1/55. Identification of an erythrocyte pyruvate kinase variant in a family from Latium with non-spherocytic congenital haemolytic anaemia.Erythrocyte PK deficiency was detected in a family from Latium in italy. This PK variant is characterized by normal or increased activity immediately after blood collection, instability to storage, to heat and to urea. Only in the propositus the mutant enzyme exhibited an increased Michaelis constant for PEP, slightly increased inhibition by ATP and an altered optimum pH value. The kinetic anomaly was only partially corrected by activation with F-1, 6-DP and by addition of 2-ME. From these results it can be concluded that in the family observed two distinct erythrocyte PK alterations were demonstrable: instability in the propositus and his father; low affinity for PEP and altered optimum pH value only in the propositus.- - - - - - - - - - ranking = 1keywords = anaemia (Clic here for more details about this article) |
2/55. Hereditary non-spherocytic haemolytic anaemia due to red blood cell glutathione synthetase deficiency in four unrelated patients from spain: clinical and molecular studies.In four unrelated patients with chronic haemolysis and markedly reduced red blood cell (RBC) glutathione (49.5%, 12.6%, 11.5% and 15% of the normal concentration respectively), a severe glutathione synthetase (GSH-S, EC 6.3.2.3) deficiency was found. One case exhibited a neonatal haemolytic anaemia associated with oxoprolinuria, but without neurological manifestations. The family study revealed GSH-S activity in both parents to be around half the normal level, a finding consistent with the presumed autosomal recessive mode of inheritance of this enzymopathy. Two cases exhibited a well-compensated haemolytic syndrome without anaemia or splenomegaly at steady state. One of these cases was diagnosed after an episode of acute haemolytic anaemia after fava bean ingestion. The remaining patient suffered from moderate to severe chronic non-spherocytic haemolytic anaemia and splenomegaly, and required occasional blood transfusion for a haemolytic crisis associated with drug ingestion. In this patient, the anaemia was corrected by splenectomy. In addition to GSH-S, a panel of 16 other RBC enzyme activities was also studied in all the patients. hexokinase, aldolase, glucose-6-phosphate dehydrogenase and pyruvate kinase activities all increased; these increases were to be expected, given the rise in the number of circulating reticulocytes. In two patients, the incubation of RBCs with hydrogen peroxide revealed an enhanced production of malonyldialdehyde. dna analysis showed a homozygous state for 656 A-->G mutation in patients 2 and 3. The GSH-S gene of patient 1, studied elsewhere, revealed an 808 T-->C. The GSH-S gene of patient 4 was not available for study. The present study demonstrates that GSH-S deficiency is also present in spain and further supports the molecular and clinical heterogeneity of this enzymopathy- - - - - - - - - - ranking = 2.25keywords = anaemia (Clic here for more details about this article) |
3/55. Chronic haemolytic anaemia and glucose-6 phosphate dehydrogenase deficiency. Case report and review of the literature.Deficiency in glucose-6-phosphate dehydrogenase (G6PD) is the most common enzymopathy, and more than 125 different mutations causing G6PD deficiency have been identified. Chronic haemolytic anaemia (CHA) associated with G6PD deficiency is rare, but there is a cluster of mutations causing CHA between amino acids 361-428 which are encoded by exon 10 of the G6PD gene. This region is involved in the dimer formation of the active G6PD enzyme and therefore plays an important role for enzyme stability and activity. Here, we report a 17-year-old patient with CHA, who carries a rare G --> A mutation at nucleotide 1160 which causes an R387H amino acid substitution. We review the reports of the seven previously described patients with this mutation, concluding that G6PD deficiency should be considered as a rare differential diagnosis of chronic haemolytic, non-spherocytic anaemia.- - - - - - - - - - ranking = 1.5keywords = anaemia (Clic here for more details about this article) |
