Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
1.
Blood ; 136(17): 1956-1967, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32693407

RESUMO

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.


Assuntos
Grânulos Citoplasmáticos/patologia , Heterogeneidade Genética , Síndrome da Plaqueta Cinza , Sistema Imunitário/patologia , Fenótipo , Biópsia , Proteínas Sanguíneas/genética , Estudos de Casos e Controles , Estudos de Coortes , Grânulos Citoplasmáticos/metabolismo , Diagnóstico Diferencial , Frequência do Gene , Estudos de Associação Genética , Síndrome da Plaqueta Cinza/classificação , Síndrome da Plaqueta Cinza/genética , Síndrome da Plaqueta Cinza/imunologia , Síndrome da Plaqueta Cinza/patologia , Humanos , Sistema Imunitário/fisiologia , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Mutação
2.
Hum Mol Genet ; 28(1): 133-142, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30247636

RESUMO

Severe thrombocytopenia, characterized by dysplastic megakaryocytes and intracranial bleeding, was diagnosed in six individuals from a consanguineous kindred. Three of the individuals were successfully treated by bone marrow transplant. Whole-exome sequencing and homozygosity mapping of multiple family members, coupled with whole-genome sequencing to reveal shared non-coding variants, revealed one potentially functional variant segregating with thrombocytopenia under a recessive model: GALE p.R51W (c.C151T, NM_001127621). The mutation is extremely rare (allele frequency = 2.5 × 10-05), and the likelihood of the observed co-segregation occurring by chance is 1.2 × 10-06. GALE encodes UDP-galactose-4-epimerase, an enzyme of galactose metabolism and glycosylation responsible for two reversible reactions: interconversion of UDP-galactose with UDP-glucose and interconversion of UDP-N-acetylgalactosamine with UDP-N-acetylglucosamine. The mutation alters an amino acid residue that is conserved from yeast to humans. The variant protein has both significantly lower enzymatic activity for both interconversion reactions and highly significant thermal instability. Proper glycosylation is critical to normal hematopoiesis, in particular to megakaryocyte and platelet development, as reflected in the presence of thrombocytopenia in the context of congenital disorders of glycosylation. Mutations in GALE have not previously been associated with thrombocytopenia. Our results suggest that GALE p.R51W is inadequate for normal glycosylation and thereby may impair megakaryocyte and platelet development. If other mutations in GALE are shown to have similar consequences, this gene may be proven to play a critical role in hematopoiesis.


Assuntos
Galactosemias/genética , Trombocitopenia/genética , UDPglucose 4-Epimerase/genética , Adulto , Alelos , Feminino , Galactose/metabolismo , Frequência do Gene/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , UDPglucose 4-Epimerase/metabolismo , Sequenciamento do Exoma
3.
Harefuah ; 160(12): 822-826, 2021 Dec.
Artigo em Hebraico | MEDLINE | ID: mdl-34957720

RESUMO

INTRODUCTION: Autosomal recessive renal tubular dysgenesis (RTD;OMIM: 267430) is a rare kidney disease secondary to mutations in genes encoding the renin-angiotensin system which have a role in renal tissue development during fetal life and in the maintenance of blood pressure and electrolyte balance. The disease is characterized by oligohydramnios, prematurity, neonatal renal failure, hypotension and abnormalities in cranial bone development. Nearly all affected individuals die either in-utero or within the first few days of life, although a few long term survivors were reported during the last decade. We describe the management of 5 newborns diagnosed with RTD in pregnancy who survived the neonatal period, four of them belong to an extended Bedouin family. In 4/5 patients we identified a mutation in angiotensin converting enzyme (ACE) gene. Variable presentation was noticed in the patients, starting with peritoneal dialysis and extreme low blood pressure treated with vasopressors and plasma infusions and ending with no symptoms. Currently, the patients are 5-20 years old with variable stages of chronic kidney disease. In conclusion, the spectrum of RTD is wider than previously reported. Prompt diagnosis is necessary for optimal decision-making by families and physicians. Intensive treatment of low blood pressure in the postnatal period is critical for their survival and better prognosis.


