RESUMEN
The clinical course for Hereditary Spherocytosis (HS) patients is highly varied, even within families with identical driving mutations. Here, we describe four siblings with HS attributed to an unreported SPTB mutation. All patients displayed an increased fraction of mitochondria-positive erythrocytes. This was associated with increased reactive oxygen species (ROS) generation and alteration to alterations to bioactive membrane lipids associated with oxidant stress. Given the early promise for mitophagy-inducing agents in sickle cell disease and ready availability of antioxidants, this concept warrants continued exploration as a disease-modifying factor and a potential target for therapy.
Asunto(s)
Lípidos de la Membrana , Mitocondrias , Estrés Oxidativo , Esferocitosis Hereditaria , Humanos , Esferocitosis Hereditaria/metabolismo , Esferocitosis Hereditaria/genética , Esferocitosis Hereditaria/patología , Masculino , Mitocondrias/metabolismo , Femenino , Lípidos de la Membrana/metabolismo , Niño , Preescolar , Especies Reactivas de Oxígeno/metabolismo , Mutación , AdolescenteRESUMEN
While sickle cell anemia (SCA) and hereditary spherocytosis (HS) share common features of increased spleen erythrophagocytosis due to increased red blood cell (RBC) turnover, SCA is specifically characterized by susceptibility to infections. In this study, histological lesions in the spleens of pediatric patients with SCA were analyzed, in close correlation with past clinical history and comparatively to HS, healthy and transfused ß-thalassemia patients (TDT). An evaluation of red pulp elementary lesions (red pulp fibrosis, iron deposition, number of Gandy-Gamna, and RBC trapping) combined into a severity score was established, as well as B-cell follicles analysis. Quantification on digitalized slides of iron deposition, RBC trapping, and red pulp fibrosis was additionally performed. Spleens from 22 children with SCA, eight with HS, eight with TDT, and three healthy controls (HC) were analyzed. Median age at splenectomy was not different between SCA and HS patients, 6.05 years (range: 4.5-16.0) versus 4.75 (range: 2.2-9.5). Marked heterogeneity was found in SCA spleens in contrast to other conditions. Contrary to previous reports, B-cell follicles were generally preserved in SCA. While RBC trapping was significantly increased in both SCA and HS (compared to TDT and HC), quantitative fibrosis and overall red pulp severity score were significantly increased in SCA spleens compared to other conditions. Moreover, there was an inverse correlation between quantitative fibrosis and number of B-cell follicles, linking these two compartments as well as spleen fibrosis to infectious susceptibility in SCA, potentially through impaired red pulp macrophage scavenging and B-cell subpopulations defects.
Asunto(s)
Anemia de Células Falciformes , Esferocitosis Hereditaria , Bazo , Humanos , Anemia de Células Falciformes/patología , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/sangre , Niño , Bazo/patología , Adolescente , Masculino , Femenino , Preescolar , Esferocitosis Hereditaria/patología , Esferocitosis Hereditaria/sangre , Talasemia beta/patología , Talasemia beta/complicaciones , Esplenectomía , Fibrosis , Linfocitos B/patologíaRESUMEN
Red blood cell (RBC) morphology is, in general, the key diagnostic feature for hereditary spherocytosis (HS) and hereditary elliptocytosis (HE). However, in hereditary pyropoikilocytosis (HPP), the severe clinical form of HE, the morphological diagnosis is difficult due to the presence of a RBC morphological picture characterized by a mixture of elliptocytes, spherocytes, tear-drop cells, and fragmented cells. This difficulty increases in new-borns and/or patients requiring frequent transfusions, making impossible the prediction of the disease course or its severity. Recently, it has been demonstrated that the measurement of osmotic gradient ektacytometry (OGE), using a laser-assisted optical rotational ektacytometer LoRRca (MaxSis, RR Mechatronics), allows a clear differentiation between HS and HE, where the truncated osmoscan curve reflects the inability of the already elliptical cells to deform further under shear stress in the face of hypotonicity. In HPP, however, the RBCs appear to have a significantly decreased ability to maintain deformability in these conditions, and the classical trapezoidal profile of HE is less evident or indistinguishable from HS. Here, two unrelated patients with hereditary hemolytic anemia (HHA) due to HPP and HS, respectively, are described with the joint inheritance of a complex set of five genetic defects. Two of these defects are novel alpha-spectrin gene (SPTA1) variants, one is a microdeletion that removes the entire SPTA1 gene, and two are well-known low-expression polymorphic