発作性夜間ヘモグロビン尿症

Background and Clinical Significance: Tarui disease, or glycogen storage disease type VII, is a rare autosomal recessive metabolic myopathy caused by muscle phosphofructokinase deficiency. Its manifestations include exercise intolerance, exertional myalgia, muscle cramps, myoglobinuria, rhabdomyolysis, hyperuricemia, and compensated hemolysis. The hematologic phenotype may obscure the underlying metabolic disorder and raise concern for a clonal myeloid neoplasm. Case Presentation: A 23-year-old man was referred for persistent mild thrombocytopenia following evaluation for jaundice and hepatosplenomegaly. He had undergone cholecystectomy at 18 years of age and reported exercise-induced myalgia, muscle cramps, and episodes of dark urine. Laboratory investigations demonstrated mild monocytosis, reticulocytosis, thrombocytopenia, hyperuricemia, elevated lactate dehydrogenase, and predominantly unconjugated hyperbilirubinemia, with a negative direct antiglobulin test. Selected inherited hemolytic disorders, hemoglobinopathies, and paroxysmal nocturnal hemoglobinuria were excluded. Bone marrow examination showed marked erythroid hyperplasia and mild megakaryocytic dysplasia. Testing for JAK2, CALR, and MPL mutations and an extended myeloid next-generation sequencing panel identified no pathogenic variants, and monocytosis resolved during follow-up. Whole-exome sequencing identified a homozygous PFKM missense variant, NM_001354735.1:c.1087A>T, p.(Ile363Phe), classified as a variant of uncertain significance. The patient subsequently developed severe rhabdomyolysis, with a creatine kinase level of 225,000 U/L and recovered after intensive intravenous hydration without renal impairment. Conclusions: Tarui disease should be considered in young patients with compensated hemolysis, hyperuricemia, exertional muscle symptoms, dark urine, or rhabdomyolysis, even when hematologic abnormalities suggest a myeloid disorder. The highly concordant phenotype and homozygous PFKM variant support a clinically probable diagnosis, although pathogenicity remains unconfirmed. Functional and segregation evidence may strengthen causal interpretation and support future variant reclassification.

Platelets express several glycophosphatidylinositol-(GPI-) anchored receptors, mainly involved in protection against lysis by activated complements. Most of these are well-characterised and are expressed on other blood cells. More recently, CD109 with a mass of 175 kDa was also shown to be a GPI-anchored receptor, surface expressed only on activated platelets, with a role as a co-receptor for transforming growth factor-β (TGF-β). CD109 is expressed on a wide range of cells and is a marker for various types of tumors. Activated platelets express an even larger GPI-anchored receptor at about 500 kDa. We have now isolated this and identified it as fibrocystin L, also known as polycystic kidney hepatic disease L1 (PKHD1L1). Fibrocystin L, like other platelet GPI-anchored receptors, is missing or deficient in paroxysmal nocturnal hemoglobinuria. Fibrocystin L is also expressed in activated T-cells and may be involved in immune responses. Recently, there have been additional reports of PKHD1L1 expression and roles as a coat protein of hair-cell stereocilia essential for normal hearing, as well as reports of them in the dentate gyrus in mice involved in susceptibility to seizure. In all these cases, GPI anchors were not reported, but neither were they tested for. During the fluorescence microscopy studies, we used CD109 as a control and observed that it is also a granule protein that had not been previously reported.

Pancytopenia is a significant hematological complication in patients with systemic lupus erythematosus (SLE), with an estimated prevalence of 10-40%. It is defined as a simultaneous decrease in red blood cells, white blood cells, and platelets. Although isolated cytopenias are more common, pancytopenia may indicate severe disease activity or secondary complications, such as bone marrow suppression or hemophagocytic syndromes. This review aims to summarize and synthesize current knowledge on the etiology, pathophysiology, diagnostic approach, and treatment strategies for pancytopenia in SLE, as well as its differentiation from other causes of bone marrow failure. The pathogenesis of pancytopenia in SLE is multifactorial and includes drug-induced bone marrow suppression, hypersplenism, myelofibrosis, macrophage activation syndrome (MAS), and autoimmune bone marrow failure. The diagnostic evaluation includes hematologic assessment, bone marrow examination, and exclusion of alternative diagnoses, such as aplastic anemia and paroxysmal nocturnal hemoglobinuria. Therapeutic management depends on the underlying cause. We also summarize published case reports comparing treatment approaches and clinical outcomes. The role of rituximab (RTX) in the management of pancytopenia and isolated cytopenias associated with SLE is discussed in detail. Particular attention is given to its mechanisms of action, safety profile and mixed clinical outcomes, documented in multicenter retrospective cohort studies, meta-analyses, and case series. Early recognition of pancytopenia remains a clinical challenge and requires well-structured diagnostic and therapeutic strategies. A thorough understanding of its underlying mechanisms and clinical manifestations is essential to avoid delays in treatment and prevent complications.