Assuntos
Sistema Renina-Angiotensina , Anormalidades Urogenitais , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Túbulos Renais Proximais/anormalidades , Mutação , Peptidil Dipeptidase A/genética , Gravidez , Sistema Renina-Angiotensina/genética , Adulto Jovem
4.
Eur J Haematol ; 105(2): 216-222, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32302424

RESUMO

OBJECTIVE: Pegylated IFN-α2a has been reported in two case reports as being efficacious in treating CDA-I patients. This study aims to assess its efficacy on a series of CDA-I patients. METHODS: Study sample consisted of seven CDA type 1 transfusion-dependent patients. They received pegylated interferon alpha-2a at an initial dose of 90-180 µg once a week, tapered according to clinical response and side effects. Good response was defined as Hb ≥ 10 g/dL for ≥3 months, partial response was defined as 7 ≤ Hb<10 g/dL for ≥3 months, and no response was defined as HB < 7 g/dL for over 3 months on treatment. Time to response was defined as the time needed to achieve hemoglobin levels ≥ 10 g/dL without transfusion. Patients were evaluated periodically by abdominal ultrasounds to rule out liver adenomas. RESULTS: Five patients (71%) had a good response to treatment. One patient stopped treatment due to side effects. One patient had partial response. One patient, with more severe phenotype and poor compliance, had poor response to treatment. No abnormal findings were found in ultrasound examination. No effect on serum ferritin level could be established. CONCLUSION: Pegylated interferon α2a therapy is efficacious in CDA-I patients with a reasonable safety profile.


Assuntos
Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/terapia , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adolescente , Anemia Diseritropoética Congênita/complicações , Anemia Diseritropoética Congênita/etiologia , Biomarcadores , Transfusão de Sangue , Criança , Pré-Escolar , Terapia Combinada , Gerenciamento Clínico , Índices de Eritrócitos , Feminino , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/etiologia , Masculino , Fenótipo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento
5.
Ann Hum Genet ; 83(5): 361-366, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30977917

RESUMO

Four affected individuals of consanguineous kindred presented at infancy with an apparently autosomal recessive syndrome of polyuria and hypokalemic metabolic alkalosis, following maternal polyhydramnios and premature delivery, culminating in severe failure to thrive. Hypercalciuria, nephrocalcinosis, and hyperaldosteronism were further apparent as well as an unusual finding of intermittent hypernatremia. Additionally, all patients demonstrated variable micrognathia with upper respiratory airway abnormalities. As neither postnatal hyperkalemia nor permanent hearing deficits were shown, clinical assessment was consistent with antenatal Bartter syndrome (ABS) type I, which was never described before in the Israeli Bedouin population. Through genome-wide linkage analysis, we identified a single ∼3.3 Mbp disease-associated locus on chromosome 15q21.1, segregating within the pedigree. Whole-exome sequencing revealed a single novel homozygous missense mutation within this locus, in SLC12A1, encoding the Na-K-Cl cotransporter, NKCC2, in accordance with the clinical diagnosis. In this concise study, we report a novel missense mutation within the SLC12A1 gene, causing a severe form of ABS type I, the first to be described in Israeli Bedouins, with unusual clinical features of hypernatremia caused by nephrogenic diabetes insipidus and putatively related micrognathia with upper airway abnormalities .


Assuntos
Árabes/genética , Síndrome de Bartter/genética , Mutação de Sentido Incorreto , Membro 1 da Família 12 de Carreador de Soluto/genética , Consanguinidade , Feminino , Ligação Genética , Homozigoto , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Israel , Masculino , Linhagem
6.
Brain ; 140(4): 928-939, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334855

RESUMO

A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals also had early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified an ∼18 Mb disease-associated locus on chromosome 4 (maximal logarithm of odds score 4.4 at D4S2971; θ = 0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus, segregating as expected within the kindred and not found in a homozygous state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9's highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration within mutant rather than wild-type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through defective function of this novel activity of SLC30A9 rather than by a defect in its previously described role in transcriptional activation of Wnt signalling.


