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Re:In-Reply-To: <200101131727.BAA10169@ms1.mmh.org.tw>From: The-Hung Bui (The-Hung.Bui@ks.se)Mon Jan 15 21:16:37 2001
>From gaperina@mindspring.com Mon Jan 15 22:16:35 2001 Received: from johnson.mail.mindspring.net (johnson.mail.mindspring.net [207.69.200.177]) by mail.medispecialty.com (8.9.3/8.9.3) with ESMTP id WAA31433 for <ultrasound@obgyn.net>; Mon, 15 Jan 2001 22:16:34 -0600 Received: from jim (user-38ld05s.dialup.mindspring.com [209.86.128.188]) by johnson.mail.mindspring.net (8.9.3/8.8.5) with SMTP id XAA32467; Mon, 15 Jan 2001 23:16:24 -0500 (EST) Message-ID: <002a01c07f73$c5ddfc00$0200000a@jim> From: "James S. Smeltzer, MD" <gaperina@mindspring.com> To: <ultrasound@obgyn.net>, <The-Hung.Bui@ks.se> References: <5.0.2.1.0.20010115133738.00abe880@pop3.norton.antivirus> Subject: Re: Alpha Thalassemia Date: Mon, 15 Jan 2001 23:21:15 -0500 MIME-Version: 1.0 Content-Type: text/plain; charset="iso-8859-1" Content-Transfer-Encoding: 8bit X-Priority: 3 X-MSMail-Priority: Normal X-Mailer: Microsoft Outlook Express 5.00.2919.6600 X-MimeOLE: Produced By Microsoft MimeOLE V5.00.2919.6600 Hi, Regarding testing for fetal anemia, Mari has shown that the MCA maximum velocity is strongly predictive of hematocrit. Weekly testing may be required, though. Last week I transfused a fetus with early hydrops, an MCA VMax of 74 (high) and a hemoglobin of 3 at 25 weeks, one week after there were no signs of hydrops and the MCA VMax was 42 (upper normal). Here is his reference: Title Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses [see comments] Author Mari G; Deter RL; Carpenter RL; Rahman F; Zimmerman R; Moise KJ Jr; Dorman KF; Ludomirsky A; Gonzalez R; Gomez R; Oz U; Detti L; Copel JA; Bahado-Singh R; Berry S; Martinez-Poyer J; Blackwell SC Address Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Conn 06520-8063, USA. giancarlo.mari@yale.edu Source N Engl J Med, 342(1):9-14 2000 Jan 6 Abstract BACKGROUND: Invasive techniques such as amniocentesis and cordocentesis are used for diagnosis and treatment in fetuses at risk for anemia due to maternal red-cell alloimmunization. The purpose of our study was to determine the value of noninvasive measurements of the velocity of blood flow in the fetal middle cerebral artery for the diagnosis of fetal anemia. METHODS: We measured the hemoglobin concentration in blood obtained by cordocentesis and also the peak velocity of systolic blood flow in the middle cerebral artery in 111 fetuses at risk for anemia due to maternal red-cell alloimmunization. Peak systolic velocity was measured by Doppler velocimetry. To identify the fetuses with anemia, the hemoglobin values of those at risk were compared with the values in 265 normal fetuses. RESULTS: Fetal hemoglobin concentrations increased with increasing gestational age in the 265 normal fetuses. Among the 111 fetuses at risk for anemia, 41 fetuses did not have anemia; 35 had mild anemia; 4 had moderate anemia; and 31, including 12 with hydrops, had severe anemia. The sensitivity of an increased peak velocity of systolic blood flow in the middle cerebral artery for the prediction of moderate or severe anemia was 100 percent either in the presence or in the absence of hydrops (95 percent confidence interval, 86 to 100 percent for the 23 fetuses without hydrops), with a false positive rate of 12 percent. CONCLUSIONS: In fetuses without hydrops that are at risk because of maternal red-cell alloimmunization, moderate and severe anemia can be detected noninvasively by Doppler ultrasonography on the basis of an increase in the peak velocity of systolic blood flow in the middle cerebral artery. Regarding the etiology, given the name of the author (and it's Asian origin), I agree that alpha-thalassemia is the most likely diagnosis, as the fetus is unable to make any normal hemoglobin tetrameres of any type: embryonic, fetal or adult. It is quite common in Asian populations: Title Frequency of alpha-thalassemia-1 of the Southeast Asian-type among pregnant women in northern Thailand determined by PCR technique. Author Kitsirisakul B; Steger HF; Sanguansermsri T Address Human Genetics Unit, Faculty of Medicine, Chiang Mai University, Thailand. Source Southeast Asian J Trop Med Public Health, 27(2):362-3 1996 Jun Abstract Five hundred pregnant women were analyzed for the presence of alpha-thalassemia-1 of the Southeast Asian (SEA)-type by polymerase chain reaction (PCR) technique at the Maharaj Nakhon Chiang Mai University Hospital in Chiang Mai during the period from April to June 1995. Forty-four of them (8.8%) were recognized as carriers, corresponding to a frequency of 0.044. Homozygous alpha-thalassemia-1 of the SEA-type, the fatal condition of hemoglobin Bart's hydrops fetalis, has an expected frequency of 0.00194, or about 2 hydrops fetalis cases per 1,000 births in this population. If this is the case, both parents will be microcytic and not necessarily very anemic. If this is the case, the risk for any particular future child to have this problem