BACKGROUND: Aplastic anaemia (AA) and paroxysmal nocturnal haemoglobinuria (PNH) are closely related acquired bone marrow failure syndromes sharing an immune-mediated pathogenesis. Cytogenetic abnormalities are uncommon in AA-PNH overlap syndrome, and their significance remains uncertain. We report a case of non-severe AA-PNH overlap syndrome harbouring a low-level chromosome 17p deletion in the absence of morphologic or molecular evidence of myeloid neoplasm. CASE PRESENTATION: A 56-year-old female presented with recurrent aphthous ulcers and pancytopenia. Complete blood count revealed haemoglobin of 6.3 g/dL, total leukocyte count of 2800/µL with an absolute neutrophil count of 982/µL, and platelet count of 10,000/µL. Bone marrow aspirate showed adequate erythropoiesis with normoblastic to megaloblastic maturation and active myelopoiesis. Bone marrow biopsy revealed a markedly hypocellular marrow (10% cellularity) with focal erythroid prominence. No dysplasia, excess blasts, ring sideroblasts, and abnormal topography were identified. Flow cytometric PNH evaluation demonstrated a large type III clone involving 78% of neutrophils and 64% of monocytes. FISH analysis using TP53/CEP17 probes revealed chromosome 17p deletion in 12 of 200 nuclei (6%). Next-generation sequencing did not identify TP53 or other myeloid-associated mutations. The patient was treated with horse anti-thymocyte globulin, cyclosporine, romiplostim, erythropoietin, and irradiated blood products. She achieved transfusion independence and remains clinically stable on follow-up of 27 months. CONCLUSION: Low-level chromosome 17p deletion may occur in AA-PNH overlap syndrome without morphologic or molecular evidence of myeloid neoplasm. Careful clinicopathologic correlation and long-term surveillance are essential before attributing such abnormalities to clonal evolution.

OBJECTIVE: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare acquired clonal abnormality that makes hematopoietic cells highly vulnerable to complement-mediated destruction. Fatigue is one of the most commonly reported unresolved symptoms by patients with PNH. In this study, the fatigue status of PNH patients receiving eculizumab treatment and the factors affecting fatigue were evaluated using a quality-of-life questionnaire. MATERIALS AND METHODS: The study included 18 centers from Türkiye. The quality of life of PNH patients receiving eculizumab treatment was assessed through face-to-face surveys using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale. RESULTS: A total of 104 PNH patients treated with eculizumab were included in the study, of whom 51 (49%) were female and 53 (51%) were male. The mean (±SD) age of the patients was 48.04 (±16.16) years at the time of the survey. The mean (±SD) FACIT-Fatigue score was 32.63 (±11.79). A total of 39 (37.5%) patients had a fatigue score of 30 or below, which was defined as severe fatigue. Patients with severe fatigue had lower hemoglobin levels both at diagnosis and at the time of the survey [8.05 g/dL vs. 9.15 g/dL (p = 0.017) and 10.09 g/dL vs. 11.38 g/dL (p = 0.006), respectively]. The mean (±SD) duration of additional medication use was longer in the severe fatigue group compared to patients with a fatigue score >30 [97.92(±51.98) months vs. 75.94 (±50.55) months, p = 0.039]. In the multivariate analysis, the independent variables 'female gender,' 'presence of comorbidities,' 'duration of additional medication,' and 'initial hemoglobin level' were statistically significantly associated with severe fatigue. The female gender increased the likelihood of severe fatigue by 3.3 times, while the presence of comorbidities increased it by 7.1 times. CONCLUSION: In this study, which evaluated the fatigue status of PNH patients at various stages of eculizumab treatment in a real-life setting, more than one-third of the patients reported severe fatigue. Female patients experienced severe fatigue more than male patients, and anemia was not the sole factor contributing to severe fatigue in PNH patients. Comorbidities and medications related to these conditions also played a significant role in their quality of life.