Assuntos
Proteínas de Transporte de Cátions/genética , Proteínas de Ciclo Celular/genética , Neuropatia Hereditária Motora e Sensorial/genética , Homeostase/genética , Deficiência Intelectual/genética , Nefropatias/genética , Proteínas Nucleares/genética , Zinco/metabolismo , Idade de Início , Árabes , Mapeamento Cromossômico , Consanguinidade , Citosol/metabolismo , Citosol/ultraestrutura , Feminino , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Lactente , Masculino , Mutação , Linhagem , Síndrome , Fatores de Transcrição , Via de Sinalização Wnt/genética
7.
Eur J Haematol ; 98(1): 13-18, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27206021

RESUMO

Congenital dyserythropoietic anemia type I (CDAI) is a rare autosomal recessive disease characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. To better define the natural history of the disease among adult patients, we studied 32 Bedouin patients (median age 34 yr; range 21-60) all carrying the same CDAN1 founder mutation. Follow-up studies included complete blood count, blood chemistry, abdominal ultrasound, echocardiography, and T2*MRI. Main complications were due to anemia and ineffective erythropoiesis [osteoporosis (8/9, 89%), cholelithiasis (21/30, 70%), pulmonary arterial hypertension (PAH) (6/25, 24%)] and iron overload [hypothyroidism (9/24, 38%), and diabetes mellitus (6/32, 19%)]. T2* MRI revealed increased liver iron but no cardiac iron (13/13). Anemia improved in the majority of patients who underwent splenectomy (5/6). Three patients died (9%) at the age of 46-56 due to PAH (1) and sepsis (2). All previously underwent splenectomy. Analyzing both our patients and the 21 patients previously described by Heimpel et al. (Blood 107:334, 2006), we conclude that adults with CDA I suffer significant morbidity and mortality. Careful monitoring of iron overload and prompt iron chelation therapy is mandatory. Due to possible complications and inconsistent response to splenectomy α-interferon, transfusion therapy or stem cell transplantation should be considered as alternatives to this procedure in severely affected patients.


Assuntos
Anemia Diseritropoética Congênita/epidemiologia , Adulto , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/mortalidade , Anemia Diseritropoética Congênita/terapia , Biomarcadores , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Mortalidade , Estudos Retrospectivos , Adulto Jovem
8.
Eur J Haematol ; 99(4): 366-371, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28755517

RESUMO

INTRODUCTION: Congenital dyserythropoietic anemias are rare blood disorders characterized by congenital anemia and a wide range of morphological and functional abnormalities of erythroid precursors. OBJECTIVES: To analyze the relative frequency of both light microscopic (LM) and electron microscopic (EM) morphological features of erythroblasts in a large group of patients with molecular proven congenital dyserythropoietic anemia type I (CDAI). METHODS: We retrospectively evaluated the LM and EM of bone marrow (BM) erythroblasts in 35 patients with CDAI. Thirty-four patients carried the CDAN1 Arg1042Trp founder mutation and one the p.Pro1130Leu mutation. BM slides of 24 patients were available for LM examination. EM studies were performed in all 35 patients. RESULTS: On LM, marked erythroid hyperplasia, binuclear erythroblasts, and various non-specific dyserythropoietic features were documented in every case; internuclear chromatin bridges were detected in 19 patients (79%). In all, EM of erythroblasts revealed a spongy appearance of heterochromatin, a widening of nuclear pores, and invagination of cytoplasm into the nuclear region. CONCLUSIONS: EM studies revealed high morphological frequency of specific ultrastructural changes in erythroblasts which facilitate prompt diagnosis of CDAI. Due to low specificity of BM LM findings, when BM EM is unavailable diagnostic approach should also include other inherited anemias.


Assuntos
Anemia Diseritropoética Congênita/diagnóstico , Medula Óssea/patologia , Eritroblastos/patologia , Anemia Diseritropoética Congênita/sangue , Medula Óssea/ultraestrutura , Eritroblastos/ultraestrutura , Humanos , Microscopia , Microscopia Eletrônica
9.
Pediatr Hematol Oncol ; 33(7-8): 457-461, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27960647

