sinais da Síndrome Velocardiofacial (SVCF) para verificar diferenças entre eles quanto à extensão e espessura velar, profundidade nasofaríngea, razão entre profundidade nasofaríngea e extensão velar (PNF/EV), tamanho da falha velofaríngea, ângulo velar, movimento do véu palatino e das paredes laterais e posterior da faringe e à presença da tonsila faríngea; diferenças para as medidas de extensão e espessura velar, profundidade nasofaríngea e razão PNF/EV dos grupos estudados com os valores de normalidade propostos por Subtelny (1957); e correlação entre o tamanho da falha velofaríngea e a razão PNF/EV. Material e Método: estudo prospectivo com 60 indivíduos de ambos os sexos sem fissura palatina evidente e com disfunção velofaríngea (DVF), não operados, sendo 30 com sinais clínicos da SVCF (G1) (idade de 5,4 a 51 anos, com média de 15,7±9,5 anos) e 30 sem os sinais da SVCF (G2) (idade de 4,5 a 33 anos, com média de 15±7,6 anos). O exame videofluoroscópico foi realizado nas projeções lateral e frontal para análise da extensão e espessura velar, profundidade nasofaríngea, falha velofaríngea e ângulo velar, movimento do véu palatino, paredes laterais e posterior da faringe e presença da tonsila faríngea. Resultados: quanto às medidas de extensão e espessura velar, profundidade nasofaríngea e razão PNF/EV, não houve diferença entre os grupos quando se comparou os casos maiores de 18 anos, bem como os menores de 18 anos pareados por idade; mas quando a idade não foi pareada nos casos menores de 18 anos, a espessura velar foi menor (p=0,019) e a razão PNF/EV foi maior (p=0,048) no G1 e, ao se analisar independente da faixa etária, a razão PNF/EV foi maior no G1 (p=0,024). Em relação às medidas de normalidade, a extensão velar foi menor no G1 (p=0,007), a espessura velar foi menor no G1 (p=0,000) e G2 no (p=0,000), a profundidade nasofaríngea e a razão PNF/EV foram maiores no G1 (p=0,000) e no G2 (p=0,000), entretanto ao se considerar a variação de 2 desvios-padrão em relação aos valores de normalidade, não houve diferença entre os grupos para todas as medidas. Também não houve diferença entre os grupos quanto ao ângulo de elevação velar (p=0,232) e presença (p=0,698) e tamanho da falha velofaríngea (p=0,293), movimento velar (p=0,085) e das paredes laterais (p=0,763) e posterior (p=0,237) da faringe, além do tamanho da tonsila faríngea (p=0,307). Não houve correlação entre a falha velofaríngea e a razão PNF/EV no G1 (p=0,153) e no G2 (p=0,598). Conclusões: a razão PNF/EV foi maior nos indivíduos com DVF e sinais da SVCF comparados aos indivíduos com DVF sem os sinais da síndrome, sugerindo ser este um indicador velofaríngeo para a SVCF, enquanto os aspectos funcionais da velofaringe não diferiram entre os indivíduos com e sem os sinais da SVCF. Não houve correlação entre o tamanho da falha no fechamento velofaríngeo e a razão PNF/EV nos grupos com e sem sinais da SVCF. / Objective: to study individuals with (G1) and without (G2) signs of velocardiofacial syndrome (VCFS), so as to verify differences in terms of length and thickness of the soft palate, nasopharyngeal depth, ratio of nasopharyngeal depth to velar length (PD/VL), velopharyngeal gap size, velar angle, soft palate movement, lateral and posterior pharyngeal walls movement and the presence of adenoidal tissue; differences for the measurements of velar length and thickness, nasopharyngeal depth and PD/VL ratio for the groups studied with the normality values proposed by Subtelny (1957); and correlation between the size of velopharyngeal gap and the PD/VL ratio. Methods: a prospective study with 60 subjects from both genders, with no evident cleft palate, with velopharyngeal dysfunction (VPD), non operated, being 30 with clinical signs of VCFS (age range 5.4 to 51 yrs, mean 15.7±9.5 yrs), and 30 with no signs of VCFS (age range 4.5 to 33 yrs, mean 15±7.6 yrs). The videofluoroscopy was performed in lateral and frontal views, for the analysis of velar length and thickness, nasopharyngeal depth, velopharyngeal gap, velar angle, soft palate movement, lateral and posterior pharyngeal walls movement and the presence of adenoidal tissue. Results: there was no difference in the measurements of velar length and