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PubMed2005

Caring for adults with thalassemia in a pediatric world.

Improved technology and medical advances have increased the life span for patients with thalassemia. Therefore, serious consideration must now be given to adult issues such as fertility, employment opportunities, medical insurance, and long-term coping with chronic illness. Since thalassemia is a childhood illness, most adults are seen in pediatric hospitals-often, in centers with a specialty for thalassemia. Compared to a decade ago, many more patients in thalassemia centers are adolescents or older. Unfortunately, pediatric hospitals are not fully equipped to meet the changing and complex needs of adults. Emergency room care, hospital admissions, decentralized care, comprehensive care, and psychosocial issues are current challenges that must be addressed. In this study, six adult patients were asked to keep track of their care for one month to further examine self-care for thalassemia, a high-maintenance disease. From a qualitative perspective, the issues and challenges that adults face are examined and solutions for improved care are discussed.

Adolescent↗
PubMed2005

Thalassemia and learning: Neurocognitive functioning in children.

As more effective management and even cure of thalassemia become possible, attention is beginning to be directed to the potential neurologic and resulting neurocognitive effects of this illness on adults and children. Recent studies indicate that for adults with beta-thalassemia major and intermedia, and for children with sickle beta-thalassemia (Sbeta-thalassemia), there is a substantial risk for silent brain infarcts that may be associated with neurocognitive impairment similar to that reported for children with sickle cell anemia. Here the available literature in this area is reviewed and the limited outcomes are compared with those available from large, multicenter longitudinal studies of sickle cell anemia. On the basis of these comparisons, it is recommend that children with thalassemia be screened for specific neuropsychological impairments and that they be provided early intervention and special education access as available under the Individuals with Disabilities Education Act (IDEA) or the 504 Regulations of the Rehabilitation Act of 1973.

Adolescent↗
PubMed1979

Sickle cell syndromes. III. Silent-carrier alpha-thalassemia in combination with hemoglobin S and hemoglobin C.

Silent carrier alpha-thalassemia was identified in two individuals, one with sickle-cell trait and the other hemoglobin (Hb) C trait. Both are parents of a child with characteristic hematologic features of the Hb SC-alpha thalassemia syndrome, including microcytosis and an unbalanced pattern of globin synthesis. In contrast to the typical findings that accompany heterozygous Hb S or Hb C with concomitant alpha-thalassemia trait, neither of the parents had microcytosis nor a percent of the abnormal hemoglobin in their erythrocytes that was below the normal range. In both, however, globin synthesis of peripheral blood reticulocytes was unbalanced, consistent with mild alpha-thalassemia. These findings suggest that the alpha-thalassemia silent carrier may be hematologically indistinguishable from the nonthalassemic individual, even when hemoglobin S or C are present.

Anemia, Sickle Cell↗
PubMed1984

Longitudinal study of a newborn with a combination of deletion and nondeletion alpha-thalassemia-2.

In this study we have characterized by DNA analysis the molecular basis of an alpha-thalassemia condition found in an infant, with 16% Hb Bart's at birth, who developed an hematologic picture similar to the alpha-thalassemia carrier state. Restriction endonuclease analysis and hybridization with alpha and zeta specific probes have provided strong evidence that this patient carries a genetic compound of deletion alpha-thalassemia-2 lesion (-alpha) and a non-deletion defect [(alpha alpha)th] with both alpha-structural genes intact on chromosome 16. He inherited the deletion alpha-thalassemia-2 chromosome (-alpha) from the father and the chromosome with non-deletion alpha-thalassemia defect from the mother. Because the deletion of one, two, or three alpha-globin structural genes is associated with 1-2%, 5-6%, or 25%, Hb Bart's respectively, these findings suggest that the non-deletion chromosome [(alpha alpha)th] contains two alpha-globin structural genes that are less active than a single alpha gene (-alpha).

Child, Preschool↗
PubMed2000

A reliable screening test to identify adult carriers of the (--SEA) alpha zero-thalassemia deletion. Detection of embryonic zeta-globin chains by enzyme-linked immunosorbent assay.