RESUMO

Congenital dyserythropoietic anemia type I (CDA I) is associated, as other anemic noninflammatory states, with ineffective erythropoiesis and increased iron absorption, which may lead to complication of iron overload. The latter complication requires iron-chelating therapy, which may be associated with adverse effects and toxicity. Gastric acid production is known to be an important factor that facilitates non-heme iron absorption. The purpose of this study was to examine whether treatment with proton pump inhibitors (PPIs) can decrease iron absorption in patients with CDA I. Eight CDA I patients (4 boys) aged 12-18 years with mild iron overload (not yet requiring chelating therapy) received 20 mg/d omeprazole for 6 months. Blood samples were obtained for ferritin, C-reactive protein, hemoglobin, calcium, and magnesium at baseline, at the end of months intervention and 6 months after its cessation. The mean ferritin level decreased from 585 ± 180 ng/ml at baseline to 522 ± 172 ng/ml at the end of 6-month treatment and 660 ± 256 ng/ml 6 months after cessation of omeprazole treatment (p  =  0.009). Omeprazole treatment caused a nonsignificant reduction in the mean iron level (iron 159 ± 42, 136 ± 54,167 ± 34 µg/dl, p  =  0.302). However, mean hemoglobin level was mildly but significantly reduced (Hg 10.0 ± 0.8, 9.55 ± 1.0, 10.4 ± 10.7 g/dl, p  =  0.002). No adverse effects were reported. Our investigation suggests that administration of PPI to patients with CDA I may reduce iron absorption and may lower iron overload and the need for chelation therapy.


Assuntos
Anemia Diseritropoética Congênita , Sobrecarga de Ferro , Ferro/sangue , Omeprazol/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Adolescente , Anemia Diseritropoética Congênita/sangue , Anemia Diseritropoética Congênita/complicações , Anemia Diseritropoética Congênita/tratamento farmacológico , Proteína C-Reativa/metabolismo , Cálcio/sangue , Criança , Feminino , Ferritinas/sangue , Hemoglobinas/metabolismo , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Magnésio/sangue , Masculino
10.
J Pediatr Hematol Oncol ; 37(1): 60-2, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24309603

RESUMO

Among the many associated features of persistent pulmonary hypertension of the neonate (PPHN), severe congenital anemia has been described only occasionally and is not included in the list of conditions that may cause PPHN in the neonate. We describe the clinical course of a group of 12 full-term neonates with PPHN and congenital anemia due to congenital dyserythropoietic anemia (7/12), α thalasemia (1/12), Diamond-Blackfan (1/12), and epsilon gamma delta beta thalassemia (3/12). The association of congenital anemia and PPHN is more common than previously thought; it can exist with various etiologies and severity of anemia. Congenital anemia has not been described until now as a cause or risk factor for PPHN; it should be considered as such alone or in combination with other known causes to be recognized early and treated appropriately to improve outcome. In families with known cases of congenital anemia due to the above-mentioned diagnosis, closer prenatal follow-up should be offered to anticipate possible fetal distress and/or fetal anemia and PPHN after birth.


Assuntos
Anemia/congênito , Síndrome da Persistência do Padrão de Circulação Fetal/etiologia , Feminino , Humanos , Recém-Nascido , Masculino
11.
Eur J Haematol ; 90(1): 31-6, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23095116

RESUMO

OBJECTIVE: Congenital dyserythropoietic anemia (CDA) is a rare group of red blood cell disorders with ineffective erythropoiesis and secondary hemochromatosis. Inappropriate suppression of hepcidin and high levels of growth differentiation factor 15 (GDF15) have been described in CDA I and II patients, probably contributing to secondary hemochromatosis. Hemojuvelin (HJV) is an important regulator of serum hepcidin, while soluble form of HJV (s-HJV) competitively down-regulates hepcidin. METHODS: We determined the soluble hemojuvelin (s-HJV) levels in 17 patients with CDA I and in 17 healthy volunteers (HV) and looked for correlations with other parameters of iron overload and erythropoiesis. RESULTS: Significantly higher levels of s-HJV were found in patients (2.32 ± 1.40 mg/L) compared with healthy volunteers (0. 69 ± 0.44 mg/L) (P = 0.001). Western blot analysis confirmed the presence of high levels of s-HJV in CDA I patients. s-HJV positively correlated with serum ferritin, erythropoietin, soluble transferrin receptor, and GDF15 and negatively correlated with hepcidin to ferritin ratios. CONCLUSIONS: We for the first time documented high levels of serum s-HJV in CDA I patients, suggesting that it may contribute to iron loading pathology in CDA I and eventually in other anemias with ineffective erythropoiesis.