4/55. Congenital stomatocytosis and chronic haemolytic anaemia.A new case of congenital stomatocytosis associated with haemolytic anaemia, increased autohaemolysis, abnormalities in the erythrocyte metabolism, increased osmotic fragility and shortened erythrocyte survival is described. Intracellular cation concentrations are abnormal: Red cell sodium is high, and potassium is low. The pump rate for monovalent cations is increased.- - - - - - - - - - ranking = 1.25keywords = anaemia (Clic here for more details about this article) |
5/55. A novel missense mutation (1060G --> C) in the phosphoglycerate kinase gene in a Japanese boy with chronic haemolytic anaemia, developmental delay and rhabdomyolysis.We report the case of a 3-year-old Japanese boy with phosphoglycerate kinase 1 (PGK1) deficiency (Online Mendelian Inheritance in Man entry 311800). The patient had anaemia and jaundice at birth, necessitating exchange transfusions for 2 d. After one red blood cell transfusion at age 2 months, his Hb level was 8-9 g/dl, his reticulocyte counts were 300-500 x 109/l, and his total bilirubin level was 25.65-42.75 micro mol/l. The patient suffered two episodes of respiratory infection-associated haemolytic crisis and rhabdomyolysis during early infancy. At age 3.0 years, his developmental milestones (developmental quotients measured using the Tsumori-Inage methods) score was 49% (normal 74-131%), and his height was below average by -2.0 standard deviations. The diagnosis of PGK1 deficiency was made based on his remarkably low (< 10% of normal) erythrocyte PGK enzyme activity level and the identification of a novel missense (1060G-->C) PGK1 gene mutation. This mutation results in the Ala-353Pro amino acid substitution, which has been designated PGK Kyoto. The patient developed the full clinical symptoms of PGK1 deficiency including haemolytic anaemia, myopathy, central nervous system disorder and growth retardation, which is unusual.- - - - - - - - - - ranking = 1.5keywords = anaemia (Clic here for more details about this article) |
6/55. Human aldolase A natural mutants: relationship between flexibility of the C-terminal region and enzyme function.We have identified a new mutation in the FBP (fructose 1,6-bisphosphate) aldolase A gene in a child with suspected haemolytic anaemia associated with myopathic symptoms at birth and with a subsequent diagnosis of arthrogryposis multiplex congenita and pituitary ectopia. sequence analysis of the whole gene, also performed on the patient's full-length cDNA, revealed only a Gly346-->Ser substitution in the heterozygous state. We expressed in a bacterial system the new aldolase A Gly346-->Ser mutant, and the Glu206-->Lys mutant identified by others, in a patient with an aldolase A deficit. Analysis of their functional profiles showed that the Gly346Ser mutant had the same Km as the wild-type enzyme, but a 4-fold lower kcat. The Glu206-->Lys mutant had a Km approx. 2-fold higher than that of both the Gly346-->Ser mutant and the wild-type enzyme, and a kcat value 40% less than the wild-type. The Gly346-->Ser and wild-type enzymes had the same Tm (melting temperature), which was approx. 6-7 degrees C higher than that of the Glu206-->Lys enzyme. An extensive molecular graphic analysis of the mutated enzymes, using human and rabbit aldolase A crystallographic structures, suggests that the Glu206-->Lys mutation destabilizes the aldolase A tetramer at the subunit interface, and highlights the fact that the glycine-to-serine substitution at position 346 limits the flexibility of the C-terminal region. These results also provide the first evidence that Gly346 is crucial for the correct conformation and function of aldolase A, because it governs the entry/release of the substrates into/from the enzyme cleft, and/or allows important C-terminal residues to approach the active site.- - - - - - - - - - ranking = 0.25keywords = anaemia (Clic here for more details about this article) |