alleles: α-LELY and α-LEPRA. In the HPP patient (ID1), with many circulating spherocytes, the interactions between the two SPTA1 gene variants may lead, in addition to an elongation defect (elliptocytes), to a loss of membrane stability and vesiculation (spherocytes), and RBCs appear to have a significantly decreased ability to maintain deformability in hypotonic conditions. Due to this, the classical trapezoidal profile of HE may become less evident or indistinguishable from HS. The second patient (ID2) was a classical severe form of HS with the presence of more than 20% of spherocytes and few pincered cells. The severity of clinical manifestation is due to the coinheritance of a microdeletion of chromosome 1 that removes the entire SPTA1 gene with a LEPRA SPTA1 variant in trans. The diagnostic interest of both observations is discussed.
Asunto(s)
Anemia Hemolítica Congénita/genética , Eliptocitosis Hereditaria/genética , Eritrocitos Anormales/patología , Espectrina/genética , Esferocitosis Hereditaria/genética , Adulto , Anemia Hemolítica Congénita/patología , Enfermedad Crónica , Eliptocitosis Hereditaria/patología , Femenino , Variación Genética , Humanos , Lactante , Masculino , Esferocitosis Hereditaria/patologíaRESUMEN
Heterogeneous red blood cell (RBC) membrane disorders and hydration defects often present with the common clinical findings of hemolytic anemia, but they may require substantially different management, based on their pathophysiology. An accurate and timely diagnosis is essential to avoid inappropriate interventions and prevent complications. Advances in genetic testing availability within the last decade, combined with extensive foundational knowledge on RBC membrane structure and function, now facilitate the correct diagnosis in patients with a variety of hereditary hemolytic anemias (HHAs). Studies in patient cohorts with well-defined genetic diagnoses have revealed complications such as iron overload in hereditary xerocytosis, which is amenable to monitoring, prevention, and treatment, and demonstrated that splenectomy is not always an effective or safe treatment for any patient with HHA. However, a multitude of variants of unknown clinical significance have been discovered by genetic evaluation, requiring interpretation by thorough phenotypic assessment in clinical and/or research laboratories. Here we discuss genotype-phenotype correlations and corresponding clinical management in patients with RBC membranopathies and propose an algorithm for the laboratory workup of patients presenting with symptoms and signs of hemolytic anemia, with a clinical case that exemplifies such a workup.
Asunto(s)
Anemia Hemolítica Congénita/diagnóstico , Eliptocitosis Hereditaria/diagnóstico , Membrana Eritrocítica/patología , Hidropesía Fetal/diagnóstico , Esferocitosis Hereditaria/diagnóstico , Anemia Hemolítica Congénita/genética , Anemia Hemolítica Congénita/patología , Anemia Hemolítica Congénita/terapia , Manejo de la Enfermedad , Eliptocitosis Hereditaria/genética , Eliptocitosis Hereditaria/patología , Eliptocitosis Hereditaria/terapia , Pruebas Genéticas , Humanos , Hidropesía Fetal/genética , Hidropesía Fetal/patología , Hidropesía Fetal/terapia , Lactante , Masculino , Mutación , Esferocitosis Hereditaria/genética , Esferocitosis Hereditaria/patología , Esferocitosis Hereditaria/terapiaRESUMEN
Hereditary erythrocytes disorders include a large group of conditions with heterogeneous molecular bases and phenotypes. We analyzed here a case series of 155 consecutive patients with clinical suspicion of hereditary erythrocyte defects referred to the Medical Genetics Unit from 2018 to 2020. All of the cases followed a diagnostic workflow based on a targeted next-generation sequencing panel of 86 genes causative of hereditary red blood cell defects. We obtained an overall diagnostic yield of 84% of the tested patients. Monogenic inheritance was seen for 69% (107/155), and multi-locus inheritance for 15% (23/155). PIEZO1 and SPTA1 were the most mutated loci. Accordingly, 16/23 patients with multi-locus inheritance showed dual molecular diagnosis of dehydrated hereditary stomatocytosis/xerocytosis and hereditary spherocytosis. These dual inheritance cases were fully characterized and were clinically indistinguishable from patients with hereditary spherocytosis. Additionally, their ektacytometry curves highlighted alterations of dual inheritance patients compared to both dehydrated hereditary stomatocytosis and hereditary spherocytosis. Our findings expand the genotypic spectrum of red blood cell disorders and indicate that multi-locus inheritance should be considered for analysis and counseling of these patients. Of note, the genetic testing was crucial for diagnosis of patients with a complex mode of inheritance.