Assuntos
Anemia Diseritropoética Congênita/sangue , Proteínas Ligadas por GPI/sangue , Adulto , Peptídeos Catiônicos Antimicrobianos/metabolismo , Estudos de Casos e Controles , Eritropoese , Feminino , Ferritinas/sangue , Proteína da Hemocromatose , Hepcidinas , Humanos , Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Eur J Haematol ; 90(2): 127-33, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23206178

RESUMO

OBJECTIVE: The epsilon gamma delta beta (εγδß)-thalassemias are rare sporadic disorders caused by deletion of the ß-globin gene cluster. The main clinical feature is marked prenatal and neonatal anemia that resolves spontaneously within a few months. Reports originating mainly from Europe have so far identified 30 such deletions The aim of the present work was to describe a novel 1.78-Mb deletion, the longest ever reported, and to detail the clinical features in 12 members of an extended Bedouin family. METHODS: The deletion was identified by globin gene multiplex ligation-dependent probe amplification (MLPA) of the ß-globin cluster and further characterized by comparative genomic hybridization. Past and present clinical and laboratory data of ten symptomatic and two asymptomatic patients were collected. RESULTS: A 1.78-Mb εγδß-deletion, the largest ever described, was identified in all patients. Although other genes were included in the deletion, no other symptoms were observed. Of the ten symptomatic fetuses and neonates, three died of the disease. The remainder required packed cell transfusions during the first months of life. Pregnancy complications included intrauterine growth restriction and oligohydramnios, as well as additional neonatal complications including prematurity and persistent pulmonary hypertension of the neonate. CONCLUSIONS: We suggest that εγδß-thalassemia be added to the list of hemoglobinopathies that can cause neonatal anemia and that MLPA of the ß-globin cluster be used to confirm its diagnosis. Careful surveillance during pregnancy is important to reduce neonatal mortality and morbidity, especially given the dramatic improvement that occurs later.


Assuntos
Anemia Neonatal , Retardo do Crescimento Fetal , Mutação INDEL , Família Multigênica , Oligo-Hidrâmnio , Talassemia , Globinas beta/genética , Adolescente , Adulto , Anemia Neonatal/diagnóstico , Anemia Neonatal/genética , Anemia Neonatal/fisiopatologia , Anemia Neonatal/terapia , Árabes , Transfusão de Eritrócitos , Feminino , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Retardo do Crescimento Fetal/fisiopatologia , Retardo do Crescimento Fetal/terapia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Reação em Cadeia da Polimerase Multiplex , Oligo-Hidrâmnio/diagnóstico , Oligo-Hidrâmnio/genética , Oligo-Hidrâmnio/patologia , Oligo-Hidrâmnio/fisiopatologia , Oligo-Hidrâmnio/terapia , Gravidez , Talassemia/classificação , Talassemia/diagnóstico , Talassemia/genética , Talassemia/patologia , Talassemia/fisiopatologia , Talassemia/terapia
13.
Nat Genet ; 31(2): 171-4, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12032570

RESUMO

Familial hypomagnesemia with secondary hypocalcemia (OMIM 602014) is an autosomal recessive disease that results in electrolyte abnormalities shortly after birth. Affected individuals show severe hypomagnesemia and hypocalcemia, which lead to seizures and tetany. The disorder has been thought to be caused by a defect in the intestinal absorption of magnesium, rather than by abnormal renal loss of magnesium. Restoring the concentrations of serum magnesium to normal values by high-dose magnesium supplementation can overcome the apparent defect in magnesium absorption and in serum concentrations of calcium. Life-long magnesium supplementation is required to overcome the defect in magnesium handling by these individuals. We previously mapped the gene locus to chromosome 9q in three large inbred kindreds from Israel. Here we report that mutation of TRPM6 causes hypomagnesemia with secondary hypocalcemia and show that individuals carrying mutations in this gene have abnormal renal magnesium excretion.


