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Akiko Shimamura

Publications and source records attributed to Akiko Shimamura.

10 recordsLinked to original sources
PubMed2026

Preemptive hematopoietic stem cell transplantation in RUNX1 familial platelet disorder: a shared decision-making framework.

RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35-50% lifetime risk of hematologic malignancy (HM). Like all germline HM predisposition syndromes, RUNX1-FPD can only be cured with allogeneic hematopoietic stem cell transplantation (HSCT). Current genetic screening techniques allow for early detection of germline predisposition and, consequently, the opportunity for HSCT before overt development of HM (i.e., preemptive HSCT). However, there is as yet no consensus on the use of preemptive HSCT for RUNX1-FPD. Described here is the case of an individual with RUNX1-FPD and a family history of HM who underwent preemptive HSCT. We introduce a shared decision-making framework designed to support individuals with RUNX1-FPD, their families, and their multidisciplinary clinical teams in evaluating whether and when to pursue preemptive HSCT versus continued surveillance. The framework reviews key medical factors that influence the decisions regarding timing of HSCT, including germline and somatic variants, clonal changes over time, familial history of HM, early morphologic or hematologic features, impacts on bleeding-related quality of life, and donor availability. The framework also summarizes the major risks and uncertainties potentially associated with preemptive HSCT while highlighting the associated ethical challenges. Together, the case and framework provide a structured, patient-centered approach for navigating the complex clinical decision of preemptive HSCT. Ongoing collaborative efforts to define cytogenetic and clonal changes preceding malignant transformation in RUNX1-FPD will refine the framework and bolster individualized treatment strategies aimed at preventing HM and improving the quality of life of individuals with RUNX1-FPD.

Humans↗
PubMed2025

Diagnostic Implications and Correlates of Plasma Adenosine Deaminase 2 Activity and ADA2 Variants.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease manifested as polyarteritis nodosa, stroke, and bone marrow failure. Leveraging an international cohort of 200 DADA2 cases, we aimed to characterize the diagnostic utility of a plasma ADA2 enzyme activity assay and understand the implications of residual ADA2 activity. METHODS: Data were collected from individuals who underwent ADA2 testing from 2018 to 2025. Plasma ADA2 activity was determined using an established spectrophotometric assay. ADA2 variants were analyzed in transfected cells by enzyme assay and western blotting. RESULTS: We determined that plasma ADA2 activity is 99.0% and 96.0% sensitive and 99.7% and 98.8% specific in distinguishing genetically confirmed DADA2 cases from controls and carriers, respectively. Eighteen individuals with DADA2 (9%) possessed detectable ADA2 activity, including several cases with levels seen in carriers. Residual ADA2 activity was associated with the vasculitis/inflammatory phenotype but not with disease severity. Genotype analysis revealed that 14 of 18 cases with residual plasma activity possessed at least one hypomorphic missense variant with greater than 20% residual ADA2 function when overexpressed in 293T cells, often occurring in trans with a more deleterious variant. In vitro analysis revealed that missense ADA2 variants exert variable dominant-negative effects by forming large intracellular protein aggregates via disulfide bond formation at a cysteine residue (Cys408). CONCLUSION: We confirmed the utility of plasma ADA2 activity as a diagnostic assay and showed that the inflammatory phenotype of DADA2 occurred in cases with residual activity. In vitro findings illustrate potential interactions of ADA2 variants to synergistically disrupt protein function.

Humans↗
PubMed2006

Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive marrow failure syndrome associated with exocrine pancreatic insufficiency and leukemia predisposition. Bone marrow failure typically manifests with neutropenia, but anemia, thrombocytopenia, or aplastic anemia may also develop. Additional organ systems, such as liver or bone, may also be affected. Clonal cytogenetic abnormalities, particularly those involving chromosome 7 such as monosomy 7 or isochromosome 7, may develop. Mutations in the SBDS gene are found in approximately 90% of patients meeting clinical diagnostic criteria. SBDS is a highly conserved gene of unknown function. Studies of the yeast orthologue YLR022c and structurally related proteins suggest a role in RNA metabolism. In human cells, the SBDS protein localizes to both the cytoplasm and the nucleus, and shuttles in and out of the nucleolus in a cell cycle-dependent manner. A discussion of diagnostic workup, medical management, and treatment is presented.

Bone Marrow Diseases↗
PubMed2006

Inherited bone marrow failure syndromes: molecular features.

Recent advances resulting from the identification of the genes responsible for four inherited marrow failure syndromes, Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, are reviewed. The interpretation of genetic testing should be guided by an understanding of the limitations of such testing for each disorder. The possibility of an inherited basis for marrow failure must be considered for adults as well as children with aplastic anemia. Shared molecular themes are emerging from functional studies of the genes underlying the different inherited disorders. Genomic instability may result from impaired DNA repair in Fanconi anemia or telomere dysregulation in dyskeratosis congenita. Mutations affecting ribosome assembly or function are associated with Diamond-Blackfan anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome. These findings raise new questions about the molecular mechanisms regulating hematopoiesis and leukemogenesis. Clinical implications arising from these molecular studies are explored.

Anemia, Diamond-Blackfan↗
PubMed2005

The Shwachman-Diamond SBDS protein localizes to the nucleolus.