Asunto(s)
Anemia Hemolítica Congénita/genética , Proteínas Portadoras/genética , Enfermedades Hematológicas/genética , Hidropesía Fetal/genética , Canales Iónicos/genética , Proteínas de Microfilamentos/genética , Esferocitosis Hereditaria/genética , Adulto , Anemia Hemolítica Congénita/sangre , Anemia Hemolítica Congénita/patología , Eritrocitos/patología , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Enfermedades Hematológicas/sangre , Enfermedades Hematológicas/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hidropesía Fetal/sangre , Hidropesía Fetal/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Esferocitosis Hereditaria/sangre , Esferocitosis Hereditaria/patologíaRESUMEN
BACKGROUND/AIMS: Hereditary Spherocytosis (HS) is the most common erythrocyte membrane disorder causing hemolytic anemia. The wide heterogeneity of both clinical and laboratory manifestations of HS contributes to difficulties associated with the diagnosis of this disorder. Although massive data previously reported worldwide, there is yet no data on HS among the Tunisian population. Here we aim to characterize HS in Tunisian patients at biochemical and cellular levels, identify the membrane protein deficiency, and compare the accuracy of the diagnostic tests to identify the most appropriate assay for HS diagnosis. METHODS: We investigated 81 patients with hemolytic anemia and 167 normal controls. The exploration of HS based on clinical and family history, physical examination, and the results of laboratory tests: blood smear, osmotic fragility test (OFT), cryohemolysis test (CT), pink test (PT), eosine-5'-maleimide (EMA) test, and erythrocyte membrane protein electrophoresis. RESULTS: We identified 21 patients with HS, classified as severe (6/21;28.5%), moderate (10/21;47.6%), and mild (5/21;23.8%). The most prevalent protein deficiency was the band 3 protein detected in ten Tunisian HS patients. The EMA test showed a high specificity (97.5%) and sensitivity (94.7%) for HS diagnosis compared to the other screening tests. Interestingly, fourteen among sixteen patients presenting with homozygous sickle cells HbSS showed an increase of EMA fluorescence intensity compared to other anemic patients. CONCLUSION: Our study highlights the efficiency of the EMA dye for the detection of HS whatever the nature of the involved protein deficiency. We report for the first time, the most prevalent protein deficiency among Tunisians with HS. Moreover, we found that the combination of the EMA-binding test with PT or incubated OFT improves the diagnosis sensitivity while maintaining a good specificity.