Assuntos
Hipocalcemia/genética , Canais Iônicos/genética , Magnésio/sangue , Mutação , Análise Mutacional de DNA , Humanos , Hipocalcemia/etiologia , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNA , Canais de Cátion TRPM
14.
Nephrol Dial Transplant ; 27(3): 1035-41, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21810765

RESUMO

BACKGROUND: Elevated serum uric acid (UA) is associated with gout, hypertension, cardiovascular and renal disease. Hereditary renal hypouricemia type 1 (RHUC1) is caused by mutations in the renal tubular UA transporter URAT1 and can be complicated by nephrolithiasis and exercise-induced acute renal failure (EIARF). We have recently shown that loss-of-function homozygous mutations of another UA transporter, GLUT9, cause a severe type of hereditary renal hypouricemia with similar complications (RHUC2). METHODS: Two unrelated families with renal hypouricemia were clinically characterized. DNA was extracted and SLC22A12 and SLC2A9 coding for URAT1 and GLUT9, respectively, were sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of the GLUT9 mutations found. A molecular modeling study was undertaken to structurally characterize and probe the effects of these mutations. RESULTS: Two novel homozygous GLUT9 missense mutations were identified: R171C and T125M. Mean serum UA level of the four homozygous subjects was 0.15 ± 0.06 mg/dL and fractional excretion of UA was 89-150%. None of the affected subjects had nephrolithiasis, EIARF or any other complications. Transport assays revealed that both mutant proteins had a dramatically reduced ability to transport UA. Modeling showed that both R171C and T125M mutations are located within the inner channel that transports UA between the cytoplasmic and extracellular regions. CONCLUSIONS: This is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose/genética , Homozigoto , Mutação/genética , Erros Inatos do Transporte Tubular Renal/genética , Ácido Úrico/sangue , Cálculos Urinários/genética , Adulto , Idoso de 80 Anos ou mais , Animais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Modelos Moleculares , Simulação de Dinâmica Molecular , Linhagem , Erros Inatos do Transporte Tubular Renal/sangue , Cálculos Urinários/sangue , Xenopus laevis/genética , Xenopus laevis/metabolismo , Adulto Jovem
15.
J Pediatr Hematol Oncol ; 33(6): 467-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21792044

RESUMO

BACKGROUND: Iron deficiency anemia (IDA) is the most common hematologic disorder worldwide. Measures to prevent IDA in infants have been successful with questionable sustainability. AIM: To evaluate the incidence of developing IDA in the second year of life, in infants who were nonanemic at the age of 1 year on routine blood test. METHODS: Blood samples were obtained from 193, 24-month-old toddlers, from 2 large clinics of both main sectors in Southern Israel, comparable for lower economic status. IDA was defined as hemoglobin < 11 gr% and microcytosis as mean corpuscular volume < 70 fL. RESULTS: IDA was detected in 8 of 118 Bedouins (5 males) and in 10 of 75 Jewish (6 males) infants (P < 0.01). The probability of a nonanemic child to develop IDA in the second year of life for the whole study population was 9.3% (18 of 193 infants) and significantly higher in the Jewish population (13.3.0% vs. 6.8%, P < 0.01). CONCLUSIONS: Given the difficulty of toddlers to maintain a non-IDA status, and the very low probability of iron overload, our results clearly support the need to continue iron supplementation into the second year.


Assuntos
Anemia Ferropriva/epidemiologia , Anemia Ferropriva/prevenção & controle , Deficiências de Ferro , Ferro/administração & dosagem , Pré-Escolar , Feminino , Hemoglobinas/análise , Humanos , Incidência , Lactente , Ferro/sangue , Israel/epidemiologia , Masculino , Fatores de Tempo
16.
Blood ; 112(13): 5241-4, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18824595

RESUMO

Congenital dyserythropoietic anemia (CDA) is a rare group of red blood cell disorders characterized by ineffective erythropoiesis and increased iron absorption. To determine whether growth differentation factor 15 (GDF15) hyper-expression is associated with the ineffective erythropoiesis and iron-loading complications of CDA type I (CDA I), GDF15 levels and other markers of erythropoiesis and iron overload were studied in blood from 17 CDA I patients. Significantly higher levels of GDF15 were detected among the CDA I patients (10 239 +/- 3049 pg/mL) compared with healthy volunteers (269 +/- 238 pg/mL). In addition, GDF15 correlated significantly with several erythropoietic and iron parameters including Hepcidin-25, Ferritin, and Hepcidin-25/Ferritin ratios. These novel results suggest that CDA I patients express very high levels of serum GDF15, and that GDF15 contributes to the inappropriate suppression of hepcidin with subsequent secondary hemochromatosis.