thickness, nasopharyngeal depth and PD/VL ratio, between the groups, when cases over 18 yrs, as well as those under 18, paired by age, were compared; however, when age was not paired in the cases under 18 yrs, the velar thickness was smaller (p=0.019) and the PD/VL ratio was greater (p=0.048) in G1 and, by analyzing regardless the age range, the PD/VL ratio was greater in G1 (p=0.024). In relation to normality measurements, the velar length was smaller in G1 (p=0.007), the velar thickness was smaller in G1 (p=0.000) and G2 (p=0.000), the nasopharyngeal depth and the PD/VL ratio were greater in G1 (p=0.000) and G2 (p=0.000), nevertheless, when considering the variation of 2 standard deviations in relation to the normality values, there was no difference between the groups for all measurements. No difference was seen between the groups, as to the velar angle (p=0.232) and presence (p=0.698) and size of velopharyngeal gap (p=0.293), velar movement (p=0.085) and lateral (p=0.763) and posterior (p=0.237) pharyngeal walls movement, besides the size of adenoidal tissue (p=0.307). No correlation was seen between the velopharyngeal gap and the PD/VL ratio in G1 (p=0.153) and G2 (p=0.598). Conclusions: the PD/VL ratio was greater in individuals with VPD and signs of VCFS, as compared to individuals with VPD with no signs of the syndrome, suggesting that this is a velopharyngeal indicator for VCFS, whereas velopharyngeal functional aspects did not differ between individuals with and without signs of VCFS. There was no correlation between the size of the velopharyngeal gap and the PD/VL ratio, in the groups with and without signs of VCFS.

The past two decades have witnessed an accelerated effort to understand the nature of schizophrenia and related psychotic disorders, but no causative gene(s) has been discovered yet. Family, twin, and adoption studies indicate that genetic factors are clearly implicated in the etiology of these disorders (Cardno and Gottesman, 2000; Cardno et al., 2002; McGuffin et al., 2003; Weinberger, 2005). Several aspects of 22q11 Deletion Syndrome (22qDS) - the most common chromosomal microdeletion found in humans - create a unique opportunity for susceptibility gene identification. For instance, the reported risk of psychotic disorders in 22qDS is 25-fold higher than in the general population (Murphy et al., 1999) and genome-wide linkage studies in families with schizophrenia without 22qDS indicate that the 22q11.2 region is a strong susceptibility locus for psychosis (Badner and Gershon, 2002; Lewis et al., 2003). This thesis aims to identify genetic factors associated with the development of psychosis in 22qDS by i) investigating the relationship between the length of the 22q11.2 deletions and the presence of a psychotic disorder in patients with 22qDS; ii) studying diagnostic molecular methods that improve detection of 22q11.2 deletions and duplications; and iii) exploring the relationship between 22qDS-psychotic phenotype and gene expression patterns. The central hypothesis was that psychosis in 22qDS would not be associated with haploinsufficiency (having one copy of the gene), but rather, it would be associated with distinct 22q11.2 gene expression profiles. Chapter 2 showed that 22q11.2 deletion size did not appear to be associated with the development of psychosis in adults with 22qDS. In Chapter 3, a molecular method that detects and size 22q11.2 deletions and duplications of various sizes was shown to be superior to the traditional molecular diagnostic technique used for molecular diagnostic of 22qDS. Finally, in Chapter 4, decreased gene expression of three genes located in the 22q11.2 region (SNAP29, COMT and BID) was significantly associated with psychosis in adults with 22qDS. Focusing on genes located in the 22q11.2 region has helped revealing genetic alterations associated with the frequent development of psychosis in 22qDS. Future studies focusing on investigating the heterogeneity of the psychotic presentation in 22qDS and further elucidating potential genetic mechanisms likely to explain the gene expression changes in the 22q11.2 region demonstrated here will help advance the scientific understanding of the etiology of psychosis.