is 1/4. I believe that DNA testing is available and likely to be informative. Prenatal identification is important because this disease is potentially cureable by a stem cell transplant into the fetus, on an investigational compassionate need basis. Abortion is not really a factor because the disease is universally fatal in its homozygous severe form (the one seen in the fetal hydrops deaths). Theoretically another alternative would be serial intrauterine transfusions like for Rh, and an ultimate curative bone marrow transplant, which is now done for beta thalassemia: Berloni Foundation against thalassemia THE BONE MARROW TRANSPLANTATION CENTER OF PESARO All founds assigned to the Berloni Foundation are directed towards the Bone Marrow Transplantation Center, Pesaro - Haematology Division of the Hospital San Salvatore - which occupies a position of international leadership in the fight of Thalassemia due to the development of the Center's Clinical and Scientific Research programmes. Thalassemia, in its homozigote form, is the most widespreaded genetic disease in the world. In the Mediterranean and Middle East only, there are over 200,000 thalassemic children. In Italy there are 8,000 and 250,000 are born every year. Their survival depens on the possibulity of transfusion from age of 3 to 6 months, every 15 days and receiving subcutaneous injections of desferrioxamine every day - continuosly - for serious anaemia and to remove part of the iron contained in the trasfusions. During the first 10 years the mortality rate in 5%, in the next ten years between 5% and 10% and after the age of twenty it reaches 50%. Up until december 1981 thalassemic children and their families were left completely in the dark when it came the possibility of a cure. Since then, however, against all odds, criticism and biological barriers considered insurmountable, the Bone Marrow Transplantation Center, after surviving the initial mortalities has performed hundreds and hundreds transplants, 65% of them in thalassemic children. Today the 80% of those children are at home cured of the disease. Apart from childrem Sardinia, Sicily, Calabria, Lombardia, Piemonte and alla other regions in Italy, transplants have been performed on children from Iran, India, Palestine, Arab Countries and many other nations including USA, Russia, Romania, Argentina, South Africa, Tobago. Due to the requests for transplants arriving from all over the world the current waiting list at the Bone Marrow Transplantation Center of Pesaro has reached 14 months. The impact of this discovery in Italy on the international scientific community has been of enormous proportions, but still more important has been the light of hope instilled in hearts of the families with thalassemic children. All results obtained at the Bone Marrow Transplantation Center are passed on to University Clinics an Italian and foreign Hospitals who are committed to curing Thalassemia by way of transplant protocol which is today known as "The Pesaro Protocol". Due to the increase od doctors' request for clinical-scientific training at the Pesaro Center, exchanges on an international basis are expected. To this end, scientific and didactic collaboration programmes have been established, in according whit the Ministery of foreign Countries, with various countries including Iran, Russia, Romania and India. It is the hope that one day, in these countries, autonomous Bone Marrow Transplantation Centers will be in operation, like the one already realized at Minsk in Belarousse with the finances of the Berloni Foundation. Prof. Guido Lucarelli Scientific Programme Chief Bone Marrow Transplantation Center Chief Physician Haematology Department San Salvatore Hospital, Pesaro The following from OMIM may be helpful: http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141800 TEXT The alpha and beta loci determine the structure of the 2 types of polypeptide chains in the tetrameric adult hemoglobin, Hb A, alpha-2/beta-2. The alpha locus also determines a polypeptide chain, the alpha chain, in fetal hemoglobin (alpha-2/gamma-2), in hemoglobin A2(alpha-2/delta-2), and in embryonic hemoglobin (alpha-2/epsilon-2). The number of normal alpha genes (3, 2, 1 or none) in Asian cases of alpha-thalassemia results in 4 different alpha-thalassemia syndromes (Kan et al., 1976). Three normal alpha genes gives a silent carrier state. Two normal alpha genes results in microcytosis (so-called heterozygous alpha-thalassemia). One normal alpha gene results in microcytosis and hemolysis (so-called Hb H disease). No normal alpha gene results in 'homozygous alpha-thalassemia' manifested as fatal hydrops fetalis. By studies of somatic cell hybrids, Deisseroth et al. (1976) showed that the alpha and beta loci are on different chromosomes. Gandini et al. (1977) concluded, incorrectly as it turned out, that the alpha loci are on the long arm of chromosome 4 (4q28-q34). The conclusion was based on a finding of excessive synthesis of alpha chains in patients with duplication of this region. Deisseroth