Assuntos
Anemia Diseritropoética Congênita/etiologia , Fator 15 de Diferenciação de Crescimento/sangue , Peptídeos Catiônicos Antimicrobianos/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Eritropoese , Feminino , Ferritinas/sangue , Hepcidinas , Humanos , Ferro/metabolismo , Sobrecarga de Ferro , Israel , Masculino
17.
Pediatr Nephrol ; 25(12): 2531-4, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20607303

RESUMO

Inherited renal tubular dysgenesis (RTD) is caused by mutations in the genes encoding components of the renin-angiotensin cascade: angiotensinogen, renin, angiotensin-converting enzyme (ACE), and angiotensin ΙΙ receptor type 1. It is characterized by oligohydramnios, prematurity, hypotension, hypocalvaria, and neonatal renal failure. The histological hallmark is the absence or poor development of renal proximal tubules. Except for a few cases, the prognosis has been thought to be universally poor, with patients dying either in utero or shortly after birth. We report a 3-year-old infant diagnosed clinically with RTD. The infant survived the neonatal period after 2 weeks of anuria subsequently subsiding. Hypotension and hyperkalemia normalized eventually with administration of fludrocortisone. A revision of renal tissue obtained from a sibling that died shortly after birth revealed normal glomeruli and distal tubules but no identifiable proximal tubules. A novel mutation in the ACE gene was found in the surviving child, who remains with stage 4 chronic kidney disease and normal neurodevelopment. As the number of surviving cases of RTD increases, it should be emphasized to the parents and the neonatal care team that it may not be universally fatal as previously reported. A trial of fludrocortisone may correct hyperkalemia and hypotension.


Assuntos
Mutação , Peptidil Dipeptidase A/genética , Anuria/genética , Pré-Escolar , Feminino , Fludrocortisona/uso terapêutico , Predisposição Genética para Doença , Hereditariedade , Humanos , Hiperpotassemia/tratamento farmacológico , Hiperpotassemia/genética , Hipotensão/tratamento farmacológico , Hipotensão/genética , Túbulos Renais Proximais/anormalidades , Túbulos Renais Proximais/enzimologia , Masculino , Oligo-Hidrâmnio/genética , Diálise Peritoneal , Fenótipo , Gravidez , Resultado do Tratamento , Anormalidades Urogenitais/enzimologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/terapia
18.
Harefuah ; 149(3): 180-5, 193, 2010 Mar.
Artigo em Hebraico | MEDLINE | ID: mdl-20684172

RESUMO

Genetic kidney diseases (GKDs) are an important and well-known entity in pediatric nephrology. Advances in genetic and molecular approaches in the last 15 years have enabled elucidation of the underlying molecular defects in many of these disorders. Herein, the authors summarize the progress that has been made over this period in disclosing the molecular basis of several novel GKDs which were characterized in this area and include Bartter syndrome type IV, type II Bartter syndrome and transient neonatal hyperkalemia, cystinuria and mental retardation, familial hypomagnesemia with secondary hypocalcemia, infantile nephronophthisis and familial hemolytic uremic syndrome with factor H deficiency. Retrospective analysis of the authors' data reveals that GKDs are over-represented among the pediatric population in southern Israel. GKD are seen 4 times more often than end-stage renal disease (ESRD) and comprise 38% of all cases of ESRD in our area. This high rate of GKD is mainly due to the high frequency of consanguineous marriages that prevails in this area. Understanding of the genetic and molecular background of these diseases is a result of a fruitful collaboration between the pediatric nephrologists and scientists, and has a direct implication on the diagnosis and treatment of the affected families.