Homozygous (--SEA) alpha zero-thalassemia deletion, the cause of up to 80% of fetal hydrops in Southeast Asia, is encountered in many other countries. Heterozygous carrier rates of the deletion in Southeast Asian populations range from 4% to 14%. The laboratory screening for adult carriers of (--SEA) and other alpha zero-thalassemia deletions currently rests primarily with microscopic detection of hemoglobin H inclusion bodies within erythrocytes (Hb H screen). This test is laborious and observer dependent and has poor sensitivity. We assessed a colorimetric enzyme-linked immunosorbent assay (ELISA) to detect embryonic zeta-globin chains in adult hemolysates as an alternative to detect (--SEA) alpha zero-thalassemia deletion carriers. Blood samples from 221 adults with a mean corpuscular volume less than 80 micron 3 (80 fL) were studied prospectively by currently accepted hemoglobin screening tests and ELISA. Suspected cases of alpha-thalassemia were confirmed by DNA-based diagnostics. ELISA was highly sensitive (1.0) and specific (0.94) for the detection of adult carriers of (--SEA) alpha zero-thalassemia deletion. The hemoglobin H screen had a sensitivity of 0.47 and specificity of 0.99. The zeta-globin ELISA proved simple to perform, rapid, and applicable to high volume or population-based screening programs.

Adult↗
PubMed2005

Measurement of reticulocyte and red blood cell indices in patients with iron deficiency anemia and beta-thalassemia minor.

New parameters correlated with the hemoglobin content in reticulocytes (RET-Y) and in red blood cells (RBC-Y) have been suggested as helpful in diagnosing iron deficiency anemia. We have studied RET-Y and RBC-Y indices in two groups of patients with microcytosis to verify if these parameters could be used to differentiate iron deficiency anemia from beta-thalassemia minor. Blood samples from 33 iron-deficient patients, 25 beta-thalassemic minor patients and 50 normal individuals were analyzed on a Sysmex XE-2100 instrument. A significant difference was observed in reticulocyte counting and immature reticulocyte fraction between iron deficiency anemia and beta-thalassemia minor groups, but not in RBC-X and RET-Y parameters. Reticulocyte counting was higher in beta-thalassemia minor and the immature reticulocyte fraction was higher in severe iron deficiency anemia. The ratio RET-Y/mean cell volume was tested and was significantly different when beta-thalassemia minor was compared with mild and severe iron deficiency anemia, and showed better performance than the Mentzer ratio and the Green and King function. A great overlap of RET-Y and RBC-Y individual values was observed in both groups of microcytic anemias; we conclude that these new indices may be used with caution as indicative of iron deficiency, mainly in populations where beta-thalassemia minor is frequent.

Anemia, Iron-Deficiency↗
PubMedDate not supplied

Comparison of red cell distribution width and a red cell discriminant function incorporating volume dispersion for distinguishing iron deficiency from beta thalassemia trait in patients with microcytosis.

The red cell distribution width (RDW), and another red cell discriminant function incorporating RDW (MCV2 x RDW/Hgb x 100) were determined in a group of 30 patients with iron deficiency anemia, 30 patients with beta thalassemia trait, and 30 normal subjects. Both RDW and (MCV2 x RDW/Hgb x 100) mean values were significantly higher in iron deficiency anemia than in beta thalassemia trait (p < 0.001). Taking RDW equal or above 21.0 percent among microcytic anemia patients, we identified correctly 90.0 percent of patients with iron deficiency anemia. The sensitivity and specificity of the test were 90.0 percent (IC 95 percent: 0.75-0.98) and 77.0 percent (IC 95 percent: 0.60-0.88), respectively. RDW values below 21.0 percent identified correctly 77.0 percent of beta thalassemia trait with a sensitivity and a specificity of 77.0 percent (IC 95 percent: 0.60-0.88) and 90.0 percent (IC 95 percent: 0.75-0.96), respectively. Taking values of (MCV2 x RDW/Hgb x 100) above and below 80.0 percent as indicative of iron deficiency and beta thalassemia trait, respectively, we identified correctly 97.0 percent of those patients in each group. Both sensitivity and specificity were 97.0 percent (IC 95 percent: 0.84-0.99). These results indicated that the red cell discriminant function incorporating volume dispersion (MCV2 x RDW/Hgb x 100) is a highly sensitive and specific method in the initial screening of patients with microcytic anemia and is better than RDW in differentiating iron deficiency anemia from beta thalassemia trait.