The past two decades have witnessed an accelerated effort to understand the nature of schizophrenia and related psychotic disorders, but no causative gene(s) has been discovered yet. Family, twin, and adoption studies indicate that genetic factors are clearly implicated in the etiology of these disorders (Cardno and Gottesman, 2000; Cardno et al., 2002; McGuffin et al., 2003; Weinberger, 2005). Several aspects of 22q11 Deletion Syndrome (22qDS) - the most common chromosomal microdeletion found in humans - create a unique opportunity for susceptibility gene identification. For instance, the reported risk of psychotic disorders in 22qDS is 25-fold higher than in the general population (Murphy et al., 1999) and genome-wide linkage studies in families with schizophrenia without 22qDS indicate that the 22q11.2 region is a strong susceptibility locus for psychosis (Badner and Gershon, 2002; Lewis et al., 2003). This thesis aims to identify genetic factors associated with the development of psychosis in 22qDS by i) investigating the relationship between the length of the 22q11.2 deletions and the presence of a psychotic disorder in patients with 22qDS; ii) studying diagnostic molecular methods that improve detection of 22q11.2 deletions and duplications; and iii) exploring the relationship between 22qDS-psychotic phenotype and gene expression patterns. The central hypothesis was that psychosis in 22qDS would not be associated with haploinsufficiency (having one copy of the gene), but rather, it would be associated with distinct 22q11.2 gene expression profiles. Chapter 2 showed that 22q11.2 deletion size did not appear to be associated with the development of psychosis in adults with 22qDS. In Chapter 3, a molecular method that detects and size 22q11.2 deletions and duplications of various sizes was shown to be superior to the traditional molecular diagnostic technique used for molecular diagnostic of 22qDS. Finally, in Chapter 4, decreased gene expression of three genes located in the 22q11.2 region (SNAP29, COMT and BID) was significantly associated with psychosis in adults with 22qDS. Focusing on genes located in the 22q11.2 region has helped revealing genetic alterations associated with the frequent development of psychosis in 22qDS. Future studies focusing on investigating the heterogeneity of the psychotic presentation in 22qDS and further elucidating potential genetic mechanisms likely to explain the gene expression changes in the 22q11.2 region demonstrated here will help advance the scientific understanding of the etiology of psychosis.