Assuntos
Nefropatias/epidemiologia , Nefropatias/genética , Síndrome de Bartter/epidemiologia , Síndrome de Bartter/genética , Criança , Doenças Genéticas Inatas/genética , Humanos , Hipocalcemia/genética , Israel/epidemiologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/genética , Erros Inatos do Metabolismo/genética , Linhagem
19.
Int J Cardiol ; 317: 96-102, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512057

RESUMO

BACKGROUND: Congenital dyserythropoietic anemia type 1 (CDA1) is a rare autosomal recessive disease characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. Left-ventricular noncompaction (LVNC) is a cardiomyopathy that is commonly attributed to intrauterine arrest of normal compaction during the endomyocardial morphogenesis. LV hypertrabeculation/noncompaction (LVHT/NC) morphology, however, might exist in various hemoglobinopathies. Our primary objective was to determine whether the pattern of LVHT/NC is more prevalent among patients with CDA1, in comparison to subjects without CDA1, and to find potential risk factors for LVHT/NC among these patients. Our secondary objective was to evaluate the clinical implication of LVHT/NC. METHODS: We retrospectively assessed 32 CDA1 patients (median age 17.5, range 6-61) that underwent routine assessment of iron overload by cardiac magnetic resonance. Number and distribution of noncompacted LV segments were assessed in CDA1 patients and compared to 64 age- and gender-matched patients without CDA1. The ratio of noncompacted to compacted myocardium (NC/C ratio) in end-diastole was calculated for each of the three long-axis views. NC/C ratio > 2.3 was considered diagnostic for LVHT/NC. RESULTS: In multivariate analysis, the presence of CDA1 was independently associated with NC/C ratio > 2.3, a feature of LVHT/NC (adjusted OR = 11.46, 95%CI = 2.6-50.68, p = .001). CDA1 was strongly associated with increased number of myocardial segments exhibiting LVHT/NC pattern. Cardiac volumes and ejection fraction were preserved without clinical adverse events in long term follow-up. CONCLUSIONS: CDA1 patients have a higher prevalence of LVHT/NC than normal individuals, independent of myocardial iron overload and without effect on ejection fraction or clinical outcome.


Assuntos
Anemia Diseritropoética Congênita , Cardiomiopatias , Cardiopatias Congênitas , Adolescente , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/epidemiologia , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/epidemiologia , Humanos , Prevalência , Estudos Retrospectivos
20.
Eur J Haematol ; 81(4): 317-21, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18573172

RESUMO

OBJECTIVES: Congenital dyserythropoietic anemia type I (CDA I) is a rare inherited disease characterized by moderate to severe macrocytic anemia and abnormal erythroid precursors with nuclear chromatin bridges and spongy heterochromatin. Moderate to severe maternal anemia is a recognized independent risk factor for low birth weight (LBW) and complicated delivery. The aim of the study was to review the outcome of pregnancies in women with CDA I. METHODS: The clinical and laboratory records of 28 spontaneous pregnancies in six Bedouin women with CDA I were reviewed. The results were compared with findings from a retrospective review of a large population-based registry including all pregnancies in Bedouin women during the same 15-yr period. RESULTS: Eighteen pregnancies in women with CDA I (64%) were complicated. One pregnancy was aborted spontaneously in the first trimester and one resulted in a non-viable fetus (stillborn at 26 wk). Cesarean section (CS) was performed in 10 pregnancies (36%). Eleven of the 26 newborns (42%) had a LBW: six were born prematurely and five were small for gestational age. The odds ratio for CS in women with CDA I compared with healthy Bedouin women was 4.5 [95% confidence interval (CI) 1.2-10.3], and for a LBW infant, 5.5 (95% CI 2.4-12.3). Careful follow-up was associated with significantly better fetal outcome (P = 0.05). CONCLUSIONS: Pregnancies in women with CDA I are at high risk for delivery-related and outcome complications. To improve fetal outcome, women with CDA I should be carefully monitored during pregnancy.


Assuntos
Anemia Diseritropoética Congênita , Complicações na Gravidez , Resultado da Gravidez , Adolescente , Adulto , Feminino , Humanos , Monitorização Fisiológica , Gravidez , Estudos Retrospectivos , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa