PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response.

Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy. PSMD11 loss-of-function variants caused early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity in 10 unrelated children. Our findings demonstrate that the cognitive impairment observed in these individuals could be recapitulated in Drosophila melanogaster with depletion of the PMSD11 ortholog Rpn6, which compromised reversal learning. Our investigations in subject samples further revealed that PSMD11 loss of function resulted in impaired 26S proteasome assembly and the acquisition of a persistent type I interferon (IFN) gene signature, mediated by the integrated stress response (ISR) protein kinase R (PKR). In summary, these data identify PSMD11 as an additional member of the growing family of genes associated with neurodevelopmental proteasomopathies and provide insights into proteasomal biology in human health.

Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Biallelic variants in GTF3C5, a regulator of RNA polymerase III-mediated transcription, cause a multisystem developmental disorder.

General transcription factor IIIC subunit 5 (GTF3C5) encodes transcription factor IIIC63 (TFIIIC63). It binds to DNA to recruit another transcription factor, TFIIIB, and RNA polymerase III (Pol III) to mediate the transcription of small noncoding RNAs, such as tRNAs. Here, we report four individuals from three families presenting with a multisystem developmental disorder phenotype with biallelic variants in GTF3C5. The overlapping features include growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Using lymphoblastoid cell lines (LCLs) from two affected individuals, we observed a reduction in TFIIIC63 protein levels compared to control LCLs. Genome binding of TFIIIC63 protein is also reduced in LCL from one of the affected individuals. Additionally, approximately 40% of Pol III binding regions exhibited reduction in the level of Pol III occupancy in the mutant genome relative to the control, while approximately 54% of target regions showed comparable levels of Pol III occupancy between the two, indicating partial impairment of Pol III occupancy in the mutant genome. Yeasts with subject-specific variants showed temperature sensitivity and impaired growth, supporting the notion that the identified variants have deleterious effects. gtf3c5 mutant zebrafish showed developmental defects, including a smaller body, head, and eyes. Taken together, our data show that GTF3C5 plays an important role in embryonic development, and that biallelic variants in this gene cause a multisystem developmental disorder. Our study adds GTF3C5-related disorder to the growing list of genetic disorders associated with Pol III transcription machinery.

A rare mutation in hypophosphatasia: a case report of adult form and review of the literature

SUMMARY Hypophosphatasia is a rare inborn error of metabolism characterized by low serum alkaline phosphatase activity due to loss-of-function mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Extracellular accumulation of TNSALP substrates leads to dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Mild hypophosphatasia usually has autosomal dominant inheritance, severe cases are either autosomal recessive or due to a dominant negative effect. Clinical manifestations of hypophosphatasia are extremely variable, ranging from life threatening to asymptomatic clinical presentations. The clinical presentation of the adult-onset hypophosphatasia is highly variable. Fractures, joint complications of chondrocalcinosis, calcifying polyarthritis and multiple pains may reveal minor forms of the disease in adults. It is important to recognize the disease to provide the best supportive treatment and to prevent the use of anti-resorption drugs in these patients. Bone-targeted enzyme-replacement therapy (asfotase alfa) was approved in 2015 to treat pediatric-onset hypophosphatasia. We present a case of a 41-year-old male diagnosed with adult form of hypophosphatasia with a rare ALPL mutation that has been previously described only once and review the literature on the adult form of the disease and its genetic mechanism.