Objetivos: estudar indivíduos com (G1) e sem (G2) sinais da Síndrome Velocardiofacial (SVCF) para verificar diferenças entre eles quanto à extensão e espessura velar, profundidade nasofaríngea, razão entre profundidade nasofaríngea e extensão velar (PNF/EV), tamanho da falha velofaríngea, ângulo velar, movimento do véu palatino e das paredes laterais e posterior da faringe e à presença da tonsila faríngea; diferenças para as medidas de extensão e espessura velar, profundidade nasofaríngea e razão PNF/EV dos grupos estudados com os valores de normalidade propostos por Subtelny (1957); e correlação entre o tamanho da falha velofaríngea e a razão PNF/EV. Material e Método: estudo prospectivo com 60 indivíduos de ambos os sexos sem fissura palatina evidente e com disfunção velofaríngea (DVF), não operados, sendo 30 com sinais clínicos da SVCF (G1) (idade de 5,4 a 51 anos, com média de 15,7±9,5 anos) e 30 sem os sinais da SVCF (G2) (idade de 4,5 a 33 anos, com média de 15±7,6 anos). O exame videofluoroscópico foi realizado nas projeções lateral e frontal para análise da extensão e espessura velar, profundidade nasofaríngea, falha velofaríngea e ângulo velar, movimento do véu palatino, paredes laterais e posterior da faringe e presença da tonsila faríngea. Resultados: quanto às medidas de extensão e espessura velar, profundidade nasofaríngea e razão PNF/EV, não houve diferença entre os grupos quando se comparou os casos maiores de 18 anos, bem como os menores de 18 anos pareados por idade; mas quando a idade não foi pareada nos casos menores de 18 anos, a espessura velar foi menor (p=0,019) e a razão PNF/EV foi maior (p=0,048) no G1 e, ao se analisar independente da faixa etária, a razão PNF/EV foi maior no G1 (p=0,024). Em relação às medidas de normalidade, a extensão velar foi menor no G1 (p=0,007), a espessura velar foi menor no G1 (p=0,000) e G2 no (p=0,000), a profundidade nasofaríngea e a razão PNF/EV foram maiores no G1 (p=0,000) e no G2 (p=0,000), entretanto ao se considerar a variação de 2 desvios-padrão em relação aos valores de normalidade, não houve diferença entre os grupos para todas as medidas. Também não houve diferença entre os grupos quanto ao ângulo de elevação velar (p=0,232) e presença (p=0,698) e tamanho da falha velofaríngea (p=0,293), movimento velar (p=0,085) e das paredes laterais (p=0,763) e posterior (p=0,237) da faringe, além do tamanho da tonsila faríngea (p=0,307). Não houve correlação entre a falha velofaríngea e a razão PNF/EV no G1 (p=0,153) e no G2 (p=0,598). Conclusões: a razão PNF/EV foi maior nos indivíduos com DVF e sinais da SVCF comparados aos indivíduos com DVF sem os sinais da síndrome, sugerindo ser este um indicador velofaríngeo para a SVCF, enquanto os aspectos funcionais da velofaringe não diferiram entre os indivíduos com e sem os sinais da SVCF. Não houve correlação entre o tamanho da falha no fechamento velofaríngeo e a razão PNF/EV nos grupos com e sem sinais da SVCF. / Objective: to study individuals with (G1) and without (G2) signs of velocardiofacial syndrome (VCFS), so as to verify differences in terms of length and thickness of the soft palate, nasopharyngeal depth, ratio of nasopharyngeal depth to velar length (PD/VL), velopharyngeal gap size, velar angle, soft palate movement, lateral and posterior pharyngeal walls movement and the presence of adenoidal tissue; differences for the measurements of velar length and thickness, nasopharyngeal depth and PD/VL ratio for the groups studied with the normality values proposed by Subtelny (1957); and correlation between the size of velopharyngeal gap and the PD/VL ratio. Methods: a prospective study with 60 subjects from both genders, with no evident cleft palate, with velopharyngeal dysfunction (VPD), non operated, being 30 with clinical signs of VCFS (age range 5.4 to 51 yrs, mean 15.7±9.5 yrs), and 30 with no signs of VCFS (age range 4.5 to 33 yrs, mean 15±7.6 yrs). The videofluoroscopy was performed in lateral and frontal views, for the analysis of velar length and thickness, nasopharyngeal depth, velopharyngeal gap, velar angle, soft palate movement, lateral and posterior pharyngeal walls movement and the presence of adenoidal tissue. Results: there was no difference in the measurements of velar length and thickness, nasopharyngeal depth and PD/VL ratio, between the groups, when cases over 18 yrs, as well as those under 18, paired by age, were compared; however, when age was not paired in the cases under 18 yrs, the velar thickness was smaller (p=0.019) and the PD/VL ratio was greater (p=0.048) in G1 and, by analyzing regardless the age range, the PD/VL ratio was greater in G1 (p=0.024). In relation to normality measurements, the velar length was smaller in G1 (p=0.007), the