Asunto(s)
Eosina Amarillenta-(YS)/análogos & derivados , Membrana Eritrocítica , Citometría de Flujo , Proteínas de la Membrana/metabolismo , Adolescente , Adulto , Niño , Preescolar , Eosina Amarillenta-(YS)/química , Membrana Eritrocítica/metabolismo , Membrana Eritrocítica/patología , Femenino , Humanos , Lactante , Masculino , Fragilidad Osmótica , Proteómica , Esferocitosis Hereditaria/metabolismo , Esferocitosis Hereditaria/patología , TúnezRESUMEN
PURPOSE: Objective to summarize the clinical features and laboratory findings of 28 Chinese children with hereditary spherocytosis (HS), and analyze these mutations. METHOD: Collected and analyzed the clinical data of all children and their parents, and completed the relevant laboratory examinations of all children. Analyzed the sequence of related genes by second-generation sequencing technology, and verified the suspected mutations by Sanger sequencing method. Analyzed all biological information using the Single Nucleotide Polymorphism database, the 1000 Human Genome Project, and the Exosome Aggregation Consortium. RESULT: New mutations were detected in the HS coding region of 28 children. Among them, there were 13 cases (46.4%) with ANK1 mutation, 10 cases (35.7%) with SPTB mutation, three cases (10.7%) with SLC4A1 mutation, and two cases (7.2%) with SPTA1 mutation. All mutations cause amino acid changes in the coding gene, as well as subsequent changes in protein structure or loss of function. CONCLUSION: All the newly discovered gene coding region mutation sites detected are the suspected pathogenic causes of the 28 Chinese children. At the same time, the second-generation gene sequencing technology is an effective means to diagnose HS. Different mutation types and different mutation regions have no significant correlation with the severity of anemia. The novel gene mutation sites in 28 children studied in this paper have not yet been included in the human genome database, dbSNP (v138), or ExAC database. The new gene mutations found in HS children can provide a theoretical basis for further exploring the genetic causes of HS in Chinese children.
Asunto(s)
Mutación con Pérdida de Función , Fenotipo , Esferocitosis Hereditaria/genética , Proteína 1 de Intercambio de Anión de Eritrocito/genética , Ancirinas/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Espectrina/genética , Esferocitosis Hereditaria/patologíaRESUMEN
By the advent of the effective therapies for many coagulation diseases and hereditary spherocytosis (HS), patient's survival has been improved significantly; however, if patients are diagnosed late or left untreated, both diseases could ominously be life threatening. Concurrent occurring of factor VII (FVII) deficiency and HS is extremely rare and there is no literature report that explain this condition, thus far. In this study, we confronted a 9-year-old female patient diagnosed with HS and enlarged spleen as a result of this blood disorder. Given to her sever signs and symptoms of splenomegaly, she was candidate for emergent splenectomy. However, assessment of coagulation tests revealed a prolonged prothrombin time, suggesting the moderate FVII deficiency. With a multidisciplinary consultation, we decided to performed total splenectomy with prophylaxis administration of totally 6 doses of active recombinant FVII, initiated 1 hour before surgery and followed until 30 hours postoperation. As a result of cautious undertaken in Mofid Children's Hospital, the patient did not experience any hemostatic defect. Patient is now 14-year-old, generally well-being under regular surveillance of FVII deficiency.
Asunto(s)
Deficiencia del Factor VII/cirugía , Índice de Severidad de la Enfermedad , Esferocitosis Hereditaria/cirugía , Esplenectomía/métodos , Esplenomegalia/cirugía , Niño , Manejo de la Enfermedad , Deficiencia del Factor VII/complicaciones , Deficiencia del Factor VII/patología , Femenino , Humanos , Pronóstico , Esferocitosis Hereditaria/complicaciones , Esferocitosis Hereditaria/patología , Esplenomegalia/complicaciones , Esplenomegalia/patologíaRESUMEN
Red blood cell (RBC) membrane disorders are predominantly caused by mutations resulting in decreased RBC deformability and permeability. We present a family in which, the proband and his daughter presented with pseudohypokalaemia. Studies on the temperature dependence of pseudohypokalaemia suggested a maximum decrease in serum potassium when whole blood is stored at 37°C. Routine haematology suggested mild haemolysis with a hereditary spherocytosis phenotype. These two cases present a novel variant in temperature-dependent changes in potassium transport. A new variant was identified in the SLC4A1 gene which codes for band 3 protein (anion exchanger 1) in RBC membrane which may contribute to the phenotype. This is the first report of familial pseudohypokalaemia associated with changes in RBC membrane morphology. The clinical implications of pseudohypokalaemia are that it can lead to inappropriate investigation or treatment. However, many questions remain to be solved and other RBC membrane protein genes should be studied.