et al. (1977) combined the methods of somatic cell hybridization and DNA-cDNA hybridization to establish assignment of the alpha-globin locus to chromosome 16. This represents an extension of the cell hybridization method permitting mapping of genes that are not functional in the cultured cell. Weitkamp et al. (1977) presented data concerning linkage of the alpha and beta loci to 34 marker loci. Data on alpha-thalassemia, combined with those on the Hopkins-2 variant, excluded linkage of alpha and haptoglobin at a recombination fraction less than 0.15. Deisseroth and Hendrick (1978) confirmed the assignment of the alpha locus to chromosome 16 by means of cotransfer of this gene with the human APRT gene, known to be on 16 (see 102600), into mouse erythroleukemia cells. (The APRT gene is on the long arm of chromosome 16.) On the basis of findings in a case of partial trisomy 16, Wainscoat et al. (1981) concluded that the alpha-globin genes are on segment 16p12-pter. By combining somatic cell hybridization with a cDNA probe in the study of a cell line with reciprocal translocation between 16q and 11q, Koeffler et al. (1981) showed that the alpha-globin genes are on the short arm of 16. Gerhard et al. (1981) used an improved method of in situ hybridization to confirm the assignment of the alpha-globin cluster to chromosome 16p. The evidence on the precise location of HBAC is conflicting, with assignments from 16p13.33 to 16p13.11 (Reeders, 1986). The fact that adult polycystic kidney disease (APKD; 173900) is proximal to HBAC and is on the 5-prime side of HBAC appears to indicate that the order is 16cen--APKD--5-prime HBZ1--HBA1--3-prime HVR--pter. (3-prime HVR is the hypervariable region used in mapping APKD to 16p.) On the basis of the findings in a fetus with an unbalanced translocation involving 16p, Breuning et al. (1987) concluded that the HBA cluster is distal to PGP. By a combination of in situ hybridization, Southern blot analysis, and linkage analysis using the fragile site 16p12.3 and translocation breakpoints within band 16p13.1, Simmers et al. (1987) mapped the alpha-globin gene complex to 16pter-p13.2. Buckle et al. (1988) described a child in whom cytogenetic analysis indicated monosomy for 16pter-p13.3. DNA studies showed that the patient had not inherited either maternal alpha-globin allele. The child had the alpha-thalassemia trait as well as moderate mental retardation and dysmorphic features. They determined that the gene is located in the 16pter-p13.3 segment. After reviewing earlier data placing the alpha-globin cluster slightly more proximal, they concluded that the findings in this child may be more reliable. Orkin (1978) identified alpha-globin gene fragments in restriction endonuclease digests of total DNA after electrophoresis by hybridization with P32-labeled cDNA probes. The data indicated that the alpha genes occur in duplicate and that the 2 copies lie close together. Thus direct physical evidence is provided for the duplication deduced from the findings with mutant alpha chains and with the alpha-thalassemias and the kinetics of hybridization in solution. The 2 alpha chains lie about 3.7 kilobases apart. Leder et al. (1978) presented evidence that the alpha and beta genes of all adult mammalian hemoglobins have 2 intervening sequences at analogous positions. Wilson et al. (1977) described a possible nucleotide polymorphism in the untranslated 3-prime region of the alpha-globin gene and suggested that the heterogeneity is related to the existence of 2 alpha gene loci. Musumeci et al. (1978) pointed out that the combination of alpha-thalassemia and beta-thalassemia leads to less severe clinical expression of homozygous beta-thalassemia. The rarity of a chromosome 16 with both alpha loci deleted (as demonstrated by the restriction endonuclease mapping technique of Southern) explains the rarity of severe forms of alpha-thalassemia in Africans, e.g., Hb H disease which requires loss of 3 alpha loci and homozygous alpha-thalassemia which requires loss of 4 alpha loci (Dozy et al., 1979). By restriction endonuclease mapping, Goossens et al. (1980) identified 12 persons heterozygous for a chromosome carrying 3 alpha genes. There were no hematologic abnormalities. The frequency was 0.0036 in American Blacks and 0.05 in Greek Cypriots. They had previously shown a frequency of 0.16 for the single alpha-globin locus in black Americans. The single locus had a frequency of 0.18 in Sardinians, but none of 125 Sardinians had a triple alpha locus, suggesting that the former had a selective advantage. Greek Cypriots have a frequency of 0.07 for the single alpha locus. Among 645 Japanese subjects studied, Nakashima et al. (1990) found 10 persons heterozygous for a chromosome with the triplicated alpha-globin locus. Thus, the frequency of the triplicate alpha locus was 0.008 in this population, while that of the single alpha-locus, i.e., the alpha-thalassemia-2 gene, may be lower than 0.0008. Analysis of haplotypes suggested that the triple alpha loci may have had multiple origins. Nakashima et al. (1990) commented on the fact that in Melanesia the frequency of the triplicated genotype is about the same (Flint et al., 1986) as in Japan, whereas the frequency of the single alpha gene is much higher, compatible with a selective advantage vis-a-vis malaria. Liebhaber et al. (1981) found identity of the alpha-1-globin genes from an Asian and a Caucasian. Furthermore, the alpha-1 and alpha-2 genes have a much higher degree of homology than would be predicted from the timing of the duplication before the bird-mammal divergence (about 300 Myr ago). Liebhaber et al. (1981) presented this as evidence for the existence of mechanisms for suppression of allelic polymorphisms and for exchange of genetic information within the alpha-globin gene complex. See 142200 for a discussion of gene conversion in relation to a comparably surprising homology of the 2 gamma-globin genes. Lehmann and Carrell (1984) suggested the use of the following nomenclature for alpha-thalassemias based on the number of alpha-globin genes that are missing or abnormal: 1-alpha-thalassemia (silent type); 2-alpha-thalassemia, trans or cis (thalassemia trait); 3-alpha-thalassemia (Hb H disease); and 4-alpha-thalassemia (Hb Bart's hydrops fetalis). In this scheme, homozygous Hb Constant Spring is a 2-alpha-thalassemia which, if combined with a cis 2-alpha-thalassemia heterozygous Hb Constant Spring, gives a 3-alpha-thalassemia and results in Hb H disease. Lehmann and Carrell (1984) also proposed that the 2 alpha-globin genes be designated as 5-prime (now alpha-2) and 3-prime (now alpha-1). Liebhaber and Cash (1985) described a method for identifying whether the alpha-1 or alpha-2 locus is the site of particular alpha-globin mutations. Rubin and Kan (1985) described a sensitive method for determining how many alpha-globin genes are present. It had the advantages of not requiring restriction enzyme digestion and gel electrophoresis and using the much more stable isotope (35)S rather than 32(P) for labeling. Only a small sample of DNA is needed. Application of the approach to diagnosis of Down syndrome was proposed. Assum et al. (1985) added a fourth restriction site polymorphism in the alpha-globin gene cluster. Compared to the beta-globin cluster, the alpha-globin cluster seemed to show a poverty of DNA polymorphism; however, Higgs et al. (1986) demonstrated a remarkable degree of DNA polymorphism in the alpha-globin gene cluster. In addition, the RFLP haplotype is associated with hypervariable regions of DNA. Pseudo-alpha-1 (HBAP1), a pseudogene, is defective in several respects, including splice junction mutations and premature termination codons. Hardison et al. (1986) identified a previously undetected pseudogene in the alpha-globin cluster. It was not detected by hybridization studies but was found only on sequence analysis. Hardison et al. (1986) suggested that 'divergent copies of a large number of genes may comprise a substantial fraction of the slowly renaturing DNA of mammalian genomes.' The newly detected pseudogene, which will be symbolized HBAP2, is only 65 bp 3-prime to the polyadenylation site of zeta-1 (HBZP). The sequence is: 5-prime--HBZ--HBZP--HBAP2--HBA2--HBA1--3-prime. (The functional Hba gene of the mouse is on chromosome 11, but pseudogenes are dispersed to other chromosomes (e.g., Hba-ps3 to mouse chromosome 15) (Popp et al., 1981; Leder et al., 1981; Eicher and Lee, 1991).) Vandenplas et al. (1987) described a new form of alpha-0 thalassemia in a South African family ascertained through a case of Hb H disease. A novel deletion of 22.8-22.7 kb of DNA removed 3 pseudogenes as well as the alpha-2 and alpha-1 genes. Since the alpha-2-globin gene encodes the majority of alpha-globin, a thalassemic mutation of the alpha-1-globin gene would be expected to result in a less severe loss of alpha-chain synthesis. Moi et al. (1987) described an initiation codon mutation, AUG-to-GUG, in the alpha-1-globin gene. As predicted, the degree of interference with alpha-globin synthesis was less in this mutation than in the mutation in the initiation codon of the alpha-2-globin gene (see 141850). Hill et al. (1987) described a unique nondeletion form of Hb H disease in Papua New Guinea: all 4 alpha genes were intact. Hill et al. (1987) commented on the striking difference in the hemoglobinopathies that occur in Southeast Asia and in Melanesia. In the former area, Hb E, Hb Constant Spring, and the Southeast Asian form of deletion alpha-0-thalassemia are all common, whereas these forms have never been found in Melanesians or Polynesians. Jarman and Higgs (1988) identified a highly polymorphic region approximately 100 kb upstream of the alpha-globin genes and referred to it as 5-prime HVR. This is a valuable genetic marker for 16p. Higgs et al. (1989) gave a comprehensive review of the molecular genetics of the alpha-globin gene cluster, including its diseases. Hatton et al. (1990) presented evidence for the existence of an alpha-locus activating region (LAR), called alpha-dominant control region (alpha-DCR) or locus control region, alpha (LCRA; 152422), located 5-prime to the alpha-globin gene cluster. (This is comparable to the beta-DCR, or beta-LAR, which controls expression of the beta-like genes; see 152424.) Hatton et al. (1990) studied an English patient with alpha-thalassemia in which the basis appeared to be a deletion of 62 kb from a region upstream of the alpha-globin genes. Romao et al. (1992) likewise described alpha-thalassemia in a person with truncation of 16p, which they referred to as the locus control region (LCR), with resulting inactivation of the adjacent intact alpha-globin genes. Hemoglobinopathies of alpha-globin can result from missense mutations at either of the 2 alpha-globin loci, HBA1 or HBA2. Since the normal HBA1 and HBA2 genes encode an identical alpha globin, these mutants cannot be assigned to their specific loci on the basis of protein structural analysis. A clue to the encoding locus, HBA1 versus HBA2, is provided by the relative concentration of the alpha-globin mutant in the erythrocyte based on the 2- to 3-fold higher level of expression of the HBA2 gene (Liebhaber et al., 1986). However, since variables such as protein stability, efficiency of hemoglobin tetramer formation, and other factors can affect the steady-state levels of globin mutants, a definitive locus assignment must be directly determined. Cash et al. (1989) quantitated the expression of 2 alpha-globin structural mutants found in the Caribbean basin, Fort de France and Spanish Town, and showed that they are HBA1 and HBA2 mutants, respectively, on the basis of low or high expression. Liebhaber et al. (1990) identified an individual with alpha-thalassemia in whom structurally normal alpha-globin genes were inactivated in cis by a discrete de novo 35-kb deletion located about 30 kb 5-prime to the alpha-globin gene cluster. They concluded that the deletion inactivates expression of the alpha-globin genes by removing one or more of the previously identified upstream regulatory sequences that are critical to expression of the alpha-globin genes. Wilkie et al. (1991) described major polymorphic length variation in the terminal region of 16p (16p13.3) by physically linking the alpha-globin locus with probes to telomere-associated repeats. They found 3 alleles in which the alpha-globin genes lie 170 kb, 350 kb, or 430 kb from the telomere. The 2 most common alleles were found to contain different terminal segments, starting 145 kb distal to the alpha-globin genes. Beyond this boundary these alleles are nonhomologous, yet each contains sequences related to other, different chromosome termini. This chromosome-size polymorphism probably arose by occasional exchanges between the subtelomeric regions of nonhomologous chromosomes. Wilkie et al. (1991) raised the possibility that the high frequency of trisomy 16 may be related to this nonhomology of the 2 common 16pter alleles in their subtelomeric region. Huisman et al. (1996) found that of the 141 codons of the alpha-globin genes (there are no sequence differences between the coding regions of the alpha-2 and alpha-1 genes), as many as 99 have been found to be mutated; for several, 3 or 4 mutations have been discovered, while 5 mutations are known for codons 23, 75, and 94, and 6 for codon 141. The mutations appear to occur at random; thus, either one of the 3 bases are replaced in the 199 known alpha-globin gene mutants. The suggestion that alpha(+)-thalassemia has achieved a high frequency in some populations as a result of selection by malaria is based on a number of epidemiologic studies. In the southwest Pacific region, there is a striking geographic correlation between the frequency of alpha(+)-thalassemia and the endemicity of Plasmodium falciparum. Allen et al. (1997) undertook a prospective case-control study of children with severe malaria on the north coast of Papua New Guinea, where malaria transmission is intense and alpha(+)-thalassemia affects more than 90% of the population (homozygotes comprise approximately 55% and heterozygotes 37% of the population). Compared with normal children, the risk of having severe malaria was 0.40 in alpha(+)-thalassemia homozygotes and 0.66 in heterozygotes. Unexpectedly, the risk of hospital admission with infections other than malaria also was reduced to a similar degree in homozygotes (0.36) and heterozygotes (0.63). This clinical study demonstrated that a malaria resistance gene protects against disease caused by infections other than malaria. A reduction in mortality greater than that attributable directly to malaria had been observed after the prevention of malaria by insecticides, chemoprophylaxis, and insecticide-impregnated bed nets. Previous observations that direct malaria mortality cannot account for observed hemoglobin S gene frequencies suggest that the findings of this study may apply equally to other malaria resistance genes. Fung et al. (1999) reported 3 cases of homozygous alpha-thalassemia who survived beyond the newborn period, all with hypospadias. Review of the literature identified 2 additional cases. Fung et al. (1999) suggested that the hypospadias may have been secondary to the in utero edema leading to failure of fusion of urogenital folds or due to defect or deletion of another gene at 16p13.3. For a review of hydrops fetalis caused by alpha-thalassemia, see Chui and Waye (1998).