velar thickness was smaller in G1 (p=0.000) and G2 (p=0.000), the nasopharyngeal depth and the PD/VL ratio were greater in G1 (p=0.000) and G2 (p=0.000), nevertheless, when considering the variation of 2 standard deviations in relation to the normality values, there was no difference between the groups for all measurements. No difference was seen between the groups, as to the velar angle (p=0.232) and presence (p=0.698) and size of velopharyngeal gap (p=0.293), velar movement (p=0.085) and lateral (p=0.763) and posterior (p=0.237) pharyngeal walls movement, besides the size of adenoidal tissue (p=0.307). No correlation was seen between the velopharyngeal gap and the PD/VL ratio in G1 (p=0.153) and G2 (p=0.598). Conclusions: the PD/VL ratio was greater in individuals with VPD and signs of VCFS, as compared to individuals with VPD with no signs of the syndrome, suggesting that this is a velopharyngeal indicator for VCFS, whereas velopharyngeal functional aspects did not differ between individuals with and without signs of VCFS. There was no correlation between the size of the velopharyngeal gap and the PD/VL ratio, in the groups with and without signs of VCFS.

No description available.

Fragestellung: Querschnittstudien konnten bei Kindern und Jugendlichen mit Deletion 22q11.2 eine Tendenz zu mit dem Alter zunehmenden Verhaltensauffälligkeiten verbunden mit einem Anstieg der elterlichen Stressbelastung zeigen. Die aktuelle Längsschnittstudie sollte diese Ergebnisse überprüfen. Methodik: Mit Hilfe der deutschen Selbsthilfegruppe KiDS 22q11 wurden alle Hauptbezugspersonen, die bereits vier Jahre zuvor an einer Befragung zu Verhaltensauffälligkeiten und Stress teilgenommen hatten, anonymisiert um die Bearbeitung verschiedener Fragebögen gebeten. Ergebnisse: 59 von 94 Hauptbezugspersonen sandten ausgefüllte Fragebögen zurück. Dabei wurden 54% aller Kinder und Jugendlichen (29 männlich, 30 weiblich, im Alter von 5,8 bis 18,9 Jahren, Mittelwert: 10,8 Jahre) von ihren Hauptbezugspersonen als verhaltensauffällig eingestuft (Gesamtwert Child Behavior Checklist [CBCL] bzw. Fragebogen über das Verhalten junger Erwachsener [YABCL]). In nahezu allen Bereichen der Child Behavior Checklist, mit der die Erfassung der Verhaltensauffälligkeiten erfolgte, kam es im Verlauf zu einer statistisch signifikanten Zunahme. Auch stieg die Stressbelastung der Hauptbezugspersonen, erfasst mittels Fragebogen Soziale Orientierungen von Eltern behinderter Kinder, im Vergleich zur Erstbefragung signifikant an, ohne dass sich jedoch die Lebenszufriedenheit signifikant verändert hätte. Das Ausmaß der elterlichen Stressbelastung korrelierte signifikant mit dem Gesamtproblemwert der CBCL. Schlussfolgerungen: Die Ergebnisse der aktuellen Längsschnittstudie bestätigen die Befunde früherer Querschnittuntersuchungen hinsichtlich Verhaltensauffälligkeiten bei Kindern und Jugendlichen mit Deletion 22q11.2. Aufgrund der zunehmenden Verhaltensprobleme und der damit einhergehenden Stressbelastung ist mit einem erhöhten Beratungsbedarf der Hauptbezugspersonen und einer zunehmenden Behandlungsbedürftigkeit der Patienten zu rechnen. / Backround: Cross-sectional studies have shown a tendency to age increasing behaviour problems associated with an increase in parental stress in children and adolescents with 22q11.2 deletion. The current longitudinal study should review these results. Method: Using the German self-help group KiDS 22q11 all main caregivers who had four years earlier participated in a survey about behaviour problems and stress, were asked anonymously to answer again different questionnaires. Results: 59 of 94 primary caregivers sent back the completed questionnaires. 54% (29 male, 30 female, aged 5.8 to 18.9 years, mean 10.8 years) were classified clinical for behaviour problems by their primary caregivers (total problems scale of Child Behavior Checklist [CBCL] resp. Young Adult Behavior Checklist [YABCL]). In almost all areas of the Child Behavior Checklist occurred in the course a statistically significant increase. The stress of the main caregivers rose, recorded by questionnaire Social orientations of parents of disabled children, compared to the initial survey significantly, without any significantly change in life satisfaction. The extent of parental stress was significantly correlated with the total problems score of the CBCL. Conclusion: The results of this longitudinal study confirm the findings of previous cross-sectional studies on behaviour problems in children and adolescents with 22q11.2 deletion. Due to the increasing behaviour problems and the associated stress is to be expected with an increased need for counseling the main caregivers and an increasing need for treatment of patients.

