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4.
J Clin Pathol ; 71(3): 275-278, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29055896

RESUMO

SIFD describes a heritable, syndromic condition characterised principally by sideroblastic anaemia (SA) with immunodeficiency, fevers and developmental delay, arising in mutations within the TRNT1 gene. Other clinical manifestations of SIFD include cardiomyopathy, seizures, sensorineural hearing loss, renal dysfunction, metabolic abnormalities, hepatosplenomegaly and retinitis pigmentosa.Presentation of SIFD is variable but typically in early childhood with SA or with fever. In this report, we extend the described SIFD phenotype. We describe a kindred in which the index case presented with fetal hydrops, and early neonatal death, and the second child had severe anaemia at delivery. Both cases had prominent extramedullary erythropoiesis and numerous circulating nucleated red blood cells.


Assuntos
Anemia Neonatal/etiologia , Anemia Sideroblástica/complicações , Deficiências do Desenvolvimento/complicações , Hidropisia Fetal/etiologia , Síndromes de Imunodeficiência/complicações , Ferro/metabolismo , Anemia Neonatal/patologia , Anemia Sideroblástica/patologia , Medula Óssea/patologia , Deficiências do Desenvolvimento/patologia , Evolução Fatal , Feminino , Hematopoese Extramedular , Humanos , Hidropisia Fetal/patologia , Imuno-Histoquímica , Síndromes de Imunodeficiência/congênito , Síndromes de Imunodeficiência/patologia , Recém-Nascido , Masculino , Fenótipo
7.
Clin Genet ; 91(3): 441-447, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27102574

RESUMO

NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the "supernumerary" group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in the X-linked nuclear-encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early-onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects.


Assuntos
Acidose Láctica/genética , Anemia Sideroblástica/genética , Complexo I de Transporte de Elétrons/genética , Microftalmia/genética , Acidose Láctica/complicações , Acidose Láctica/fisiopatologia , Anemia Sideroblástica/complicações , Anemia Sideroblástica/fisiopatologia , Criança , DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/deficiência , Predisposição Genética para Doença , Humanos , Masculino , Microftalmia/fisiopatologia , Mutação , Linhagem , Fenótipo , Tirosina-tRNA Ligase
12.
Am J Hematol ; 91(5): 492-8, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26874914

RESUMO

Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n = 82), anemia (P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P =.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n = 48), univariate analysis showed association between poor survival and presence of SETBP1 (P = 0.04) or ASXL1 (P = 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P = 0.04); the number of concurrent mutations did not provide additional prognostication (P = 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively (P = 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutation-enhanced prognostic model.


Assuntos
Anemia Refratária com Excesso de Blastos/mortalidade , Anemia Sideroblástica/mortalidade , Códon sem Sentido , Análise Mutacional de DNA/métodos , Mutação da Fase de Leitura , Análise de Sequência de DNA/métodos , Trombocitose/etiologia , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária com Excesso de Blastos/complicações , Anemia Refratária com Excesso de Blastos/genética , Anemia Sideroblástica/complicações , Anemia Sideroblástica/genética , Medula Óssea/química , Medula Óssea/patologia , Proteínas de Transporte/genética , Aberrações Cromossômicas , Progressão da Doença , Feminino , Hemoglobinas/análise , Humanos , Janus Quinase 2/genética , Estimativa de Kaplan-Meier , Cariotipagem , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Fosfoproteínas/genética , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Processamento de RNA , Proteínas Repressoras/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Trombocitose/genética
14.
Int J Hematol ; 101(5): 514-9, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25547425

RESUMO

Sideroblastic anemias are a heterogeneous group of disorders characterized by anemia of varying severity and the presence of ringed sideroblasts in bone marrow. The most common form of inherited sideroblastic anemia is X-linked sideroblastic anemia (XLSA). In many XLSA patients, anemia responds variably to supplementation with pyridoxine (vitamin B6). We describe the case of a pregnant female with XLSA who had a novel mutation on the ALAS2 gene (c.1218G > T, p.Leu406Phe). Oral chelation therapy was contraindicated and high-dose vitamin B6 would have possible side effects in pregnancy. Serum hepcidin level was very low, indicating increased absorption of iron secondary to ineffective erythropoiesis. Therapy was begun with a low dose of pyridoxine that was increased post-partum. The patient's liver showed moderate iron deposits. During a subsequent 3-month period of pyridoxine supplementation, serum ferritin level and transferrin saturation decreased, hemoglobin content and serum hepcidin level normalized, and morphologic red cell abnormalities improved markedly. The patient responded well to treatment, showing the pyridoxine responsiveness of this novel ALAS2 mutation. The baby girl had the same mutation heterozygously, and although she was neither anemic nor showed abnormalities in a peripheral blood smear, she had a mild increment in RDW and her condition is now being followed.