>From work on the mouse model of alpha-thalassemia, Leder et al. (1999) N.B.: Alpha-globin variants for which it is unknown whether HBA1 or HBA2 is involved have arbitrarily been included in this entry. Carver and Kutlar (1995) listed 191 alpha-globin variants as of January 1995. The syllabus by Huisman et al. (1996) listed 199 alpha-chain hemoglobin variants as of January 1996. These included single-base mutations in the alpha-2 and alpha-1 genes as well as 2-base mutations. Not included in their syllabus were deletions in mutations that result in alpha-thalassemia, even if such a change (point mutation or frameshift) occurred in one of the coding regions of the gene. Information about the alpha-thalassemias was provided by Higgs et al. (1989). Also, Activation of the other components such as epsulon may be possible to replace missing alpha subunits: WESTPORT, Nov 10 (Reuters Health) - US researchers believe that reactivation of embryonic zeta- or epsilon-globin genes might be used to treat individuals with alpha or beta-thalassemia.That is based on experiments showing that expression of human embryonic globin genes can rescue mice with inactivated alpha- and beta-globin genes. Dr. J. Eric Russell and Stephen A. Liebhaber, writing in the November 1st issue of Blood, point out that patients with thalassemia have intact embryonic globin genes, but these are silenced during development.The researchers, from the University of Pennsylvania School of Medicine, Philadelphia, speculated that reactivating the "back-up" embryonic globin genes could be a potential therapeutic approach for human thalassemia. The researchers generated two strains of mice, one that expressed human embryonic zeta-globin genes in adulthood and another that expressed human embryonic epsilon-globin.They mated the mice with the zeta gene with mice that carried a mutation in the alpha-globin genes.Mice with the epsilon gene were mated with others carrying mutations in the beta-globin genes. The blood cell morphology of the offspring from the breeding was examined for signs of thalassemia. The group found erythrocyte morphology alterations similar to those seen in human alpha-thalassemia in the offspring that carried the alpha-globin mutation but did not express zeta-globin.In contrast, those offspring that had inherited the human zeta-globin genes had normal erythrocytes. Similarly, offspring with beta-globin mutations that inherited the epsilon-globin gene had normal erythrocytes and those that did not displayed characteristics seen in severe human beta-thalassemia. "This report demonstrates that embryonic [zeta]- and [epsilon]-globins can functionally substitute for their adult [alpha]- and [beta]-globin homologues in adult erythroid cells," the researchers write. "These results illustrate the potential therapeutic utility of embryonic globins as substitutes for deficient adult globins in thalassemic individuals." Blood 1998;92:3057-3063. Of course, this has not been shown in humans. The cooperativity of the alpha and beta chains appears to be important: Thalassemia So let's move on to a discussion of thalassemia. Thalassemia is essentially the absence of one of the chains of hemoglobin. In the case of a thalassemia, that means that the a chains are missing or not functioning properly. Lacking a chains is the basic cause of a thalassemia. The basic symptom is an anemia. When the a chains are missing, the b chains are still synthesized and they can aggregate to form tetramers, b chain tetramers. These are known as hemoglobin H, they're (b)4forms of hemoglobin. The b chains are quite normal so in theory, at least, they could bind oxygen and carry out the oxygen transport function. But if you think about it, the cooperativity is essential for the proper function. If you only have one kind of chain in hemoglobin, the cooperativity is lost. The (b)4 tetramer has no cooperativity of oxygen binding. This means that the oxygen binding can't be used to properly deliver oxygen to the tissues because the lack of cooperativity means that this hemoglobin will bind oxygen but it won't release it at the right oxygen concentration. So a thalassemia is characterized by the presence of these b chain tetramers. You also find g chain tetramers, particularly of course, in the fetus and this is known as hemoglobin Barts. It has the same problem as b chain tetramers, it has no cooperativity and so no possibility of transporting oxygen. No cooperativity is the basic problem and the oxygen affinity is much too high so oxygen is taken up in the lungs but not released in the tissues. In b thalassemia much of the situation is kind of similar, this time we're lacking b chains. The a chains are