Vom Deletionssyndrom 22q11.2 Betroffene sind einem überdurchschnittlich hohen Risiko ausgesetzt im Entwicklungsverlauf psychisch zu erkranken. Häufige Störungsbilder sind unter anderem ADHS, Angsterkrankungen, affektive Störungen, Erkrankungen aus dem schizophrenen Formenkreis und Morbus Parkinson. Ziel der Studie war es, phänotypische Auffälligkeiten beim DS22q11 zu identifizieren, die dabei helfen könnten, Hochrisikogruppen innerhalb des Syndroms frühzeitig identifizieren zu können und in Form von Biomarkern messbar sind. Hierzu wurden die bereits in Forschung und teilweise auch in der Klinik etablierten Verfahren der transkraniellen Sonographie und der standardisierten Riechtestung eingesetzt. / Individuals affected with 22q11.2 Deletion Syndrome (22q11.2DS) are at an above average risk to develop neuropsychiatric disorders (such as attention-deficit/hyperactivity disorder, anxiety disorders, affective disorders, schizophrenia and Parkinson's disease). The aim of this study is to identify phenotypical characteristics in 22q11.2DS to help point out high-risk groups within the syndrome and then be measured as biomarkers. To achieve this, we performed transcranial sonography and olfactory testing which are known to be established clinical and research methods.

Speech-language impairment is one of the most common clinical features in velocardiofacial syndrome (VCFS). This report describes the speech and language development of four children with VCFS studied longitudinally from 6 to 30 months of age and compares their performance with three groups of children: (1) normally developing children, (2) children with cleft lip and palate, and (3) children with isolated cleft palate. The data show that young children with VCFS show a receptive-expressive language impairment from the onset of language. Further, speech and expressive language development were severely delayed beyond a level predicted by their other developmental or receptive language performance. The children with VCFS showed severe limitations in speech sound inventories and early vocabulary development that far exceeded those shown by the children with cleft lip and palate and children with isolated cleft palate. This study indicates that young children with VCFS emerge from a critical speech and language learning period with severe limitations in their communicative abilities. Further studies are required to describe the later course of these early speech and language impairments and to explore the relationship to learning disabilities described for older children with VCFS.