Asunto(s)
Proteína 1 de Intercambio de Anión de Eritrocito/genética , Hipopotasemia/sangre , Esferocitosis Hereditaria/sangre , Esferocitosis Hereditaria/genética , Eritrocitos/metabolismo , Eritrocitos/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Potasio/sangre , Esferocitosis Hereditaria/patologíaRESUMEN
The loss of heterozygosity localized at chromosome segment 8p11.2 causes a contiguous gene syndrome, which mostly combined phenotype of Kallmann syndrome and hereditary spherocytosis. It has been documented that this combined phenotype is in association with both the deletion of the fibroblast growth factor receptor 1 (FGFR1) and ankyrin 1 (ANK1) genes. Here, we described a 6-year-old girl with microcephaly, global developmental delay, mental retardation, and hereditary spherocytosis, associated with a heterozygous pathogenic microdeletion of 1.9 Mb size at 8p11.21. Molecular analysis confirmed that the identified microdeletion contained two OMIM (Online Mendelian Inheritance in Man)genes, including ANK1 and lysine acetyltransferase 6 A (KAT6A), but not FGFR1. Therefore, the simultaneous occurrence of mild developmental delay and distinctive facial in this patient was associated with the pathogenic variation of the KAT6A.
Asunto(s)
Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 8/genética , Discapacidades del Desarrollo/genética , Histona Acetiltransferasas/genética , Esferocitosis Hereditaria/genética , Ancirinas/genética , Niño , Trastornos de los Cromosomas/patología , Discapacidades del Desarrollo/patología , Femenino , Humanos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Esferocitosis Hereditaria/patologíaRESUMEN
BACKGROUND: Hereditary spherocytosis is clinically and genetically heterogeneous disorder and its clinical characteristics are spherocytosis, anaemia, jaundice and splenomegaly. The aetiology is associated to the genes encoding proteins involved in the interaction between the erythrocyte membrane and the lipid bilayer. Causative variants in BetaI-spectrin (SPTB) gene presenting as mild to moderately severe disease are responsible for approximately 25% cases in the USA and Europe. Among kidney disease, isolated cases of nephrotic syndrome due to membranoproliferative glomerulonephritis and macroscopic haematuria with proteinuria due to IgA nephropathy were previously reported in patients with SPTB deficiency. OBJECTIVE: Seven patients from the same family with spherocytosis were evaluated to assess the kidney failure presented in all affected adult patients. METHODS: Clinical, radiological and laboratory investigations were issued to evaluate the spherocytosis and kidney disease. In selected patients, we also performed genetics testing with next generation sequencing of genes related to hereditary spherocytosis, inherited glomerular disorders and tubulo-interstitial kidney disease. RESULTS: Among the family members with spherocytosis, two adults had end-stage kidney disease and one chronic kidney disease stage 4 with unspecific histopathological findings of interstitial fibrosis/tubular atrophy and glomerulosclerosis. At the time, there were no signs of kidney disease present in four paediatric patients. Novel nonsense variant in SPTB gene (NM_001024858; c.4796G>A; p.Trp1599Ter) was detected in all family members with spherocytosis and was predicted to be disease causing. Furthermore, all adult patients with kidney failure and two paediatric cousins of the index patients were heterozygous for the UMOD gene variant (NM_003361.3:c.552G > C, NP_003352.2:p.Trp184Cys) previously reported in patients with tubulo-interstitial kidney disease. UMOD variant was not present in the index patients. CONCLUSIONS: The co-occurrence of any two rare inherited disorders is extremely rare, while to our knowledge the co-occurrence of genetically confirmed HS and autosomal dominant tubulo-interstitial kidney disease (ADTKD) has previously not been reported. It is not possibly to evaluate whether the haemolytic crises due to HS are influencing the progression of the UMOD related renal disease, since the UMOD related ADTKD characteristics in general and in here presented family are extremely variable. Nevertheless, the observed kidney disease in the family is warranting the regular nephrological examinations in UMOD positive paediatric patients in the family in order to recognise hyperuricemia and treat it as early as possible. This is emphasising the importance of serum uric acid detection in routine laboratory screening of paediatric patients in order to identify early signs of tubular injury indicating possible ADTKD