present, and so we get a chain tetramers formed. Again, they don't work. There's no cooperativity and the oxygen affinity is too high. So, basically, we get an anemia because of the inability of the remaining hemoglobin subunits to correctly transport oxygen in the body. So thalassemias are the absence of one of the side chains Also: Silent alpha thalassemia carrier state and hemoglobin Constant-Spring can only be detected with alpha globin DNA mutation analysis. This is a method of examining the alpha globin gene for changes that prevent the gene from functioning properly. DNA testing is performed at specialty labs, and again, involves having a single blood sample taken. A doctor or genetic counselor can arrange the DNA testing if it is indicated. Also: Title Alpha-thalassemia carrier identification by DNA analysis in the screening for thalassemia. Author Galanello R; Sollaino C; Paglietti E; Barella S; Perra C; Doneddu I; Pirroni MG; Maccioni L; Cao A Address Istituto di Clinica e Biologia dell'Et`a Evolutiva Universit`a degli Studi di Cagliari, Ospedale Regionale Microcitemie, Cagliari, Italy. rgalanel@mcweb.unica.it Source Am J Hematol, 59(4):273-8 1998 Dec Abstract Differentiation between heterozygous alpha-thalassemia and several phenotypically resembling alleles at the beta-globin gene cluster such as coinherited delta- and beta-thalassemia or gammadelta beta-thalassemia is a critical step in genetic counseling. In this paper we report our experience in the identification of the alpha-thalassemia carrier state using polymerase chain reaction (PCR)-based methods, and the feasibility and simplification of screening for thalassemia using this approach. Alpha-globin genotype was determined by PCR-based method in 526 adult subjects with reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), normal hemoglobin A2 and F, and normal serum iron. To verify the reliability of the protocol used, in 68 of these subjects we performed globin chain synthesis analysis and in 101 we determined alpha-globin genotype by Southern blot analysis. Five hundred twenty-one (99%) of 526 subjects examined were identified as carriers of one or two alpha-thalassemia alleles. The identification of the alpha-thalassemia carrier state may be fast and accurate by PCR-based method, avoiding other cumbersome and expensive methods such as globin chain synthesis and Southern blot analysis. Obviously a lot is going on in this area. Other possibilities are many: Title Alpha-thalassemia carrier identification by DNA analysis in the screening for thalassemia. Author Galanello R; Sollaino C; Paglietti E; Barella S; Perra C; Doneddu I; Pirroni MG; Maccioni L; Cao A Address Istituto di Clinica e Biologia dell'Et`a Evolutiva Universit`a degli Studi di Cagliari, Ospedale Regionale Microcitemie, Cagliari, Italy. rgalanel@mcweb.unica.it Source Am J Hematol, 59(4):273-8 1998 Dec Abstract Differentiation between heterozygous alpha-thalassemia and several phenotypically resembling alleles at the beta-globin gene cluster such as coinherited delta- and beta-thalassemia or gammadelta beta-thalassemia is a critical step in genetic counseling. In this paper we report our experience in the identification of the alpha-thalassemia carrier state using polymerase chain reaction (PCR)-based methods, and the feasibility and simplification of screening for thalassemia using this approach. Alpha-globin genotype was determined by PCR-based method in 526 adult subjects with reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), normal hemoglobin A2 and F, and normal serum iron. To verify the reliability of the protocol used, in 68 of these subjects we performed globin chain synthesis analysis and in 101 we determined alpha-globin genotype by Southern blot analysis. Five hundred twenty-one (99%) of 526 subjects examined were identified as carriers of one or two alpha-thalassemia alleles. The identification of the alpha-thalassemia carrier state may be fast and accurate by PCR-based method, avoiding other cumbersome and expensive methods such as globin chain synthesis and Southern blot analysis. Title Mucopolysaccharidosis type VII associated with hydrops fetalis: histopathological and ultrastructural features with genetic implications. Author Molyneux AJ; Blair E; Coleman N; Daish P Address Department of Cellular Pathology, Northampton General Hospital NHS Trust. Source J Clin Pathol, 50(3):252-4 1997 Mar Abstract A case of mucopolysaccharidosis type VII (MPS VII, beta glucuronidase deficiency) causing fatal hydrops fetalis in the third trimester is presented. The diagnosis was suspected on histopathological examination by the presence of foam cells in many of the viscera and foamy change in the placental Hofbauer cells. Electron microscopy showed empty cytoplasmic inclusion bodies within macrophages and in the Hofbauer cells. Enzyme assay of cultured fibroblasts showed markedly deficient beta glucuronidase activity, thus confirming the diagnosis. A detailed and thorough histopathological examination of hydrops fetalis cases is