Einleitung. Personen mit Deletionssyndrom 22q11.2 (DS22q11) weisen eine hohe Prävalenz von Angststörungen auf. Ein Faktor, der in der Entstehung von Angststörungen diskutiert wird, ist eine veränderte Angstgeneralisierung. Es konnte gezeigt werden, dass Menschen mit bestimmten Angsterkrankungen eine stärkere Angstgeneralisierung aufweisen als gesunde Vergleichspersonen. Dies kann experimentell untersucht werden, indem die Übertragung einer konditionierten Angstreaktion auf andere Stimuli gemessen wird, welche dem konditioniertem Stimulus ähneln, aber nie zusammen mit dem unkonditioniertem Stimulus präsentiert wurden. Auf Grund der hohen Prävalenz von Angststörungen bei DS22q11 wurde in der vorliegenden Forschungsarbeit die Hypothese aufgestellt, dass Menschen mit DS22q11 eine ausgeprägtere Angstgeneralisierung aufweisen als gesunde Kontrollproband*innen. Menschen mit einer gesteigerten Trait-Angst neigen dazu Situationen eher als bedrohlich einzuschätzen. Eine erhöhte Trait-Angst geht wiederum mit einer stärkeren Angstgeneralisierung einher. Dieser Befund wurde auch bei Personen mit DS22q11 erwartet. Darauf aufbauend überprüft die hier vorgelegte Arbeit die Hypothese, dass die Trait-Angst bei Personen mit DS22q11 ebenso wie bei den Kontrollproband*innen positiv mit der Angstgeneralisierung korreliert. Methoden. Es wurden Proband*innen mit DS22q11 rekrutiert und mit gesunden Kontrollproband*innen nach Alter und Geschlecht gematcht. Für die Untersuchung der Angstgeneralisierung wurde auf ein bereits etabliertes Konditionierungs- und Generalisierungsparadigma zurückgegriffen, in dem weibliche Gesichter als Stimuli zum Einsatz kommen. Die Trait-Angst wurde mit dem State-Trait-Angstinventar erhoben. Ergebnisse. In der Gruppe der Kinder und Jugendlichen zeigten sich keine signifikanten Unterschiede hinsichtlich der Angstgeneralisierung zwischen den Proband*innen mit DS22q11 und den Kontrollproband*innen. Dies war ebenso bei den Erwachsenen der Fall, jedoch fanden sich hier Anhaltspunkte für eine mögliche stärkere Angstgeneralisierung seitens der Proband*innen mit DS22q11. In Bezug auf die Trait-Angst konnte bei den Kindern und Jugendlichen weder in der Gruppe mit DS22q11 noch in der Kontrollgruppe eine Korrelation mit der Angstgeneralisierung festgestellt werden. Bei den Erwachsenen hingegen korrelierte sowohl bei den Proband*innen mit DS22q11 als auch bei den Kontrollproband*innen die Trait-Angst positiv mit der Angstgeneralisierung. Des Weiteren erbrachte die Studie Hinweise darauf, dass die Eignung des verwendeten Paradigmas zur Konditionierung von Menschen mit DS22q11 limitiert ist. Diskussion. Die Beobachtung, dass in der vorliegenden Studie Kinder und Jugendliche mit DS22q11 keine stärkere Angstgeneralisierung als ihre gesunden Altersgenossen zeigten, lässt die Interpretation zu, dass der Angstgeneralisierung im Kindesalter keine bedeutende Rolle bei der Entstehung von Angststörungen zukommt. Jedoch wurden bei den eingeschlossenen Personen mit DS22q11 vorrangig spezifische Phobien festgestellt, welche laut Studienlage eher nicht mit einer gesteigerten Angstgeneralisierung einhergehen. Die erwachsenen Personen mit DS22q11 wiesen in dieser Studie geringere Raten von Angsterkrankungen auf als in der Literatur beschrieben, wodurch fehlende signifikante Unterschiede in der Angstgeneralisierung gegenüber den Kontrollproband*innen erklärt werden könnten. Zudem wurden im Erwachsenenalter ausschließlich generalisierte Angststörungen festgestellt, bei welchen unklar ist, ob eine gesteigerte Angstgeneralisierung vorliegt. Schließlich könnten die Ergebnisse auch dafür sprechen, dass bei DS22q11 andere Pathomechanismen als die Übergeneralisierung von Angst bei der Entwicklung von Angststörungen im Vordergrund stehen. Überdies könnten mögliche Defizite in der Gesichtsverarbeitung bei Menschen mit DS22q11 die Ergebnisse beeinflusst haben und die Eignung des Paradigmas für diese Population in Frage stellen. Dass die Trait-Angst bei den Kindern und Jugendlichen nicht mit der Angstgeneralisierung korrelierte, könnte darauf zurückzuführen sein, dass die Angstgeneralisierung in dieser Altersgruppe eventuell physiologischerweise schon so stark ist, dass eine erhöhte Trait-Angst diese nicht weiter steigern „kann“. Bei den Erwachsenen