7/55. Ex vivo analysis of aberrant splicing induced by two donor site mutations in PKLR of a patient with severe pyruvate kinase deficiency.Two single-nucleotide substitutions in PKLR constituted the molecular basis underlying pyruvate kinase (PK) deficiency in a patient with severe haemolytic anaemia. One novel mutation, IVS5 1G>A, abolished the intron 5 donor splice site. The other mutation, c.1436G>A, altered the intron 10 donor splice site consensus sequence and, moreover, encoded an R479H substitution. We studied the effects on PKLR pre-mRNA processing, using ex vivo-produced nucleated erythroid cells from the patient. Abolition of the intron 5 splice site initiated two events in the majority of transcripts: skipping of exon 5 or, surprisingly, simultaneous skipping of exon 5 and 6 (Delta5,6). Subcellular localization of transcripts suggested that no functional protein was produced by the IVS5 1A allele. The unusual Delta5,6 transcript suggests that efficient inclusion of exon 6 in wild-type PKLR mRNA depends on the presence of splice-enhancing elements in exon 5. The c.1436G>A mutation caused skipping of exon 10 but was mainly associated with a severe reduction in transcripts although these were, in general, normally processed. Accordingly, low amounts of PK were detected in nucleated erythroid cells of the patient, thus correlating with the patient's PK-deficient phenotype. Finally, several low-abundant transcripts were detected that represent the first examples of "leaky-splicing" in PKLR.- - - - - - - - - - ranking = 0.25keywords = anaemia (Clic here for more details about this article) |
8/55. Dehydrated hereditary stomatocytosis is associated with neonatal hepatitis.Dehydrated hereditary stomatocytosis (DHSt) is an inherited haemolytic anaemia associated with increased red cell membrane permeability to Na( ) and K( ). It is increasingly recognized that a syndrome of self-limiting perinatal ascites can accompany the haemolysis. The cause of the perinatal ascites is unknown, and it has been argued that this could be due to cardiovascular, hepatic or lymphatic problems. We describe the case of a 16-year-old girl who presented neonatally with abnormal liver function tests and ascites. She was extensively investigated at that time. A liver biopsy showed hepatitis and fatty changes. Her ascites resolved within 6 months. At the age of 15 years, she developed an episode of acute haemolysis and was re-investigated. A diagnosis of DHSt was made. Pseudohyperkalaemia, due to ex vivo loss of K( ) from red cells, was present. This study confirms the previously noted association of DHSt, pseudohyperkalaemia and perinatal ascites, and suggests that the latter is of predominantly hepatic origin.- - - - - - - - - - ranking = 0.25keywords = anaemia (Clic here for more details about this article) |
9/55. Coexistence of congenital red cell pyruvate kinase and band 3 deficiency.The authors report the case of a 9-year-old Caucasian girl, born in northern portugal, with chronic nonspherocytic haemolytic anaemia and without family history of anaemia. The aethiological study of this anaemia revealed pyruvate kinase deficiency (PKD), because of two previously described mutations (426Arg-->Trp and 510Arg-->Gln). Since the blood smear revealed features not fully compatible with PKD diagnosis, additional tests were performed for the propositus and her parents, namely red blood cell membrane protein analysis. A decrease in proteins band 3 (15%) and 4.2 (18%) was found in the propositus. Her father presented only a decrease in band 3 (11%). Coexistence of PKD and erythrocyte membrane proteins deficiency in the same patient is very uncommon. Our findings suggest that a careful blood smear observation may lead to the identification of a combined deficiency in erythrocyte membrane proteins and enzymopathies.- - - - - - - - - - ranking = 0.75keywords = anaemia (Clic here for more details about this article) |
10/55. Hemolytic anaemia due to unstable hemoglobin arising from spontaneous mutation--a case report.9 years old male child presented clinically with thalassaemia intermedia phenotype. Investigations revealed hemolytic anaemia due to an unstable hemoglobin. parents were found negative for the abnormal hemoglobin, suggesting a spontaneous mutation in the child. This is the third case of unstable hemoglobin to be reported from india. Clinically it is important that unstable hemoglobin should be suspected in a patient with thalassaemia intermedia phenotype even if both parents are haematologically normal.- - - - - - - - - - ranking = 1.25keywords = anaemia (Clic here for more details about this article) |
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