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Genetics is the second strongest risk factor for Alzheimer's disease (AD) after age. More than 70 loci have been implicated in AD susceptibility so far, and the genetic architecture of AD entails both additive and nonadditive contributions from these loci. To better understand nonadditive impact of single-nucleotide polymorphisms (SNPs) on AD risk, we examined individual, joint, and interacting (SNPxSNP) effects of 139 and 66 SNPs mapped to the BIN1 and MS4A6A AD-associated loci, respectively. The analyses were conducted by fitting three respective dominant allelic-effect models using data from four independent studies. Joint effects were analyzed by considering pairwise combinations of genotypes of the selected SNPs, i.e., compound genotypes (CompG). The individual SNP analyses showed associations of 18 BIN1 SNPs and 4 MS4A6A SNPs with AD. We identified 589 BIN1 and 217 MS4A6A SNP pairs associated with AD in the CompG analysis, although their individual SNPs were not linked to AD independently. Notably, 34 BIN1 and 10 MS4A6A SNP pairs exhibited both significant SNPxSNP interaction effects and significant CompG effects. The vast majority of nonadditive effects were captured through the CompG analysis. These results expand the current understanding of the contributions of the BIN1 and MS4A6A loci to AD susceptibility. The identified nonadditive effects suggest a significant genetic modulation mechanism underlying the genetic heterogeneity of AD in these loci. Our findings highlight the importance of considering nonadditive genetic impacts on AD risk beyond the traditional SNPxSNP approximation, as they may uncover critical mechanisms not apparent when examining SNPs individually., Competing Interests: Declarations. Ethics approval and consent to participate: This study does not involve gathering data from human subjects directly. Instead, it focuses on secondary analysis of data obtained from dbGaP, NIAGADS, and the UK Biobank. The data were accessed with the approval of the Duke University Institutional Review Board (IRB) [protocols: Pro00105245-INIT-1.0 (06/26/2020), Pro00105247-INIT-1.0 (06/26/2020), and Pro00105346-INIT-1.0 (04/15/2020)], and all analyses were performed under IRB guidelines. Conflict of interest: The authors declare no conflicts of interest., (© 2025. The Author(s), under exclusive licence to American Aging Association.)

REHem-AR was created in 2013. The progressive implementation of neonatal screening for haemoglobinopathies in Spanish autonomous communities where the registry had not been implemented, as well as the addition of new centres during this period, has considerably increased the sample of patients covered. In this study, we update our previous publication in this area, after a follow-up of more than 5 years. An observational, descriptive, multicentre and ambispective study of adult and paediatric patients with haemoglobinopathies and rare anaemias registered in REHem was performed. The data are from a cross-sectional analysis performed on 1 June, 2023. The study population comprised 1,756 patients, of whom 1,317 had SCD, 214 had thalassaemia and 224 were diagnosed with another condition. Slightly more than one third of SCD patients (37%) were diagnosed based on neonatal bloodspot screening, and the mean age at diagnosis was 2.5 years; 71% of thalassaemia patients were diagnosed based on the presence of anaemia. Vaso-occlusive crisis and acute chest syndrome continue to be the most frequent complications in SCD. HSCT was performed in 83 patients with SCD and in 50 patients with thalassaemia. Since the previous publication, REHem-AR has grown in size by more than 500 cases. SCD and TM are less frequent in Spain than in other European countries, although the data show that rare anaemias are frequent within rare diseases. REHem-AR constitutes an important structure for following the natural history of rare anaemias and enables us to calculate investment needs for current and future treatments., (© 2024. The Author(s).)

Gaucher disease is an inherited disorder in which there is a deficiency of the enzyme glucocerebrosidase, which leads to the accumulation of glucosylceramide. Although much scientific evidence is now available, there is still limited data on the impact on the different life stages of women with this disease. Among other alterations, a delay in menarche has been described, although it has not been related to fertility problems. Menorrhagia is relatively frequent, being related to the presence of thrombocytopenia, thrombocytopathies or coagulation disorders. On the other hand, pregnancy planning is an increasingly frequent concern. All patients should undergo genetic counseling, and it is important to monitor the appearance or worsening of organomegaly, bone and hematologic abnormalities to establish clinical and therapeutic recommendations. Management during the puerperium will depend on the evolution of gestation, and, during the lactation period, the potential appearance of bone complications should be assessed. An early onset of menopause, compared to the general population, has also been described, which may accelerate the development of osteopenia. Finally, although the usual screening protocols for neoplasms are currently being performed, it is recommended to watch for early signs of liver or renal neoplasms when examining the results of imaging tests performed during evaluations for this disease.