stimmt das Ergebnis, dass die Trait-Angst positiv mit der Angstgeneralisierung korrelierte, mit der überwiegenden Mehrheit der Literatur überein. Da sich die Gruppen diesbezüglich nicht signifikant voneinander unterschieden, kann davon ausgegangen werden, dass das Vorliegen von DS22q11 den Einfluss der Trait-Angst auf die Angstgeneralisierung nicht verändert. / Introduction. People with 22q11.2 deletion syndrome (DS22q11) have a high prevalence of anxiety disorders. One factor discussed in the development of anxiety disorders is an altered fear generalization. It has been shown that people with certain anxiety disorders exhibit greater fear generalization than healthy comparison subjects. This can be studied experimentally by measuring the transfer of a conditioned fear response to stimuli that are similar to the conditioned stimulus but have never been presented together with the unconditioned stimulus. Based on the high prevalence of anxiety disorders in DS22q11, it was hypothesized that individuals with DS22q11 would exhibit stronger fear generalization than healthy controls. People with high trait anxiety tend to assess situations as more threatening. Increased trait anxiety is in turn associated with stronger fear generalization. This finding was also expected in individuals with DS22q11. Based on this, the thesis presented here tests the hypothesis that trait anxiety correlates positively with fear generalization in both individuals with DS22q11 and control subjects. Methods. Individuals with DS22q11 were compared with age- and gender-matched healthy controls. For the study of fear generalization, an established conditioning and generalization paradigm with female faces as stimuli was used. Trait anxiety was assessed using the State-Trait Anxiety Inventory. Results. In the group of children and adolescents, there were no significant differences in fear generalization between the subjects with DS22q11 and control subjects. This was also the case for the adults, but there were signs for a possible stronger fear generalization in the group with DS22q11. With regard to trait anxiety, no correlation with fear generalization was found in children and adolescents in either the group with DS22q11 or the control group. In adults, however, trait anxiety correlated positively with fear generalization in both subjects with DS22q11 and control subjects. Furthermore, the study yielded evidence that the suitability of the paradigm for conditioning individuals with DS22q11 is limited. Discussion. The observation that in the present study children and adolescents with DS22q11 did not show stronger fear generalization than their healthy peers suggests that fear generalization may not play a pivotal role in the development of anxiety disorders during childhood. However, the subjects with DS22q11 were primarily found to have specific phobias, which tend not to be associated with enhanced fear generalization according to the literature. The adult subjects with DS22q11 showed lower rates of anxiety disorders in this study than described in the literature, which could explain the lack of significant differences in fear generalization compared to control subjects. In addition, only generalized anxiety disorders were found in the adult subjects, in which it is unclear whether heightened fear generalization is present. Finally, the results may also suggest that pathomechanisms other than overgeneralization of fear are decisive in the development of anxiety disorders in DS22q11. Moreover, possible deficits in face processing in individuals with DS22q11 may have influenced the results and call into question the suitability of the paradigm for this population. One reason why trait anxiety does not correlate with fear generalization in children and adolescents lies in the supposition that fear generalization in this age group may already be so strong physiologically that high trait anxiety “cannot” increase it further. In adults, the finding that trait anxiety correlates positively with fear generalization is consistent with the majority of the literature, and since the groups did not differ significantly in this regard, it can be assumed that the presence of DS22q11 does not alter the influence of trait anxiety on fear generalization.