TY - JOUR A1 - Farag, Heba Gamal A1 - Froehler, Sebastian A1 - Oexle, Konrad A1 - Ravindran, Ethiraj A1 - Schindler, Detlev A1 - Staab, Timo A1 - Huebner, Angela A1 - Kraemer, Nadine A1 - Chen, Wei A1 - Kaindl, Angela M. T1 - Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation JF - Orphanet Journal of Rare Diseases N2 - Background: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disease with severe microcephaly at birth due to a pronounced reduction in brain volume and intellectual disability. Biallelic mutations in the WD repeat-containing protein 62 gene WDR62 are the genetic cause of MCPH2. However, the exact underlying pathomechanism of MCPH2 remains to be clarified. Methods/results: We characterized the clinical, radiological, and cellular features that add to the human MCPH2 phenotype. Exome sequencing followed by Sanger sequencing in a German family with two affected daughters with primary microcephaly revealed in the index patient the compound heterozygous mutations c. 1313G>A (p.R438H) / c.2864-2867delACAG (p.D955Afs*112) of WDR62, the second of which is novel. Radiological examination displayed small frontal lobes, corpus callosum hypoplasia, simplified hippocampal gyration, and cerebellar hypoplasia. We investigated the cellular phenotype in patient-derived lymphoblastoid cells and compared it with that of healthy female controls. WDR62 expression in the patient's immortalized lymphocytes was deranged, and mitotic spindle defects as well as abnormal centrosomal protein localization were apparent. Conclusion: We propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2. KW - cell division KW - intellectual disability KW - missense mutations KW - protein KW - malformations KW - establishment KW - cytokinesis KW - genome KW - midbody KW - database KW - maintenance KW - families KW - microcephaly KW - WDR62 mutation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123505 SN - 1750-1172 VL - 8 IS - 178 ER - TY - JOUR A1 - von Bernuth, Horst A1 - Ravindran, Ethiraj A1 - Du, Hang A1 - Froehler, Sebastian A1 - Strehl, Karoline A1 - Kraemer, Nadine A1 - Issa-Jahns, Lina A1 - Amulic, Borko A1 - Ninnemann, Olaf A1 - Xiao, Mei-Sheng A1 - Eirich, Katharina A1 - Koelsch, Uwe A1 - Hauptmann, Kathrin A1 - John, Rainer A1 - Schindler, Detlev A1 - Wahn, Volker A1 - Chen, Wei A1 - Kaindl, Angela M. T1 - Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2) JF - Orphanet Journal of Rare Dieeases N2 - The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect. KW - ZBTB24 KW - ICF2 KW - granulomas KW - facial anomalies KW - centromeric instability KW - intellectual disability KW - lymphoma KW - ZBTB24 mutations KW - DNMT3B KW - TYPE-2 KW - immunodeficiency KW - microcephaly KW - DNA methyltransferase gene Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114859 VL - 9 ER - TY - JOUR A1 - Geissler, Julia A1 - Werner, Elisabeth A1 - Dworschak, Wolfgang A1 - Romanos, Marcel A1 - Ratz, Christoph T1 - Freiheitsentziehende Maßnahmen in bayerischen Heimeinrichtungen für Kinder, Jugendliche und junge Volljährige mit Intelligenzminderung JF - Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie N2 - Fragestellung: In Bayern leben etwa 10 % aller jungen Menschen mit Intelligenzminderung in Heimeinrichtungen. 2016 wurde in Presseberichten der Vorwurf unzulässiger freiheitsentziehender Maßnahmen formuliert. Im Rahmen des Projekts REDUGIA wurde in bayerischen Heimeinrichtungen eine repräsentative Erhebung zu freiheitsentziehenden Maßnahmen (FeM), herausforderndem Verhalten (hfV) und der Mitarbeiterbelastung (MaB) durchgeführt. Methodik: 65 Einrichtungen für junge Menschen mit Intelligenzminderung in Bayern wurde ein Fragebogen zu strukturellen Gegebenheiten sowie MaB, hfV und FeM zugesendet. Neben deskriptiven Auswertungen wurden korrelative Analysen bzw. Regressionsanalysen zum Zusammenhang zwischen hfV, FeM und MaB durchgeführt. Ergebnisse: Es wurden Daten zu 1839 Personen in 61 Einrichtungen erhoben. 84.3 % der Einrichtungen berichteten geringe Raten an hfV und FeM, während 15.7 % ein gehäuftes Vorkommen von hfV und FeM angaben. Auf n = 1809 Vollzeitäquivalente kam es innerhalb von 14 Tagen zu 639 körperlichen Angriffen durch Bewohner_innen. In 12 Monaten wurden problemverhaltensassoziiert 85 Krankmeldungen sowie 33 Versetzungsanträge/Kündigungen berichtet. Es zeigte sich ein signifikant positiver Zusammenhang zwischen hfV und FeM (R² = .307, F = 21.719, p < .001). Die Mitarbeiterbelastung korrelierte positiv mit hfV (r = .507, p < .001). Schlussfolgerungen: Die Studienbefunde weisen darauf hin, dass hfV sowie FeM bei jungen Menschen mit Intelligenzminderung kein flächendeckendes Phänomen darstellen, sondern sich auf wenige spezialisierte Einrichtungen fokussieren. Mögliche Maßnahmen zur Prävention von Problemverhalten und Freiheitsentzug werden diskutiert. N2 - Objective: In Bavaria, around 10 % of youths with an intellectual disability (ID) live in residential facilities. In 2015, media raised accusations of inadmissible use of coercive measures. The REDUGIA project carried out a representative survey in Bavarian facilities regarding coercive measures (FeM), challenging behavior (hfV), and employee stress (MaB). Method: We sent a questionnaire concerning structural conditions, MaB, hfV and FeM to 65 Bavarian facilities for young people with ID. In addition to preparing descriptive evaluations, we performed correlative and regression analyses concerning the relationship between hfV, FeM, and MaB. Results: We retrieved data from 1,839 subjects in 61 facilities. 84.3 % of facilities reported low rates of hfV and FeM, while 15.7 % reported an increased incidence of hfV and FeM. For n = 1809 full-time position equivalents there were 639 physical attacks by residents over the course of 14 days. We observed 85 instances of sick leave and 33 transfer apllications/resignation associated with hfV. The frequency of hfV predicted the frequency of FeM (R² = 0.307, F = 21.719, p < .001). MaB correlated positively with hfV (r = 0.507, p < .001). Conclusions: The descriptive data indicate that hfV and FeM are not general phenomena but occur mainly in a circumscript number of highly specialized facilities. This emphasizes the need for prevention of hfV and FeM. T2 - Freedom-restricting measures in Bavarian residential facilities for children, adolescents, and young adults with intellectual disabilities KW - Geistige Behinderung KW - herausforderndes Verhalten KW - freiheitsentziehende Maßnahmen KW - Heimeinrichtungen KW - Mitarbeiterbelastung KW - intellectual disability KW - challenging behavior KW - coercive measures KW - residential institutions KW - employee stress Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244859 SN - 1422-4917 SN - 1664-2880 VL - 49 IS - 4 ER -