A de novo dominant-negative variant is associated with OTULIN-related autoinflammatory syndrome

稀少遺伝性自己炎症性疾患: OTULIN関連自己炎症症候群の新たな病態を解明～既報の疾患に新たな視点を追加し、未診断患者の診断や炎症・細胞死研究の進展に期待～. 京都大学プレスリリース. 2024-04-25.OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis

A complementary approach for genetic diagnosis of inborn errors of immunity using proteogenomic analysis

博士(医学)Doctor of Philosophy in Medical Science広島大学Hiroshima Universit

Current Perspectives on Neonatal Screening for Propionic Acidemia in Japan: An Unexpectedly High Incidence of Patients with Mild Disease Caused by a Common PCCB Variant

Propionic acidemia (PA) is a disorder of organic acid metabolism which typically presents with acute encephalopathy-like symptoms associated with metabolic acidosis and hyperammonemia during the neonatal period. The estimated incidence of symptomatic PA in Japan is 1/400,000. The introduction of neonatal screening using tandem mass spectrometry has revealed a far higher disease frequency of approximately 1/45,000 live births due to a prevalent variant of c.1304T>C (p.Y435C) in PCCB, which codes β-subunit of propionyl-CoA carboxylase. Our questionnaire-based follow-up study reveals that most of these patients remain asymptomatic. However, reports on symptomatic patients exhibiting cardiac complications such as cardiomyopathy and QT prolongation have been increasing. Moreover, there were even cases in which these cardiac complications were the only symptoms related to PA. A currently ongoing study is investigating the risk of cardiac complications in patients with neonatal screening-detected PA caused by this common variant

Using the C14:1/Medium-Chain Acylcarnitine Ratio Instead of C14:1 to Reduce False-Positive Results for Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency in Newborn Screening in Japan

Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a long-chain fatty acid oxidation disorder that manifests as either a severe phenotype associated with cardiomyopathy, a hypoglycemic phenotype, or a myopathic phenotype. As the hypoglycemic phenotype can cause sudden infant death, VLCAD deficiency is included in newborn screening (NBS) panels in many countries. The tetradecenoylcarnitine (C14:1) level in dried blood specimens is commonly used as a primary marker for VLCAD deficiency in NBS panels. Its ratio to acetylcarnitine (C2) and various other acylcarnitines is used as secondary markers. In Japan, tandem mass spectrometry-based NBS, initially launched as a pilot study in 1997, was introduced to the nationwide NBS program in 2013. In the present study, we evaluated levels of acylcarnitine with various chain lengths (C18 to C2), free carnitine, and their ratios in 175 infants who tested positive for VLCAD deficiency with C14:1 and C14:1/C2 ratios. Our analyses indicated that the ratios of C14:1 to medium-chain acylcarnitines (C10, C8, and C6) were the most effective markers in reducing false-positive rates. Their use with appropriate cutoffs is expected to improve NBS performance for VLCAD deficiency

A Case Report of a Japanese Boy with Morquio A Syndrome: Effects of Enzyme Replacement Therapy Initiated at the Age of 24 Months

Background: Morquio A syndrome, mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disorder caused by the deficient activity of N-acetylgalactosamine-6-sulfatase (GalNac6S), due to alterations in the GALNS gene. This disorder results in marked abnormalities in bones and connective tissues, and affects multiple organs. Here, we describe the clinical course of a Japanese boy with MPS IVA who began enzyme replacement therapy (ERT) at the age of 24 months. Patient: the patient presented for kyphosis treatment at 22 months of age. An X-ray examination revealed dysostosis multiplex. Uronic acids were elevated in the urine and the keratan sulfate (KS) fraction was predominant. The leukocyte GalNac6S enzyme activity was extremely low. The patient exhibited the c.463G > A (p.Gly155Arg) mutation in GALNS. Based on these findings, his disease was diagnosed as classical (severe) Morquio A syndrome. An elosulfase alfa infusion was initiated at the age of 24 months. The patient’s body height improved from −2.5 standard deviation (SD) to −2 SD and his physical activity increased during the first 9 months on ERT. However, he gradually developed paralysis in the lower legs with declining growth velocity, which required cervical decompression surgery in the second year of the ERT. The mild mitral regurgitation, serous otitis media, and mild hearing loss did not progress during treatment. Conclusion: early initiation of the elosulfase alfa to our patient showed good effects on the visceral system and muscle strength, while its effect on bones appeared limited. Careful observation is necessary to ensure timely surgical intervention for skeletal disorders associated with neurological symptoms. Centralized and multidisciplinary management is essential to improve the prognosis of pediatric patients with MPS IVA