Sporadic Alzheimer's disease (AD) is a polygenic neurodegenerative disorder. Single-nucleotide polymorphisms (SNPs) in multiple genes (e.g., CLU and ABCA7 ) have been associated with AD. However, none of them were characterized as causal variants that indicate the complex genetic architecture of AD, which is likely affected by individual variants and their interactions. We performed a meta-analysis of four independent cohorts to examine associations of 32 CLU and 50 ABCA7 polymorphisms as well as their 496 and 1225 pair-wise interactions with AD. The single SNP analyses revealed that six CLU and five ABCA7 SNPs were associated with AD. Ten of them were previously not reported. The interaction analyses identified AD-associated compound genotypes for 25 CLU and 24 ABCA7 SNP pairs, whose comprising SNPs were not associated with AD individually. Three and one additional CLU and ABCA7 pairs composed of the AD-associated SNPs showed partial interactions as the minor allele effect of one SNP in each pair was intensified in the absence of the minor allele of the other SNP. The interactions identified here may modulate associations of the CLU and ABCA7 variants with AD. Our analyses highlight the importance of the roles of combinations of genetic variants in AD risk assessment.

Congenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the SEC23B gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced SEC23B mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II.

Inhibition of the heterodimeric amino acid carrier SLC7A5/SLC3A2 (LAT1/CD98) has been widely studied in tumor biology but its role in physiological conditions remains largely unknown. Here we show that the SLC7A5/SLC3A2 heterodimer is constitutively present at different stages of erythroid differentiation but absent in mature erythrocytes. Administration of erythropoietin (EPO) further induces SLC7A5/SLC3A2 expression in circulating reticulocytes, as it also occurs in anemic conditions. Although Slc7a5 gene inactivation in the erythrocyte lineage does not compromise the total number of circulating red blood cells (RBCs), their size and hemoglobin content are significantly reduced accompanied by a diminished erythroblast mTORC1 activity. Furthermore circulating Slc7a5 -deficient reticulocytes are characterized by lower transferrin receptor (CD71) expression as well as mitochondrial activity, suggesting a premature transition to mature RBCs. These data reveal that SLC7A5/SLC3A2 ensures adequate maturation of reticulocytes as well as the proper size and hemoglobin content of circulating RBCs., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Background and Aims: Hereditary anemia (HA) encloses a wide group of rare inherited disorders with clinical and hematologic overlaps that complicate diagnosis., Materials and Methods: A 48-gene panel was developed to diagnose HA by Next Generation Sequencing (NGS) in a large cohort of 165 patients from 160 unrelated families., Results: Patients were divided in: A) patients who had a suspicion of a specific type of HA (n = 109), and B) patients who had a suspicion of HA but with no clear type (n = 56). Diagnostic performance was 83.5% in group A and a change of the initial diagnosis occurred in 11% of these patients. In group B, 35.7% of patients achieved a genetic diagnosis. NGS identified 6 cases of xerocytosis, 6 of pyruvate kinase (PK) deficiency, 4 of G6PD, and 1 case of phytosterolemia with no initial suspicion of these pathologies, which is clinically relevant since they have specific treatment. Five patients were found to carry variants associated to two different pathologies (4 of them combining a metabolic deficiency and a membrane defect), and 44 new variants were identified in 41 patients., Conclusion: The use of NGS is a sensitive technique to diagnose HA and it shows better performance when patients are better characterized., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pyruvate kinase (PK) deficiency is the second most frequent enzymopathy and the most common cause of chronic hereditary non-spherocytic haemolytic anaemia. Its global prevalence is underestimated due to low clinical suspicion of mild cases, associated with difficulties in the performance and interpretation of PK enzymatic activity assays. With the advent of next generation sequencing techniques, a better diagnostic approach is achieved. Treatment remains based on red blood cell transfusions and splenectomy, with special attention to iron overload, not only in transfusion-dependent patients. Nowadays, allogeneic hematopoietic stem cell transplantation is the only curative treatment, recommended only in selected cases of severely affected patients with an HLA-identical donor. Novel pharmacological and gene therapies are in clinical trials, with promising results. In this article, the Spanish Erythropathology Group reviews the current situation of PK deficiency, paying special attention to the usefulness of different diagnostic techniques and to actual and emerging treatments., (Copyright © 2020 Elsevier España, S.L.U. All rights reserved.)

