Re: Alpha Thalassemia
From: Terry J DuBose (tjdubose@juno.com)
Mon Jan 15 21:30:34 2001
Dr. Smeltzer, this is very interesting and exciting... what a wonderful
thing for you to be able to share your literature search with someone
with an on going case in Taiwan.
Now, you say the VMax is 74... I did not see the numbers in the abstract,
but do you know if that is the upper 95% confidence in the normal
population? I assume this is due to the reduced viscosity with anemia.
Thanks for this... good job.
Peace, Terry J DuBose, M.S., RDMS
Little Rock, ARkansas USA
On Mon, 15 Jan 2001 22:18:02 -0600 "James S. Smeltzer, MD"
<gaperina@mindspring.com> writes:
> 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)
> demonstrated that a normal beta-globin allele can act as a modifying
> gene
> ameliorating the severity of alpha-thalassemia. They found that the
> phenotype of alpha-thalassemia was strongly influenced by the genetic
> background in which the mutation resided; when both mutant genes
> were on a
> chromosome derived from strain 129, the phenotype was severe,
> whereas it was
> mild when the gene was on a 129 chromosome and a C57BL/6 chromosome.
> Linkage
> mapping indicated that the modifying gene is very tightly linked to
> the
> beta-globin locus (lod score = 13.3). Furthermore, the severity of
> the
> phenotype correlated with the size of beta-globin-containing
> inclusion
> bodies, which accumulate in red blood cells and likely accelerate
> their
> destruction. The beta-major globin chains encoded by the 2 strains
> differed
> by 3 amino acids, one of which is a glycine-to-cysteine substitution
> at
> position 13. The cys13 should be available for interchain disulfide
> bridging
> and consequent aggregation between excess beta chains. This normal
> polymorphic variation between murine beta-globin chains could
> account for
> the modifying action of the unlinked beta-globin locus. Here, the
> variation
> in severity of the phenotype would not depend on a change in the
> ratio
> between alpha and beta chains but on the chemical nature of the
> normal beta
> chain, which is in excess. This work also indicated that modifying
> genes can
> be normal variants that, absent an apparent physiologic rationale,
> may be
> difficult to identify on the basis of structure alone.
>
> 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
>
>> ----- Original Message -----
> From: "The-Hung Bui" <The-Hung.Bui@ks.se>
> To: "Multiple recipients of list ULTRASOUND"
> <ultrasound@mail.medispecialty.com>
> Sent: Monday, January 15, 2001 7:43 AM
> Subject: Re:
>
> > At 11:29 2001-01-13 -0600, you wrote:
> > >Dear netters,
> > >
> > >I saw a fetus last Friday. Second trimester SGA. The mother was
> sure
> about
> > >her
> > >LMP and the gestational age was confirmed ealier by a dating scan
> at
> another
> > >hospital. The gestational age was 21+ weeks, but the fetal size
> was
> > >equivalent
> > >to 18-weeks. The anatomical screening was normal, and no
> chromosomal
> markers
> > >were found except mild dolichocephaly. The placental morphology
> was
> normal.
> > >There was only a small and unilateral notch on the uterine artery
> Doppler
> > >waveform, with normal PI. Liquor volume was around 3rd
> percentile. No
> PPROM.
> > >
> > >Placental insufficiency?
> > >
> > >The mother had a previous IUFD around 28 weeks because of hydrops
> fetalis.
> > >The
> > >previous fetus was also growth retarded. An FBS before fetal death
> revealed
> > >severe fetal anemia. No infection or anomaly was identified. This
> is all
> the
> > >information I have for the previous pregnancy.
> > >
> > >Well, my friends. First, what will you do next? Second, what will
> you
> > >recommand
> > >to scan for fetal anemia?
> > >
> > >Tung-yao Chang, MD
> > >Dept. of obstetric and Gynecology,
> > >Mackay Memorial Hospital,
> > >Taipei, Taiwan.
> >
> > In addition to what has been already proposed (workup for IUGR
> including
> > fetal infection and karyotype), you should screen both parents for
> alpha
> > (in particular but also beta)-thalassemia (because some fetuses
> from Asia
> > may have both disorder) in view of previous obstetric history and
> patient
> > from Taiwan.
> >
> > *****************************************************************
> > The-Hung Bui, M.D.
> > Senior Consultant
> > Director, Fetal Diagnosis Programme
> > Department of Molecular Medicine
> > Clinical Genetics Unit
> > Karolinska Hospital
> > S-171 76 Stockholm, Sweden
> >
> > phone: +46 8 517 74989 or 517 72472 (secretary)
> > fax: +46 8 32 77 34
> > E-mail: The-Hung.Bui@ks.se
> > ******************************************************************
> >
>