Estrés y conductas antidisciplinarias en estudiantes de una facultad de medicina de Bogotá / Stress and Misconduct in Students of a Medical School in Bogotá

Introducción: los estudiantes de medicina se someten durante su formación académica a muchos factores estresantes. A su vez, incurren en transgresiones disciplinarias con frecuencia. El tiempo transcurrido en la carrera, así como el estrés han sido propuestos como posibles factores asociados a mala conducta. Objetivo: explorar, a través de un modelo de regresión logística, la posible asociación entre estrés y variables como sexo, semestre y edad, y actitudes antidisciplinarias en estudiantes de medicina de una universidad privada de Bogotá. Materiales y métodos: estudio descriptivo de corte transversal. Se encuestaron 433 estudiantes que cursaban entre tercer y sexto año de medicina. Resultados: la frecuencia de estudiantes que está de acuerdo (61,4%) y que incurre (44,9%) con frecuencia en comportamientos antidisciplinarios es alta. El estrés (OR: 1,04; IC 95%: 1,01-1,06) y el sexo masculino (OR: 1,90; IC 95%: 1,27-2,84) predicen débilmente la posibilidad de incurrir en transgresiones, lo que indica una asociación (bondad de ajuste: p>0,9 para falta de ajuste) con significado incierto (R²=0,03). En el subgrupo de estudiantes de tercer a quinto año, el semestre que se está cursando (OR: 1,27; IC 95%: 1,11-1,45), al igual que el estrés (OR: 1,04 IC 95%: 1,01-1,07) y el sexo masculino (OR: 2,06; IC 95%: 1,32-3,21) predicen de manera igualmente débil (bondad de ajuste: p>0,38 para falta de ajuste, R²=0,053) la frecuencia de transgresiones. Conclusiones: además del estrés y el sexo, otros factores, como la subcultura estudiantil en un país del tercer mundo y la personalidad del estudiante podrían explicar la alta tendencia a no atenerse a las normas en los estudiantes de medicina encuestados.

Introduction: Medical students are subject to many stressing events during their training. Previous studies have shown that they frequently engage in misconduct. The time spent in training as well as stress have been proposed as possible risk factors that favor misconduct. Objectives: This study seeks to establish through a logistic regression model a possible association between factors such as stress, sex, time spent in training and age, and misconduct among a group of medical students in a private university in Bogotá. Materials and Methods: This was a survey-based study. The survey was completed by 433 third to sixth year medical students. Results: The frequency of students that agree with (61.4%) and admit to have engaged frequently in misconduct (44.9%) is high. Stress (OR: 1.04; 95% CI: 1.01-1.06) and male sex (OR: 1.90; 95% CI: 1.27-2.84) are weak predictors of the chance of engaging in misconduct, indicating an association (goodness-of-fit: p>0.9 for lack of fit) but with uncertain importance (R²=0.03). In a subgroup of students between third and fifth year, time spent in training (OR: 1.27; 95% CI: 1.11-1.45), stress (OR: 1.04 95% CI: 1.01-1.07) and being male (OR: 2.06; 95% CI: 1.32-3.21) also weakly predict (goodness-of-fit: p>0.38 for lack of fit, R²=0,053) the frequency of misconduct. Conclusions: Besides stress and sex, other factors, such as a particular subculture among third world students, and students’ own personality, may explain the high tendency to transgress rules among surveyed medical students.

Encuesta latinoamericana sobre la actitud de los profesionales de la salud hacia la prescripción de los psicofármacos. Estudio comparativo con la realidad peruana / Latin America survey on health professionals' attitudes towards psychopharmacotherapeutic drug prescriptions: a comparative study of peruvian reality