Assuntos
5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/genética , Anemia Sideroblástica/terapia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Complicações Hematológicas na Gravidez/genética , Complicações Hematológicas na Gravidez/terapia , Adulto , Anemia Sideroblástica/sangue , Anemia Sideroblástica/complicações , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Testes Hematológicos , Hepcidinas/sangue , Humanos , Recém-Nascido , Ferro/sangue , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/complicações , Mutação , Gravidez , Complicações Hematológicas na Gravidez/sangue , Piridoxina/uso terapêutico , Complexo Vitamínico B/uso terapêutico
15.
Blood ; 124(18): 2867-71, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25193871

RESUMO

Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.


Assuntos
Anemia Sideroblástica/congênito , Anemia Sideroblástica/genética , Deficiências do Desenvolvimento/complicações , Febre/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndromes de Imunodeficiência/complicações , Mutação/genética , RNA Nucleotidiltransferases/genética , Alelos , Anemia Sideroblástica/complicações , Anemia Sideroblástica/enzimologia , Deficiências do Desenvolvimento/genética , Febre/genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Células HEK293 , Humanos , Síndromes de Imunodeficiência/genética
16.
Hematol Oncol Clin North Am ; 28(4): 653-70, v, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25064706

RESUMO

Sideroblastic anemias (SAs) may be acquired or congenital and share the features of disrupted utilization of iron in the erythroblast, ineffective erythropoiesis, and variable systemic iron overload. Congenital forms can have associated syndromic features or be nonsyndromic, and many of them have mutations in genes encoding proteins involved in heme biosynthesis, iron-sulfur cluster biogenesis, or mitochondrial protein synthesis. The mechanism(s) for the acquired clonal SA is undefined and is under intense study. Precise diagnosis of these disorders rests on careful clinical and laboratory evaluation, including molecular analysis. Supportive treatments usually provide for a favorable prognosis and often for normal survival.


Assuntos
Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/terapia , Anemia Sideroblástica/complicações , Gerenciamento Clínico , Humanos , Sobrecarga de Ferro/etiologia
17.
Med Hypotheses ; 83(2): 238-46, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24857772

RESUMO

Iron overload is a big challenge when treating thalassemia (TM), hemochromatosis and sideroblastic anemia. It persists even after cure of TM with bone marrow transplantation. Iron overload results from increased iron absorption and repeated blood transfusions causing increased iron in plasma and interstitial fluids. Iron deposition in tissues e.g. heart, liver, endocrine glands and others leads to tissue damage and organ dysfunction. Iron chelation therapy and phlebotomy for iron overload have treatment difficulties, side effects and contraindications. As mean iron level in skin of TM patients increases by more than 200%, percutaneous iron excretion may be beneficial. Wet cupping therapy (WCT) is a simple, safe and economic treatment. WCT is a familiar treatment modality in some European countries and in Chinese hospitals in treating different diseases. WCT was reported to clear both blood plasma and interstitial spaces from causative pathological substances (CPS). Standard WCT method is Al-hijamah (cupping, puncturing and cupping, CPC) method of WCT that was reported to clear blood and interstitial fluids better than the traditional WCT (puncturing and cupping method, PC method of WCT). In other word, traditional WCT may be described as scarification and suction method (double S technique), while Al-hijamah may be described as suction, scarification and suction method (triple S technique). Al-hijamah is a more comprehensive treatment modality that includes all steps and therapeutic benefits of traditional dry cupping therapy and WCT altogether according to the evidence-based Taibah mechanism (Taibah theory). During the first cupping step of Al-hijamah, a fluid mixture is collected inside skin uplifting due to the effect of negative pressure inside sucking cups. This fluid mixture contains collected interstitial fluids with CPS (iron, ferritin and hemolyzed RBCs in thalassemia), filtered fluids (from blood capillaries) with iron and hemolyzed blood cells (hemolyzed RBCs, WBCs and platelets). That fluid mixture does not contain intact blood cells (having diameters in microns) that are too big to pass through pores of skin capillaries (6-12nm in diameter) and cannot be filtered. Puncturing skin upliftings and applying second cupping step excrete collected fluids. Skin scarifications (shartat mihjam in Arabic) should be small, superficial (0.1mm in depth), short (1-2mm in length), multiple, evenly distributed and confined to skin upliftings. Sucking pressure inside cups (-150 to -420mmHg) applied to skin is transmitted to around skin capillaries to be added to capillary hydrostatic pressure (-33mmHg at arterial end of capillaries and -13mmHg at venous end of capillaries) against capillary osmotic pressure (+20mmHg). This creates a pressure gradient and a traction force across skin and capillaries and increases filtration at arterial end of capillaries at net pressure of -163 to -433mmHg and at venous end of capillaries at net pressure of -143 to -413mmHg resulting in clearance of blood from CPS (iron, ferritin and hemolyzed blood cells). Net filtration pressure at renal glomeruli is 10mmHg i.e. Al-hijamah exerts a more pressure-dependent filtration than renal glomeruli. Al-hijamah may benefit patients through inducing negative iron balance. Interestingly, Al-hijamah was reported to decrease serum ferritin significantly (by about 22%) in healthy subjects while excessive traditional WCT was reported to cause iron deficiency anemia. Al-hijamah is a highly recommended treatment in prophetic medicine. In conclusion, Al-hijamah may be a promising adjuvant treatment for iron overload in TM, hemochromatosis and sideroblastic anemia.