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Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Esferocitosis Hereditaria/genética , Espectrina/genética , Insuficiencia Renal Crónica/genética , Glomerulonefritis/genética , Linaje , Insuficiencia Renal Crónica/patología , Esferocitosis Hereditaria/patología , Glomerulonefritis/patologíaRESUMEN
During hemolysis, macrophages in the liver phagocytose damaged erythrocytes to prevent the toxic effects of cell-free hemoglobin and heme. It remains unclear how this homeostatic process modulates phagocyte functions in inflammatory diseases. Using a genetic mouse model of spherocytosis and single-cell RNA sequencing, we found that erythrophagocytosis skewed liver macrophages into an antiinflammatory phenotype that we defined as MarcohiHmoxhiMHC class IIlo erythrophagocytes. This phenotype transformation profoundly mitigated disease expression in a model of an anti-CD40-induced hyperinflammatory syndrome with necrotic hepatitis and in a nonalcoholic steatohepatitis model, representing 2 macrophage-driven sterile inflammatory diseases. We reproduced the antiinflammatory erythrophagocyte transformation in vitro by heme exposure of mouse and human macrophages, yielding a distinctive transcriptional signature that segregated heme-polarized from M1- and M2-polarized cells. Mapping transposase-accessible chromatin in single cells by sequencing defined the transcription factor NFE2L2/NRF2 as a critical driver of erythrophagocytes, and Nfe2l2/Nrf2 deficiency restored heme-suppressed inflammation. Our findings point to a pathway that regulates macrophage functions to link erythrocyte homeostasis with innate immunity.
Asunto(s)
Hemólisis/fisiología , Hígado/citología , Hígado/fisiología , Macrófagos/citología , Macrófagos/fisiología , Fagocitos/citología , Fagocitos/fisiología , Animales , Modelos Animales de Enfermedad , Femenino , Hemo/metabolismo , Humanos , Técnicas In Vitro , Inflamación/prevención & control , Macrófagos/clasificación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Factor 2 Relacionado con NF-E2/deficiencia , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Fagocitos/clasificación , Fagocitosis/fisiología , Fenotipo , RNA-Seq , Análisis de la Célula Individual , Esferocitosis Hereditaria/genética , Esferocitosis Hereditaria/patología , Esferocitosis Hereditaria/fisiopatologíaAsunto(s)
Desequilibrio Ácido-Base , Anemia Hemolítica Congénita , Errores Diagnósticos , Membrana Eritrocítica , Errores Innatos del Metabolismo , Esferocitosis Hereditaria , Desequilibrio Ácido-Base/diagnóstico , Desequilibrio Ácido-Base/metabolismo , Desequilibrio Ácido-Base/patología , Adolescente , Anemia Hemolítica Congénita/diagnóstico , Anemia Hemolítica Congénita/metabolismo , Anemia Hemolítica Congénita/patología , Membrana Eritrocítica/metabolismo , Membrana Eritrocítica/patología , Eritrocitos Anormales/metabolismo , Eritrocitos Anormales/patología , Femenino , Hemólisis , Humanos , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/patología , Esferocitosis Hereditaria/diagnóstico , Esferocitosis Hereditaria/metabolismo , Esferocitosis Hereditaria/patologíaAsunto(s)
Infecciones por Clostridium , Clostridium perfringens/metabolismo , Neutrófilos , Sepsis , Esferocitosis Hereditaria , Anciano , Infecciones por Clostridium/metabolismo , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/patología , Femenino , Humanos , Neutrófilos/metabolismo , Neutrófilos/microbiología , Neutrófilos/patología , Sepsis/metabolismo , Sepsis/microbiología , Sepsis/patología , Esferocitosis Hereditaria/metabolismo , Esferocitosis Hereditaria/microbiología , Esferocitosis Hereditaria/patologíaRESUMEN
Hereditary spherocytosis arises from alterations in the genes encoding red blood cell membrane proteins. Although its diagnosis is mostly clinical, recent advances in next-generation sequencing (NGS) technologies have allowed for a faster cost-effective gene-based diagnosis. We report the case of a boy with spherocytic anemia and development delay in whom a de novo 2.84-Mb deletion at chromosome 14 including SPTB (ß-spectrin gene) was identified by array-based comparative genomic hybridization. This alteration, consistent with de novo spherocytosis, was missed by a NGS gene panel. When associated with other symptoms, especially neurologic, NGS may not be appropriate to genetically diagnose spherocytic anemia.