Son pocos los estudios realizados sobre la imagen de los psicofármacos. Objetivo: Describir la actitud de los profesionales de la salud latinoamericanos (médicos psiquiatras, no psiquiatras y psicólogos) hacia la prescripción de psicofármacos, la preferencia de tratamiento para las enfermedades mentales y la actitud de los pacientes ante la prescripción de los psicofármacos según la opinión de los médicos. Material y métodos: Se realizó un estudio descriptivo, transversal, comparativo y prospectivo. Se efectuó una encuesta para las siguientes enfermedades mentales: depresión, esquizofrenia, ansiedad, trastorno bipolar, epilepsia, farmacodependencia, alcoholismo, T. obsesivo compulsivo, fobias, T. de la personalidad y T. de la alimentación. Se construyó una escala acitudinal formada por 27 itemes ordinales tipo Lickert. resultados: En cuanto a los aspectos negativos se encontraron diferencias significativas entre los grupos (p menor 0.001), los psiquiatras obtuvieron una media de 2.15 mas menos 0.58 mientras que la obtenida por los psicólogos fue de 3.05 mas menos 0.73 puntos. para los aspectos positivos también mostraron diferencias significativas entre los grupos (p menor 0.001); los psiquiatras obtuvieron una media de 3.99 mas menos 0.52 mientras que la obtyenida por los psicólogos fue de 3.20 mas menos 0.64 puntos. En la actitud hacia la prescripción, los médicos psiquiatras y los psicólogos, difirieron de los médicos no psiquiatras, estos últimos mostraron mayor acuerdo en que los psicofármacos son mal administrados. El acuerdo sobre el uso conjunto de la psicoterapia y de la farmacoterapia es aceptado en general por los tres grupos estudiados, mostrando una mayor aceptación por parte de los psicólogos. La preferencia por distintos tratamientos para las enfermedades mentales mostró diferencias significativas entre los tres grupos estudiados en todos lospadecimientos. Los médicos indicaron que los pacientes aceptan los psicofármacos con objeciones y aceptan la indicación médca no muy convencidos en primer lugar y segundo lugar, respectivamente. En la actitud de los pacientes ante la prescripción de los psicofármacos, el miedo a ser dependientes ocupó el primer lugar. En segundo lugar, los pacientes abandonan el tratamiento por el consejo de sus familiares y en tercer lugar los pacientes abandonan el tratamiento por los efectos secundarios.

Valoracion abierta de la aceptacion eficacia y tolerancia de la venlafaxina en pacientes ambulatorios deprimidos / Open study on acceptability, efficacy and tolerance of venlafaxine in depressive out patients

Objetivo: estudio de Fase IV para valorar la aceptación clínica de la venlafaxina en pacientes ambulatorios y obtener información sobre la valoración subjetiva de los pacientes relacionada con su sintomatología depresiva. Métodos: se reclutaron 235 pacientes ambulatorios mayores de 18 años, que cumplían con los criterios de inclusión y presentaban diferentes grados de depresión, valorados de acuerdo a la escala de Hamilton para depresión (HAM-D) y por I a Impresión Clínica Global, durante 6 semanas de tratamiento con venlafaxina. Resultados: el puntaje de la escala de depresión de Hamilton bajó en forma sostenida desde la primera visita, comenzando con un promedio de 28.9 y finalizando con 7.1 en la quinta visita. La mejoría clínica global fue especialmente notoria en la segunda y tercera semanas, siendo estadísticamente significativa la recuperación de la enfermedad. Tampoco hubo diferencias significativas en las variaciones de los signos vitales entre las visitas 1 a 5. Los efectos colaterales más frecuentes fueron: náuseas, mareo y sequedad bucal, los cuales disminuyeron durante el curso del tratamiento. Conclusión: la venlafaxina, en una dosis promedio de 75 mg (con una variación entre 37.5 y 225 mg diarios), tuvo efectos antidepresivos estadísticamente significativos en pacientes ambulatorios, con una tolerancia aceptable

The coexistence of depression and anxiety: Task force for depression and anxiety disorders:. Unión Latinoamericana Contra la Depressión (ULAD)

En la práctica clínica, la ansiedad y la depresión comparten características de sobreposición que dan lugar al síndrome mixto depresivo-ansioso. Este presenta características propias, en ocasiones poco delimitadas, además de particularidades terapéuticas y pronosticas. Un grupo de expertos psiquiatras de diferentes países latinoamericanos analizaron algunas de las controversias relacionadas con la coexistencia de los síntomas, la patofisiología y la genética, así como sus perspectivas diagnósticas, terapéuticas y pronosticas