Anemia, Iron-Deficiency↗
PubMed1998

Diabetic nephropathy in hypertransfused patients with beta-thalassemia. The role of oxidative stress.

OBJECTIVE: Pathogenesis of diabetes-related microvascular complications involving oxidative damage by free radicals has been demonstrated. Free radical generation has been shown to derive largely from iron. Our objectives, therefore, were to determine if there is an increased incidence and/or an accelerated course of nephropathy in patients with diabetes, secondary to transfusional hemochromatosis, and to examine whether free radical activity contributes to the development of this complication. RESEARCH DESIGN AND METHODS: We evaluated nine patients with homozygous beta-thalassemia, complicated by clinically overt diabetes, for diabetic nephropathy over a 7-year period. Lipid peroxidation was quantified by measuring the presence of 20 saturated and unsaturated aldehydes, and results were compared with five normotensive type 1 diabetic patients without iron overload. RESULTS: Nephropathy developed in five of nine patients (55%) after a mean duration of overt diabetes of 3.6 +/- 2.0 years. Three patients showed evidence of progressive microalbuminuria over a 7-year period (24.7-46.2, 52.2-430.1, and 17.7-54.3 micrograms/min, respectively). Two patients with borderline microalbuminuria (19.9 and 14.5 micrograms/min, respectively) demonstrated stable albumin excretion rates over the follow-up period. Total aldehyde concentration was significantly higher in beta-thalassemia diabetic patients, compared with nonthalassemic diabetic control subjects (8,106 +/- 1,280 vs. 4,594 +/- 247 nmol/l; P < 0.0001). The three patients with progressive microalbuminuria demonstrated significantly higher total aldehyde concentration, compared with the other beta-thalassemia diabetic patients with stable albumin excretion (9,428 +/- 337 vs. 7,445 +/- 1,003 nmol/l; P < 0.01). Serum vitamin E concentrations were significantly lower in beta-thalassemia patients with diabetes, compared with diabetic patients without iron overload (12.1 +/- 6.0 vs. 25.9 +/- 11.4 mumol/l; P = 0.02). Serum vitamin C concentrations did not differ between the two groups. Multiple regression analysis demonstrated total aldehyde concentration to be the most significant predictor for the development of microalbuminuria (P = 0.01), followed by the duration of diabetes (P = 0.02) and glycemic control (P = 0.02). CONCLUSIONS: Early development and an accelerated course of diabetic nephropathy in iron-loaded patients with beta-thalassemia are observed. These findings may be attributed to high oxidative stress in these patients, which is secondary to iron-derived free radicals and to the patients' diminished antioxidant reserves.

Adult↗
PubMed2000

Relative quantitation of mRNA in beta-thalassemia/Hb E using real-time polymerase chain reaction.

beta-Thalassemia and Hb E patients, with seemingly identical genotypes, have a remarkable variability in severity. Reduction in red cell survival in beta-thalassemia is correlated with the amount of intracellular unmatched alpha-globin chains. However, it was only recently realized that mRNA, whose translation is prematurely terminated, is also unstable. No systematic attempts have been made to investigate mRNA stability in beta-thalassemia arising from nonsense mutations located upstream from the normal termination codon. In this study, one-step real-time polymerase chain reaction has been employed to compare the levels of alpha- and beta-globin mRNA in reticulocytes from beta-thalassemia/Hb E subjects. The results showed the highest alpha/beta-globin mRNA ratio (median = 5.70, n = 13) in frameshift codons 41/42 (-TTCT)/Hb E individuals compared to normal subjects (median = 1.02, n = 6), or those with Hb E trait (median = 2.15, n = 8). In addition, there was a concomitant increase in the alpha/beta-globin mRNA ratio with decrease in hemoglobin level, i.e., increase in severity. The difference in the ratio among beta-thalassemia/Hb E patients with the same genotype may be attributed to individual variations of efficiency in betaE-globin mRNA splicing and in the destruction of prematurely terminated mRNA.

Adult↗
PubMedDate not supplied

beta+-Thalassemia trait: hematologic and hemoglobin synthesis studies.