important to detect subtle features of inherited metabolic disorders. Use of a structured necropsy protocol is recommended for cases of non-immune hydrops. Electron microscopy is a useful adjunct to light microscopy in cases where an inherited metabolic disorder is suspected. Precise necropsy diagnosis is important as there are implications for genetic counselling and possible prenatal diagnosis in subsequent pregnancies. Title Recurrent nonimmune hydrops fetalis: a rare presentation of sialic acid storage disease. Author Lefebvre G; Wehbe G; Heron D; Vautjoer Brouzes D; Choukroun JB; Darbois Y Address Department of Obstetrics and Gynecology, PitiŽe-SalpŽetri`ere University Hospital, Paris, France. Source Genet Couns, 10(3):277-84 1999 Abstract A case of recurrent hydrops fetalis, diagnosed on second trimester's ultrasonography, has led to the diagnosis of sialic acid storage disease. No classic etiology was found after the first accident. The recurrence in subsequent pregnancy raised the possibility of a storage disease that was confirmed by amniocentesis. The diagnosis of Salla's disease was based on high levels of free sialic acid in amniotic fluid and fetal cells culture and by specific histologic features on fetopathologic examination. Diagnosis of inherited diseases is important because it implies a high risk of recurrence which makes mandatory genetic counseling and prenatal care in subsequent pregnancies. Title Osteopenia, abnormal dentition, hydrops fetalis and communicating hydrocephalus: unusual early clinical signs in Coffin-Lowry syndrome [letter; comment] Author Fryns JP Source Clin Genet, 50(2):112 1996 Aug Title Investigation of nonimmune hydrops fetalis: multidisciplinary studies are necessary for diagnosis--review of 94 cases. Author Lallemand AV; Doco-Fenzy M; Gaillard DA Address Laboratoire Pol Bouin, Department of Developmental Biology, CHU Reims, H^opital Maison Blanche, 45 Rue Cognacq-Jay, F-51100 Reims, France. Source Pediatr Dev Pathol, 2(5):432-9 1999 Sep-Oct Abstract This review of 94 cases of nonimmune hydrops fetalis (NIHF) over a 10-year period was undertaken to evaluate the frequency of this pathology among fetal and infant deaths and to determine the most common likely etiologies in a northeastern region of France. NIHF represented 6% of the fetal deaths examined in our laboratory. The combination of findings from morphologic examination of the placenta and fetus with the results of microbiological and cytogenetic investigations (conventional cytogenetic study, fluorescent in situ hybridization [FISH], or DNA ploidy image analysis) led to an etiologic diagnosis for NIHF in two-thirds of the cases and suggested a diagnosis in an additional 23% of cases. The most common causes of NIHF were chromosome abnormalities (33%), infections (16%), and cardiac pathology (13.8%). The detection of a cause for NIHF is important for genetic counseling and management of subsequent pregnancies. Our experience suggests that a diagnosis is possible in a large majority of NIHF when obstetricians and pathologists carefully coordinate the management of prenatal and postnatal investigations and when new techniques, such as molecular biology and DNA quantification, are used. Title Investigation of nonimmune hydrops fetalis: multidisciplinary studies are necessary for diagnosis--review of 94 cases. Author Lallemand AV; Doco-Fenzy M; Gaillard DA Address Laboratoire Pol Bouin, Department of Developmental Biology, CHU Reims, H^opital Maison Blanche, 45 Rue Cognacq-Jay, F-51100 Reims, France. Source Pediatr Dev Pathol, 2(5):432-9 1999 Sep-Oct Abstract This review of 94 cases of nonimmune hydrops fetalis (NIHF) over a 10-year period was undertaken to evaluate the frequency of this pathology among fetal and infant deaths and to determine the most common likely etiologies in a northeastern region of France. NIHF represented 6% of the fetal deaths examined in our laboratory. The combination of findings from morphologic examination of the placenta and fetus with the results of microbiological and cytogenetic investigations (conventional cytogenetic study, fluorescent in situ hybridization [FISH], or DNA ploidy image analysis) led to an etiologic diagnosis for NIHF in two-thirds of the cases and suggested a diagnosis in an additional 23% of cases. The most common causes of NIHF were chromosome abnormalities (33%), infections (16%), and cardiac pathology (13.8%). The detection of a cause for NIHF is important for genetic counseling and management of subsequent pregnancies. Our experience suggests that a diagnosis is possible in a large majority of NIHF when obstetricians and pathologists carefully coordinate the management of prenatal and postnatal investigations and when new techniques, such as molecular biology and DNA quantification, are used. An excellent case! Please let us know how it turns out! Jim Smeltzer James.Smeltzer@wellstar.org
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> Director, Fetal Diagnosis Programme
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