Asunto(s)
Eliminación de Gen , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Espectrina/genética , Esferocitosis Hereditaria/etiología , Humanos , Recién Nacido , Masculino , Pronóstico , Esferocitosis Hereditaria/patologíaRESUMEN
Idiopathic basal ganglia calcification (IBGC), also known as Fahr disease, is a rare neurodegenerative disorder characterized by the accumulation of extensive parenchymal and vascular calcifications in the basal ganglia, with variable calcifications elsewhere in the brain. Typically, IBGC presents with neurologic and psychiatric symptoms in middle-aged adults. Recent genetic studies have identified alterations in 4 genes causing IBGC, including alterations in SLC20A2 on chromosome 8p11.2. Currently, there are no clinical descriptions of patients with IBGC occurring within the context of a complex genetic syndrome. Here, we present a case of pediatric 8p11 deletion with IBGC, hereditary spherocytosis, vitreoretinopathy, and focal cortical dysplasia. We review multiple cases of IBGC with pediatric onset due to SLC20A2 deletion in the literature, and raise the consideration of IBGC in the evaluation of pediatric patients with 8p11.2 deletion syndromes.
Asunto(s)
Enfermedades de los Ganglios Basales/genética , Enfermedades de los Ganglios Basales/patología , Encéfalo/patología , Calcinosis/genética , Calcinosis/patología , Deleción Cromosómica , Cromosomas Humanos Par 8 , Esferocitosis Hereditaria/genética , Esferocitosis Hereditaria/patología , Enfermedades de los Ganglios Basales/complicaciones , Calcinosis/complicaciones , Femenino , Humanos , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/genética , Esferocitosis Hereditaria/complicacionesRESUMEN
BACKGROUND: Red cell membranopathies refers to phenotypically and morphologically heterogeneous disorders. High throughput imaging flow cytometry (IFC) combines the speed, sensitivity, and phenotyping abilities of flow cytometry with the detailed imagery and functional insights of microscopy to produce high content image analysis with quantitative analysis. We have evaluated the applications of IFC to examine both the morphology as well as fluorescence signal intensity in red cell membranopathies. METHODS: Fluorescence intensity of eosin-5-maleimide (EMA) labeled red cells was measured for diagnosis of RBC membrane protein defect on Amnis ImageStreamX followed by Image analysis on IDEAS software to study features such as circularity and shape ratio. RESULTS: The hereditary spherocytosis (HS) group showed significantly decreased MFI (52,800 ± 9,100) than normal controls (81,100 ± 4,700) (p < .05) whereas non-HS showed 78,300 ± 9,900. The shape ratio of hereditary elliptocytosis (HE) was significantly higher (43.8%) than normal controls (14.6%). The circularity score is higher in HS (64.15%) than the normal controls (44.3%) whereas the circularity score was very less in HE (10%) due to the presence of elliptocytes. CONCLUSIONS: The advantages of the IFC over standard flow cytometry is its ability to provide high-content image analysis and measurement of parameters such as circularity and shape ratio allow discriminating red cell membranopathies (HS and HE) due to variations in shape and size. It could be a single, effective, and rapid IFC test for detection and differentiation of red cell membrane disorders in hematology laboratories where an IFC is available.