In Thailand, two types of high Hb A2-beta-thalassemia genes: beta0-thalassemia (beta0-thal) or classical beta-thalassemia and beta+-thalassemia (beta+-thal) or mild beta-thalassemia exist. This study presents hematologic data and globin chain synthesis in peripheral blood of the genuine beta+-thal heterozygotes in comparison with those of the beta0-thal heterozygotes. Thirty individuals of Thai and Chinese extraction with the beta+-thal heterozygosity were hematologically examined. The hematologic means of hemoglobin concentration, MCV, MCH, MCHC, Hb A2 and alkali denaturation hemoglobin of the beta+-thal traits were, 11.7 g%, 67.8 mu3, 21.5 gammagamma, 32.1%, 4.94% and 1.20% respectively. These were not statistically different from those of the beta0-thal traits of our previous study(1). The globin chain synthesis in reticulocytes were performed by incorporation of 3H-Leucine for 3 hours. The mean of total radioactivity alpha/beta ratio in 11 normal controls was 1.07 +/- SD 0.03. The mean of alpha/beta ratio in 9 beta+-thal traits was 2.03 +/- SD 0.10 which was significantly different from that in 7 beta0-thal traits of 2.28 +/- SD 0.07. Our globin chain synthesis thus appears to be helpful of discriminating the beta+-thal trait from the beta0-thal trait.

Globins↗
PubMed1978

Delta beta-thalassemia in a Mexican family: clinical differences among homozygotes.

Three delta beta-thalassemia homozygotes were found in a Mexican family. Both parents and two sibling had heterozygous delta beta-thalassemia with about 10% Hb F, mild microcytosis and mild hypochromia, while three siblings were normal. Hb F, which was the only Hb component in the homozygotes, had equal quantities of Ggamma and Agamma chains as in BgammaAgamma-delta beta-thalassemia. The homozygotes had comparable erythrocytic indices which were about the same as those of the heterozygotes. However, two were clinically and hematologically healthy but the third had a severe chronic hemolytic anemia and a more severe in vitro chain synthesis imbalance than her homozygous sisters. Comparison of these cases with other GgammaAgamma-delta beta-thalassemia homozygotes and with GgammaAgamma-HPFH homozygotes indicates the possibility that the proliferation of F-cell precursors may be defective in delta beta-thalassemia.

Child↗
PubMed1979

Globin chain synthesis in beta-thalassemia with normal hemoglobins A2 and F.

Biosynthetic studies were performed in a patient with beta-thalassemia intermedia heterozygous for both beta-thalassemia with normal hemoglobins A2 and F and beta-thalassemia with increased Hb A2, in his both parents, one sister and one brother. In propositus the alpha/beta ratio was 1.68. In his mother with normal Hb A2, this value was 1.21. In contrast, in his father who had increased Hb A2, the alpha/beta ratio was 1.07, possibly due to combination of alpha- and beta-thalassemia. In his sister who had increased Hb A2, alpha/beta ratio was 1.57. In his brother with normal Hb A2 (2.5%) ratio was 0.6 indicating the presence of an alpha-thalassemia gene. Similar beta-thalassemic syndromes found in other countries are discussed.

Adolescent↗
PubMed1988

Homozygous beta zero-39 mutation with thalassemia intermedia in northern Sardinia: clinical, hematological and molecular analysis.

In this study, we investigated the clinical and hematological features and carried out alpha- and beta-globin gene analyses in 11 Sardinian adult beta zero-thalassemia homozygotes from Northern Sardinia who were not transfusion-dependent. Oligonucleotide analysis revealed in nine out of 11 patients the nonsense mutation at codon 39, which was associated either with haplotype II or IX (14/16 and 2/16 chromosomes, respectively). Haplotype II was linked to the A gamma T mutation. The G gamma globin level ranged from 50 to 70%. Four out of nine patients (44%) were heterozygous and 3/9 (33%) homozygous for the rightward deletional type of alpha-thalassemia; two (22%) had the normal alpha-gene complement. Patients who were alpha-thalassemia homozygotes (-alpha/-alpha) showed a more balanced globin chain synthesis ratio. This study confirms that alpha-thalassemia may ameliorate the clinical picture of homozygous beta zero-thalassemia.

Adult↗
PubMed1995

Molecular basis of alpha-thalassemia in Portugal.

