Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.

Disorders of vesicular trafficking presenting with recurrent acute liver failure: NBAS, RINT1, and SCYL1 deficiency.

Among genetic disorders of vesicular trafficking, there are three causing recurrent acute liver failure (RALF): NBAS, RINT1, and SCYL1-associated disease. These three disorders are characterized by liver crises triggered by febrile infections and account for a relevant proportion of RALF causes. While the frequency and severity of liver crises in NBAS and RINT1-associated disease decrease with age, patients with SCYL1 variants present with a progressive, cholestatic course. In all three diseases, there is a multisystemic, partially overlapping phenotype with variable expression, including liver, skeletal, and nervous systems, all organ systems with high secretory activity. There are no specific biomarkers for these diseases, and whole exome sequencing should be performed in patients with RALF of unknown etiology. NBAS, SCYL1, and RINT1 are involved in antegrade and retrograde vesicular trafficking. Pathomechanisms remain unclarified, but there is evidence of a decrease in concentration and stability of the protein primarily affected by the respective gene defect and its interaction partners, potentially causing impairment of vesicular transport. The impairment of protein secretion by compromised antegrade transport provides a possible explanation for different organ manifestations such as bone alteration due to lack of collagens or diabetes mellitus when insulin secretion is affected. Dysfunction of retrograde transport impairs membrane recycling and autophagy. The impairment of vesicular trafficking results in increased endoplasmic reticulum stress, which, in hepatocytes, can progress to hepatocytolysis. While there is no curative therapy, an early and consequent implementation of an emergency protocol seems crucial for optimal therapeutic management.

Fluoride varnishes with calcium glycerophosphate: fluoride release and effect on in vitro enamel demineralization

The aims of this study were (1) to assess the amount of fluoride (F) released from varnishes containing calcium glycerophosphate (CaGP) and (2) to assess the effect of the experimental varnishes on in vitrodemineralization. Six test groups using 5 varnishes: base varnish (no active ingredients); Duraphat® (2.26% NaF); Duofluorid® (5.63% NaF/CaF2); experimental varnish 1 (1% CaGP/5.63% NaF/CaF2); experimental varnish 2 (5% CaGP/5.63% NaF/CaF2); and no varnish were set up. In stage 1, 60 acrylic blocks were randomly distributed into 6 groups (n = 10). Then 300 µg of each varnish was applied to each block. The blocks were immersed in deionized water, which was changed after 1, 8, 12, 24, 48 and 72 hours. Fluoride concentration in the water was analyzed using a fluoride electrode. In stage 2, 60 bovine enamel samples were distributed into 6 groups (n = 10), and treated with 300 µg of the respective varnish. After 6 h the varnish was removed and the samples were subjected to a 7-day in vitro pH cycle (6 h demineralization/18 h remineralization per day). The demineralization was measured using surface hardness. The results showed that both experimental varnishes released more fluoride than Duofluorid® and Duraphat® (p < 0.05), but Duraphat® showed the best preventive effect by decreasing enamel hardness loss (p < 0.05). Therefore, we conclude that even though (1) the experimental varnishes containing CaGP released greater amounts of F, (2) they did not increase in the preventive effect against enamel demineralization.

Concordância entre os relatos do núcleo familiar em relação à qualidade de vida da criança / Agreement between the nucleus family reports regarding child's quality of life

Objetivos: Avaliar a concordância entre os relatos de pai, mãe e filhos em relação a qualidade de vida relacionada a saúde bucal (OVRSB) da criança. Métodos: Um total de 80 tríades pai-mãe-criança responderam a versão brasileira do Scale of Oral Health Outcomes for 5-year-old children (SOHO-5) validado para crianças de 5 e 6 anos de idade e seus respectivos pais O preenchimento do SOHO-5 foi realizado por meio de entrevistas independentes face-a-face. A concordância entre os escores totais e de itens foi avaliada usando a comparação de médias e a análise de correlação calculada pelo coeficiente de correlaçâo intraclasse (CCI). Resultados: Houve diferença significativa entre as médias dos relatos pai-criança nos escores totais (p<0.001) e itens relacionados a não sorrir devido à dor e à aparência (p<0,01). O CCI para o escore total dos relatos mãe-criança foi de 0,83 (IC 95% 0,74- 0,89) e de 0,41 (IC 95% 0,09- 0,63) para os relatos pai-criança, indicando uma concordância excelente e moderada, respectivamente. Conclusões: As mães relatam a QVRSB de seus filhos de forma semelhante às crianças enquanto que os pais subestimam os impactos. As mães podem ser consideradas respondentes secundárias preferíveis aos pais.

Objective: To assess the agreement between father, mother and children regarding child'l oral health-related quality of life (OHROoL). Methods: A total of 80 mother-father-child triads answered the Brazilian version of the Scale of Oral Health Outcomes for 5-year-old children (SOHO-51, validated for children aged 5-6 years and their parents. The SOHO-5 was completed through face-to-face independent interviews. Agreement between total and items scores was assessed using mean comparisons and correlation analyses by computing the Intraclass Correlation Coefficient (ICC). Results: There were significant differences between the mean total scores for father-child pairs (p<0.001) and items related to avoid smiling due to pain and avoid smiling due to appearance (p<0,01). The ICC for total score was 0.83 (CI 95% 0.74; 0.89) for mother-child pairs and 0.41 (CI 95% 0.09; 0.63) for father-child pairs indicating an excellent and moderate agreement, respectively. Conclusions: Mothers do rate their children's OHRQol similarly to children's self-reports, while fathers underreport the impact. Mothers may be considered preferable proxies than fathers.