Lysosomal diseases (LD) are a group of about 70 rare hereditary disorders (combined incidence 1:5000) in which diverse lysosomal functions are impaired, impacting multiple organs and systems. The first clinical signs and symptoms are usually unspecific and shared by hundreds of other disorders. Diagnosis of LD traditionally relies on performing specific enzymatic assays, if available, upon clinical suspicion of the disorder. However, the combination of the insidious onset of LD and the lack of awareness on these rare diseases among medical personnel results in undesirable diagnostic delays, with unchecked disease progression, appearance of complications and a worsened prognosis. We tested the usefulness of a next-generation sequencing-based gene panel for quick, early detection of LD among cases of idiopathic splenomegaly and/or thrombocytopenia, two of the earliest clinical signs observed in most LD. Our 73-gene panel interrogated 28 genes for LD, 1 biomarker and 44 genes underlying non-LD differential diagnoses. Among 38 unrelated patients, we elucidated eight cases (21%), five with LD (GM1 gangliosidosis, Sanfilippo disease A and B, Niemann-Pick disease B, Gaucher disease) and three with non-LD conditions. Interestingly, we identified three LD patients harboring pathogenic mutations in two LD genes each, which may result in unusual disease presentations and impact treatment. Turnaround time for panel screening and genetic validation was 1 month. Our results underline the usefulness of resequencing gene panels for quick and cost-effective screening of LDs and disorders sharing with them early clinical signs., Competing Interests: G.M. received grants and honoraria from Sanofi Genzyme. L.G.G.‐S. received consulting fees from Biomarin, Sanofi Genzyme, Shire Takeda and Ultragenyx. M.M. received grants and honoraria from Sanofi Genzyme. J.V. received grants and honoraria from Sanofi Genzyme and consulting fees from Shire Takeda. F.J.dC. received grants and honoraria from Sanofi Genzyme. All the other authors have no conflict of interest to declare., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Accuracy of bone marrow (BM) blast count in low-risk myelodysplastic syndromes (MDS) still remains a challenge though it is essential for prognosis. We investigated whether the enumeration of CD34+ myeloid cells by flow cytometry immunophenotyping (FCI) could be used as a consistent parameter for clinical MDS studies., Methods: Six clinical centers entered the study and information on their FCI protocols was recorded. Sixty-seven flow cytometry listmodes from BM samples of patients with low-risk MDS with <5% BM blasts were exchanged among participants in two different rounds. Interlaboratory variations on the quantification of CD34+ myeloid cells were calculated and strategies to solve differences were evaluated., Results: An overall "very good" agreement on CD34+ cell count among participants (intraclass correlation coefficient = 0.720) was observed, but agreement was "low" in 22 files. No single parameter could fully explain all discrepancies, but 3 technical issues were identified as relevant: the use of the CD34/CD45/CD117/HLA-DR mAb combination, acquisition of ≥50,000 events and a low percentage of debris/aggregates. The frequency of discordant results increased with the accumulation of pitfalls (none, 16%; 1 pitfall, 40%; 2 pitfalls, 83%; P = 0.006). Finally, the use of a common gating strategy for analysis increased the percentage of files with "very good" agreement to 100%., Conclusions: Prevention of specific technical pitfalls is mandatory to reach a good reproducibility of CD34+ cell count among centers. These recommendations set the basis for laboratory standardization and enable the use of CD34+ cell enumeration as additional information in low-risk MDS patients. © 2017 International Clinical Cytometry Society., (© 2017 International Clinical Cytometry Society.)

Background: Although consensus guidelines have been proposed in 2010 for the diagnostic screening of paroxysmal nocturnal hemoglobinuria (PNH) by flow cytometry (FCM), so far no study has investigated the efficiency of such medical indications in multicentric vs. reference laboratory settings., Methods: Here we evaluate the efficiency of consensus medical indications for PNH testing in 3,938 peripheral blood samples submitted to FCM testing in 24 laboratories in Spain and one reference center in Brazil., Results: Overall, diagnostic screening based on consensus medical indications was highly efficient (14% of PNH + samples) both in the multicenter setting in Spain (10%) and the reference laboratory in Brazil (16%). The highest frequency of PNH + cases was observed among patients screened because of bone marrow (BM) failure syndrome (33%), particularly among those with aplastic anemia (AA; 45%) and to a less extent also a myelodysplastic syndrome (MDS; 10%). Among the other individuals studied, the most efficient medical indications for PNH screening included: hemolytic anemia (19%), hemoglobinuria (48%) and unexplained cytopenias (9%). In contrast, only a minor fraction of the patients who had been submitted for PNH testing because of unexplained thrombosis in the absence of cytopenia, were positive (0.4%)., Conclusions: In summary, our results demonstrate that the current medical indications for PNH screening by FCM are highly efficient, although improved screening algorithms are needed for patients presenting with thrombosis and normal blood cell counts. © 2016 International Clinical Cytometry Society., (© 2016 International Clinical Cytometry Society.)

B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-XL and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL.

Background and Objectives: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal disease characterized by complement-mediated hemolysis, bone marrow failure and thrombosis. Eculizumab is a humanized monoclonal antibody that blocks the cytolytic component of the complement system by binding to complement C5., Material and Methods: We report the results of eculizumab treatment in 25 PNH patients from different centers in Spain. Statistical analysis was perfomed with a SPSS v15.0 software., Results: Fifty-eight per cent of the patients achieved transfusional independence after a median of 14 months. Transfusion requirements were reduced in 60% of the remaining cases. Fatigue resolved in 96% of the patients and smooth muscle dystony-related symptoms in all cases. A single case of treatment-related infection was observed., Conclusions: Eculizumab controls effectively hemolysis and greatly improves clinical symptoms. The drug is safe and well tolerated, without significant adverse effects except meningococcal infection. Patients with suboptimal response to treatment must be assessed for bone marrow insufficiency and extravascular haemolysis., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)