Assuntos
Anemia Sideroblástica/complicações , Sangria/métodos , Eliminação Cutânea/fisiologia , Hemocromatose/complicações , Sobrecarga de Ferro/terapia , Sucção/métodos , Talassemia beta/complicações , Ferritinas/metabolismo , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/etiologia
19.
J Hum Genet ; 59(4): 229-32, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24430573

RESUMO

Mitochondrial diseases are associated with defects of adenosine triphosphate production and energy supply to organs as a result of dysfunctions of the mitochondrial respiratory chain. Biallelic mutations in the YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase cause myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2), a type of mitochondrial disease. Here, we report a consanguineous Turkish family with two siblings showing severe metabolic decompensation including recurrent hypoglycemia, lactic acidosis, and transfusion-dependent anemia. Using whole-exome sequencing of the proband and his parents, we identified a novel YARS2 mutation (c.1303A>G, p.Ser435Gly) that was homozygous in the patient and heterozygous in his parents. This mutation is located at the ribosomal protein S4-like domain of the gene, while other reported YARS2 mutations are all within the catalytic domain. Interestingly, the proband showed more severe symptoms and an earlier onset than previously reported patients, suggesting the functional importance of the S4-like domain in tyrosyl-tRNA synthetase.


Assuntos
Acidose Láctica/genética , Anemia Sideroblástica/genética , Doenças Musculares/genética , Mutação , Tirosina-tRNA Ligase/genética , Acidose Láctica/complicações , Adolescente , Adulto , Anemia Sideroblástica/complicações , Criança , Pré-Escolar , Evolução Fatal , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Musculares/complicações , Linhagem , Adulto Jovem
20.
J Pediatr Hematol Oncol ; 36(5): 402-3, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23588341

RESUMO

Pearson disease is a rare, usually fatal, mitochondrial disorder affecting primarily the bone marrow and the exocrine pancreas. We report a previously healthy 10-week-old girl who presented with profound macrocytic anemia followed by pancytopenia, synthetic liver dysfunction with liver steatosis, and metabolic acidosis with high lactate levels. She had no pancreatic involvement. Multiple cytoplasmic vacuoles in myelocytes and monocytes were seen upon microscopic evaluation of the bone marrow. Genetic analysis of the mitochondrial genome revealed a 5 kbp deletion, thus establishing the diagnosis of Pearson disease.


Assuntos
Anemia Macrocítica/complicações , Anemia Sideroblástica/complicações , Doenças da Medula Óssea/complicações , Falência Hepática/complicações , Doenças Mitocondriais/diagnóstico , Pancitopenia/complicações , Anemia Macrocítica/patologia , Anemia Sideroblástica/patologia , Doenças da Medula Óssea/patologia , Feminino , Células Precursoras de Granulócitos/patologia , Humanos , Lactente , Falência Hepática/patologia , Doenças Mitocondriais/etiologia , Monócitos/patologia , Testes de Função Pancreática , Pancitopenia/patologia , Prognóstico , Síndrome
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