2009

ABSTRACT first relapse after being treated with chemotherapy alone during CR1. Methods Patients Adults with AML who had achieved CR1 were retrospectively registered in a nationwide AML database, which formed the basis of this study. Statistical analysis Data were retrospectively reviewed and analyzed as of March 2012. Distributions of patients' characteristics between groups were compared using the chi-square test for categorical variables and the Wilcoxon rank-sum test for continuous variables. A Kaplan-Meier survival analysis was performed to estimate the probabilities of overall survival, which was defined as the time from the first relapse to death or the last visit. Differences in overall survival between groups were compared by means of the log-rank test. To compare the outcomes of patients who received allogeneic HCT after relapse and those who did not, we performed landmark analyses by excluding patients who died within 120 days from relapse. The Cox regression model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). As covariates considered in univariate and multivariate analyses, we selected clinically important factors that were present at the first relapse. All statistical analyses were performed with SPSS software version 11.0.1 (SPSS, Chicago, IL, USA) and EZR (Saitama Medical Center, Jichi Medical University), which is a graphical user interface for R (The R Foundation for Statistical Computing). Results Characteristics of relapsed patients Of the total of 2516 patients, 397 were diagnosed with CBF-AML. Twenty-six patients underwent allogeneic HCT during CR1 [17 patients with t(8;21) and 9 with inv(16)]. Among the 371 patients who were treated with chemotherapy alone during the CR1, 208 (56%) experienced a first hematologic relapse, and analyses were performed in 139 [92 patients with t(8;21) and 47 with inv(16) including three with t(16;16)] for whom additional data were available We investigated the cytogenetic profile at relapse in comparison with that at diagnosis. Cytogenetic data were not available for 10% of the patients because of an insufficient count of mitotic cells or because a chromosome analysis was not performed at relapse. Different cytogenetics were observed in 36% and 28% of those with t(8;21) and inv(16), respectively, and included a decrease in cytogenetic abnormalities (1% and 6%), an increase in cytogenetic abnormalities: numerical change (0% and 11%), an increase in cytogenetic abnormalities: structural change (21% and 0%), and unrelated changes (14% and 11%). Therapeutic strategies and response after relapse Online Supplementary Table S1 and Salvage allogeneic hematopoietic cell transplantation after relapse Of the 139 relapsed patients, 96 (69%), who accounted for 71% and 66% of those with t(8;21) and inv(16), respectively, underwent allogeneic HCT after the first relapse ( Overall survival after the first relapse The median follow-up of surviving patients was 38 months from relapse, and the 3-year overall survival rate after relapse was 48% for the whole group of relapsed patients with CBF-AML ( We performed a landmark analysis to compare overall survival after relapse in patients who underwent allogeneic HCT at any time after relapse and those who did not. S. Kurosawa et al. 1528 haematologica | 2013; 98(10) Multivariate analysis for overall survival after the first relaps

Prognosis of patients with core binding factor acute myeloid leukemia after first relapse

Core binding factor acute myeloid leukemia is known to have a favorable prognosis, however, there have been no detailed analyses on prognostic factors after first relapse. Using a nationwide database, we retrospectively analyzed core binding factor acute myeloid leukemia patients who relapsed after being treated with chemotherapy alone during their first complete remission. Of a total of 397 patients who were diagnosed with core binding factor acute myeloid leukemia, 208 experienced a first relapse, and analyses were performed in 139 patients for whom additional data were available. In the entire cohort, the overall survival rate after relapse was 48% at 3 years. By multivariate analysis, younger age at diagnosis, a longer interval before relapse, and inv(16) were shown to be independently associated with better survival after relapse. Although there was no significant difference in survival after relapse between patients who underwent allogeneic hematopoietic cell transplantation and those who did not in the overall series of relapsed patients, we found that transplantation significantly improved survival among patients who had t(8;21) (54% versus 26% at 3 years, P=0.002). In addition, among patients with t(8;21), those who had different cytogenetics at relapse had a significantly improved survival after transplantation, while those who had same cytogenetics did not. We showed that the prognosis differs significantly and optimal treatment strategies may vary between groups of patients with core binding factor acute myeloid leukemia with different cytogenetic profiles at relapse. These findings may help to guide therapeutic decisions after first relapse

Agammaglobulinemia due to p.E555K <i>TCF3 </i>Dominant-Negative Variant

Transcription factor 3 (TCF3) dominant negative (DN) variant causes autosomal dominant (AD) E47 transcription factor deficiency. AD E47 transcription factor deficiency is an inborn error of immunity characterized by B-cell deficiency and agammaglobulinemia. Only the p.E555K variant has been reported as the causative variant in this disease. In this study, we describe the first Asian patient with wide phenotypes due to the p.E555K variant and highlight the unique features that contribute to the exclusivity of this variant. The patient was a 25-year-old male presenting with B-cell deficiency, agammaglobulinemia, and mild facial dysmorphic features. We confirmed the diagnosis of AD E47 transcription factor deficiency by the identification of a heterozygous missense variant c.1663G &gt;A; p.E555K in the TCF3 gene. Alanine scanning of the E47 basic region revealed the structural Utsumi T, et al.3 significance of position 555. In addition, a comprehensive mutational analysis centered on position 555 found that only the amino acid substitution for lysine has a potent DN effect. Structurally the change from glutamic acid to lysine at position 555 not only abolished hydrogen bonds related to the protein-DNA interaction but also inverted the charge in the E47 protein surface. Our study reveals a partial aspect of the exclusivity of the E555K in the TCF3 DN variant