Asunto(s)
Membrana Celular/patología , Eliptocitosis Hereditaria/diagnóstico , Citometría de Flujo , Esferocitosis Hereditaria/diagnóstico , Adolescente , Adulto , Anciano , Membrana Celular/ultraestructura , Niño , Preescolar , Eliptocitosis Hereditaria/patología , Eritrocitos/patología , Eritrocitos/ultraestructura , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Esferocitosis Hereditaria/patología , Adulto JovenRESUMEN
Ankyrins (Ank)are ubiquitously expressed proteins that play a critical role in the integrity of cytoskeleton and cellular signalling. Their presence in metazoans and evolutionary conserved protein primary sequence indicates their functional significance. Tissue-specific isoforms and an array of transcript variants make this protein one of the indispensable cellular components. Membrane-binding domains consist of ankyrin repeats that bind with several functional membrane proteins that enable maintaining cellular integrity. Cytosolic ankyrins help in cellular signal transduction. Linkage studies and recent genome-wide association studies uncovered the pathogenic roles of ankyrins (ankyrin-R, ankyrin-B and ankyrin-G) in several diseases, such as hereditary spherocytosis, long QT syndrome, intellectual disability, and CRASH syndrome, among several others. Identification of Ank3 in celiac disease may potentially explain the link between neuronal health and immunity. It is thus warranted to investigate the role of neuronal factors in immune diseases and vice versa. In this review, we briefly discussed the contribution of ankyrin genes to human diseases.
Asunto(s)
Ancirinas/genética , Esferocitosis Hereditaria/genética , Enfermedad Celíaca/genética , Enfermedad Celíaca/patología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Estudio de Asociación del Genoma Completo , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/patología , Transducción de Señal/genética , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , Esferocitosis Hereditaria/patologíaRESUMEN
This study compared outcomes following total (TS) or partial splenectomy (PS) among patients with hereditary spherocytosis. Seventy-nine patients (TS = 33, PS = 46) were identified. The follow-up period was longer after PS (59.6 vs. 24.9 months, p < .001). Long-term adverse events occurred more frequently following PS (50% vs. 29%, p = .001). Anemia, jaundice, and fatigue recurred in six patients with PS, leading to five completion splenectomies. Hemoglobin was not different between PS and TS by 5 years post-procedure (12.3 vs. 13.4 g/dL, p = .25). Both PS and TS ameliorate symptoms and improve hematologic parameters. The rate of secondary surgery following PS should be considered when planning the initial surgical procedure.
Asunto(s)
Laboratorios/normas , Esferocitosis Hereditaria/cirugía , Esplenectomía/métodos , Niño , Femenino , Humanos , Masculino , Estudios Retrospectivos , Esferocitosis Hereditaria/patología , Resultado del TratamientoRESUMEN
Hereditary spherocytosis (HS) is characterised by increased osmotic fragility and enhanced membrane loss of red blood cells (RBC) due to defective membrane protein complexes. In our diagnostic laboratory, we observed that pyruvate kinase (PK) activity in HS was merely slightly elevated with respect to the amount of reticulocytosis. In order to evaluate whether impaired PK activity is a feature of HS, we retrospectively analysed laboratory data sets from 172 unrelated patients with HS, hereditary elliptocytosis (HE), glucose-6-phosphate dehydrogenase (G6PD) or PK deficiency, sickle cell or haemoglobin C disease, or ß-thalassaemia minor. Results from linear regression analysis provided proof that PK activity decreases with rising reticulocyte counts in HS (R2 = 0·15; slope = 9·09) and, less significantly, in HE (R2 = 0·021; slope = 8·92) when compared with other haemolytic disorders (R2 ≥ 0·65; slopes ≥ 78·6). Reticulocyte-adjusted erythrocyte PK activity levels were significantly lower in HS and even declined with increasing reticulocytes (R2 = 0·48; slope = -9·74). In this report, we describe a novel association between HS and decreased PK activity that is apparently caused by loss of membrane-bound PK due to impaired structural integrity of the RBC membrane and may aggravate severity of haemolysis in HS.