Shwachman-Diamond syndrome (SDS) is an autosomal recessively inherited disorder characterized by exocrine pancreatic insufficiency and bone marrow failure. The gene for this syndrome, SBDS, encodes a highly conserved novel protein. We characterized Shwachman-Bodian-Diamond syndrome (SBDS) protein expression and intracellular localization in 7 patients with SDS and healthy controls. As predicted by gene mutation, 4 patients with SDS exhibited no detectable full-length SBDS protein. Patient DF277, who was homozygous for the IVS2 + 2 T>C splice donor mutation, expressed scant levels of SBDS protein. Patient SD101 expressed low levels of SBDS protein harboring an R169C missense mutation. Patient DF269, who carried no detectable gene mutations, expressed wild-type levels of SBDS protein to add further support to the growing body of evidence for additional gene(s) that might contribute to the pathogenesis of the disease phenotype. The SBDS protein was detected in both the nucleus and the cytoplasm of normal control fibroblasts, but was particularly concentrated within the nucleolus. SBDS localization was cell-cycle dependent, with nucleolar localization during G1 and G2 and diffuse nuclear localization during S phase. SBDS nucleolar localization was intact in SD101 and DF269. The intranucleolar localization of SBDS provides further supportive evidence for its postulated role in rRNA processing.

Case-Control Studies↗
PubMed2004

Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway.

Fanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure, chromosome fragility, and cancer susceptibility. Eight FA-associated genes have been identified so far, the products of which function in the FA/BRCA pathway. A key event in the pathway is the monoubiquitination of the FANCD2 protein, which depends on a multiprotein FA core complex. In a number of patients, spontaneous genetic reversion can correct FA mutations, leading to somatic mosaicism. We analyzed the FA/BRCA pathway in 53 FA patients by FANCD2 immunoblots and chromosome breakage tests. Strikingly, FANCD2 monoubiquitination was detected in peripheral blood lymphocytes (PBLs) in 8 (15%) patients. FA reversion was further shown in these patients by comparison of primary fibro-blasts and PBLs. Reversion was associated with higher blood counts and clinical stability or improvement. Once constitutional FANCD2 patterns were determined, patients could be classified based on the level of FA/BRCA pathway disruption, as "FA core" (upstream inactivation; n = 47, 89%), FA-D2 (n = 4, 8%), and an unidentified downstream group (n = 2, 4%). FA-D2 and unidentified group patients were therefore relatively common, and they had more severe congenital phenotypes. These results show that specific analysis of the FA/BRCA pathway, combined with clinical and chromosome breakage data, allows a comprehensive characterization of FA patients.

Adolescent↗
PubMed2003

Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.

The clinical, cytogenetic, and molecular findings of 2 Fanconi anemia (FA) subtype D1 kindreds, initially identified through a young child with a solid tumor (medullobastoma, Wilms tumor), are described. Each kindred subsequently had a second affected child; one developed Wilms tumor followed by a medulloblastoma, and the other developed T-lineage acute lymphoblastic leukemia. Cytogenetic studies revealed an unusually high spontaneous chromosome aberration rate, contrasting with other FA subtypes. Molecular analysis revealed biallelic BRCA2/FANCD1 mutations. The patients did not exhibit bone marrow failure. Our studies suggest that the D1 subtype represents a severe end of the cytogenetic spectrum within FA, consistent with a critical downstream role of BRCA2 in the FA pathway. Furthermore, this FA subgroup may be preferentially associated with an increased predisposition to solid tumors in early childhood. Recognition of this constellation of findings has significant implications for medical management and genetic counseling of FA families.

Anemia, Aplastic↗
PubMed2002

A novel diagnostic screen for defects in the Fanconi anemia pathway.

Fanconi anemia (FA) is an autosomal recessive chromosomal instability syndrome characterized by congenital abnormalities, progressive bone marrow failure, and cancer predisposition. Although patients with FA are candidates for bone marrow transplantation or gene therapy, their phenotypic heterogeneity can delay or obscure diagnosis. The current diagnostic test for FA consists of cytogenetic quantitation of chromosomal breakage in response to diepoxybutane (DEB) or mitomycin C (MMC). Recent studies have elucidated a biochemical pathway for Fanconi anemia that culminates in the monoubiquitination of the FANCD2 protein. In the current study, we develop a new rapid diagnostic and subtyping FA assay amenable for screening broad populations at risk of FA. Primary lymphocytes were assayed for FANCD2 monoubiquitination by immunoblot. The absence of the monoubiquitinated FANCD2 isoform correlated with the diagnosis of FA by DEB testing in 11 known patients with FA, 37 patients referred for possible FA, and 29 healthy control subjects. Monoubiquitination of FANCD2 was normal in other bone marrow failure syndromes and chromosomal breakage syndromes. A combination of retroviral gene transfer and FANCD2 immunoblotting provides a rapid subtyping assay for patients newly diagnosed with FA. These new FA screening assays would allow efficient testing of broad populations at risk.

Blotting, Western↗
PubMed2002

Marrow failure.

This chapter describes the clinical presentation and molecular basis of two inherited bone marrow failure syndromes, Fanconi anemia (FA), and Diamond-Blackfan anemia (DBA). It also provides an update on diagnostic and therapeutic approaches to bone marrow failure of all types (inherited and acquired) in pediatric patients. In Section I, Dr. Alan D'Andrea reviews the wide range of clinical manifestations of Fanconi anemia. Significant advances have been made in understanding the molecular pathogenesis of FA. On the basis of these advances, new diagnostic assays and treatment options are now available. In Section II, Dr. Niklas Dahl examines the clinical features and molecular pathogenesis of Diamond-Blackfan anemia. The possible links between the RPS19 gene (DBA gene) and the erythropoiesis defect are considered. In Section III, Drs. Eva Guinan and Akiko Shimamura provide an algorithm for the diagnostic evaluation and treatment of children with inherited or acquired aplastic anemia. Through the presentation of a case study of a pediatric patient with bone marrow failure, he provides an overview of the newest tests and treatment options.

Adult↗