We have estimated the incidence and molecular basis of alpha-thalassemia in a Portuguese population, mostly from the Greater Lisbon area. In a group of 100 consecutive cord blood samples, the gene frequency of the rightward deletion (-alpha 3.7) was 0.035, and the leftward deletion (-alpha 4.2) was 0.015. In this group, we have also found four heterozygotes for the triple alpha-globin gene rearrangement (alpha alpha alpha anti 3.7. gene frequency 0.020). We have characterized the subtypes of -alpha 3.7 and alpha alpha alpha anti 3.7 rearrangements. On the whole, these results give an incidence of 10% for deletional alpha-thalassemia carriers in the studied Portuguese population. In a group of 342 subjects presenting beta-thalassemia, or Hb S trait, beta-thalassemia major sickle cell disease or low red blood cell indices, the -alpha 3.7, -alpha 4.2, -SEA, -MED, (alpha alpha)MM, and alpha alpha alpha anti 3.7 haplotypes were found in different combinations. Only one nondeletional alpha-thalassemia determinant (a 5 nucleotide deletion in the alpha 2-globin gene in the second intervening sequence donor site) was detected, which might suggest a low incidence of these defects in the Portuguese population.

Adult↗
PubMed1995

The frequency of 14 beta-thalassemia mutations in the Arab populations.

The beta-thalassemias are a heterogeneous group with respect to molecular pathogenesis, and different populations and ethnic groups differ with respect to the predominating mutations. This variable spectrum of beta-thalassemia mutations has resulted in extensive studies in each population and ethnic group to identify the major mutations. In this study we investigated the prevalence of 14 mutations in 253 beta-thalassemia patients drawn from eight Arab countries (i.e. Jordan, Egypt, Syria, Lebanon, Yemen, and Saudi Arabia), living in Saudi Arabia and attending Ministry of Health hospitals. The mutations investigated included IVS-I-110 (G-->A), IVS-II-1 (G-->A), IVS-I-5 (G-->C), codon 39 (C-->T), IVS-I-1 (G-->A), frameshift at codons 8/9 (+G), frameshift at codons 41/42 (-TTCT), codon 15 (TGG-->TAG), IVS-I-6 (T-->C), frameshift at codon 16 (-C), IVS-II-745 (C-->G), codon 6(-A), IVS-I, 3' end (-25 bp), and Cap +1 (A-->C). The most frequently encountered mutations were IVS-I-110 and IVS-II-1 which were identified in the population of each Arab country. The IVS-I-1 and IVS-II-745 mutations were encountered in Jordanians, Egyptians, and Syrians. The IVS-I-5, codon 39, codon 6, IVS-I, 3' end (-25 bp), and Cap +1 mutations were encountered only in Saudis and not in other Arabs, except codon 39 which was present in the Syrians and Lebanese. Other mutations were generally rare and not specific to any Arab ethnic group. This paper presents preliminary data on the prevalence of 14 mutations in the Arab populations and shows wide variation in the molecular basis of beta-thalassemia in different Arab ethnic groups. Further detailed studies to identify the entire spectrum of beta-thalassemia mutations are stressed.

Arabs↗
PubMed1997

Is Hb A2 elevated in adults with sickle-alpha-thalassemia (beta(S)/beta(S); -alpha/-alpha)?

Thirteen patients with sickle cell anemia (SS) were found to have two alpha gene deletions with a presumptive genotype of beta(S)/beta(S); -alpha/-alpha. Hematological data showed that this group of patients had elevated Hb A2 level. In order to determine whether the elevation of Hb A2 is typical of SS with a two alpha gene deletion or is due to undiagnosed S-beta(O)-thalassemia with a two alpha gene deletion we looked for the presence or absence of beta(O)-thalassemia by molecular techniques. The latter included reverse dot-blot hybridization to rule out a beta-thalassemia mutation, digestion with CvnI endonuclease followed by Southern blotting and hybridization with a beta genomic probe, and, in selected patients, determination of the synthetic alpha/beta ratio. One of the 13 patients had S-beta(O)-thalassemia with a G-->A mutation at IVS-II-1 indicating that her genotype was beta(S)/beta(O) thalassemia; -alpha/-alpha. The remaining 12 patients were homozygous for the sickle gene, had relatively elevated Hb levels, increased Hb A2 values, and Hb F levels similar to those in patients with SS and four or three alpha genes. At the clinical level, the 12 patients with SS and a two alpha gene deletion had increased prevalence of avascular necrosis, retinopathy, and splenomegaly, but decreased prevalence of leg ulcers and cerebrovascular accidents. Together, the data indicate that SS with a two alpha gene deletion (beta(S)/beta(S); -alpha/-alpha) is a unique subset of patients with SS characterised by distinct hematological and clinical features.

Adult↗
PubMed1999

The association of Hb Khartoum [beta124(H2)Pro-->Arg] with gamma+-thalassemia is responsible for hemolytic disease in the newborn of a Sudanese family.

The unstable Hb Khartoum with a Pro-->Arg replacement at position beta124 was identified by isoelectrofocusing, high performance liquid chromatography, and peptide mapping in a mother and two male children of a Sudanese family. All three were heterozygous for the abnormal hemoglobin; the father and a third male child did not carry the mutation. The mother was also homozygous for two putative gamma+-thalassemia point mutations, one affecting both Agamma and Ggamma genes at IVS-II-115 (A-->G), and one affecting the Ggamma gene at the 3' untranslated region (-A) at position -6 from the polyadenylation site. The father had normal gamma genes. All three children were heterozygous for both the gamma+-thalassemia mutations. The two older children, who were compound heterozygotes for Hb Khartoum/gamma+-thalassemia, presented at birth with severe neonatal jaundice which necessitated exchange blood transfusions. Other causes of neonatal jaundice were excluded. The third male child, who did not carry the Hb Khartoum anomaly but was heterozygous for gamma+-thalassemia, did not develop neonatal jaundice. It is concluded that the instability of Hb Khartoum in combination with gamma+-thalassemia is responsible for neonatal hemolytic anemia in this family.

Adult↗
PubMed2004

Impaired gallbladder motility and delayed orocecal transit contribute to pigment gallstone and biliary sludge formation in beta-thalassemia major adults.

AIM: Gallbladder and gastrointestinal motility defects exist in gallstones patients and to a lesser extent in pigment gallstone patients. To investigated the role of gallbladder and gastrointestinal motility disorders in pigment gallstone formation in beta-thalassemia major. METHODS: Twenty-three patients with beta-thalassemia major (16 females; age range 18-37 years) and 70 controls (47 females, age range 18-40 years) were studied for gallbladder and gastric emptying (functional ultrasonography), orocecal transit (OCTT, H(2)-breath test), autonomic dysfunction (sweat-spot, cardiorespiratory reflex tests), bowel habits, gastrointestinal symptoms and quality of life (all with questionnaires). Gallbladder content (ultrasonography) was examined before and during 8-12 mo follow-up. RESULTS: Gallstones and/or biliary sludge were found in 13 (56%) patients. beta-thalassemia major patients had increased fasting (38.0+/-4.8 mL vs 20.3+/-0.7 mL, P = 0.0001) and residual (7.9+/-1.3 mL vs 5.1+/-0.3 mL, P = 0.002) volume and slightly slower emptying (24.9+/-1.7 min vs 20.1+/-0.7 min, P = 0.04) of the gallbladder, together with longer OCTT (132.2+/-7.8 min vs 99.7+/-2.3 min, P = 0.00003) than controls. No differences in gastric emptying and bowel habits were found. Also, patients had higher dyspepsia (score: 6.7+/-1.2 vs 4.9+/-0.2, P = 0.027), greater appetite (P = 0.000004) and lower health perception (P = 0.00002) than controls. Autonomic dysfunction was diagnosed in 52% of patients (positive tests: 76.2% and 66.7% for parasympathetic and sympathetic involvement, respectively). Patients developing sludge during follow-up (38%, 2 with prior stones) had increased fasting and residual gallbladder volume. CONCLUSION: Adult beta-thalassemia major patients have gallbladder dysmotility associated with delayed small intestinal transit and autonomic dysfunction. These abnormalities apparently contribute together with haemolytic hyperbilirubinemia to the pathogenesis of pigment gallstones/sludge in beta-thalassemia major.

Adolescent↗