G6PD deficiency from lyonization after hematopoietic stem cell transplantation from female heterozygous donors

Au, Wing‐Yan; Pang, Annie; Lam, Kui-Chan; Song, You‐Qiang; Lee, W.-M.; So, Jacqueline; Kwong, Yok–Lam

doi:10.1038/sj.bmt.1705796

Cited by 7 publications

(6 citation statements)

References 14 publications

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“…Hence, we maintain our policy that G6PD deficiency should not be a consideration factor in selecting unrelated UBC for storage and donation. These observations are also in line with published results of HSCT from adult female donors heterozygous for G6PD deficiency, 6 where erythroid progenitors harboring the inactivated normal allele did not show any competitive engraftment disadvantage. In fact, stochastic skewing of X-chromosome inactivation might favor engraftment of HSC with the G6PD-deficient allele.…”

supporting

confidence: 82%

“…In fact, stochastic skewing of X-chromosome inactivation might favor engraftment of HSC with the G6PD-deficient allele. 6 Finally, up to 10% of Chinese female newborns may be heterozygous for G6PD deficiency, which is not detectable by cord blood screening. It remains to be seen whether imbalanced skewing of X-chromosome inactivation might lead to G6PD deficiency after UCBT from female donors heterozygous for G6PD deficiency.…”

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confidence: 99%

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Engraftment of umbilical cord blood with glucose 6-phosphate dehydrogenase deficiency after double-unit unrelated cord blood transplantation

Au¹,

Lie²,

Lam³

et al. 2009

Bone Marrow Transplant

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The success of unrelated donor (URD) umbilical cord blood transplantation (UCBT) expands the potential pool of URD for hematopoietic SCT (HSCT). UCBT requires less stringent HLA matching than do other forms of HSCT, which does not apparently increase the frequency of graft failure or GVHD. Engraftment is related to total cell count per unit body weight. For adult recipients, double-unit UCB transplantation may be required for long-term engraftment. 1 Despite the infusion of two units of UCB, one unit finally engrafts. 2 A 47-year-old man with AML in second CR underwent a URD double-unit UBCT, with standard BU and CY as conditioning, and MTX and CYA as GVHD prophylaxis. Infection prophylaxis included ganciclovir, caspofungin, pentamidine, and lamivudine and isoniazid for chronic hepatitis B virus infection and past tuberculosis, respectively. He engrafted hematologically on day 25 with grade III acute GVHD of the skin and liver, associated with hemorrhagic cystitis. These complications were controlled with corticosteroids and mycophenolate mofetil. Serial peripheral blood DNA chimerism was monitored by semiquantitative PCR for polymorphic microsatellite loci as reported earlier. 3 The results showed engraftment initially of both UCB units, but ultimately of one unit only (Table 1). As one UCB unit came from a known glucose-6-phosphate dehydrogenase (G6PD)-deficient donor, serial assays of G6PD were performed. The results showed a gradual decrease of G6PD to the deficiency level, consistent with the results of DNA chimerism. 3 Therefore, the G6PD-deficient UCB had engrafted successfully, as shown both by DNA chimerism and the surrogate marker G6PD level.The incidence of G6PD deficiency in southern Chinese men is 4.8%, and all newborns are screened. Adult G6PD donors are allowed in most unrelated donor registries. 4 However, cord blood banks in some countries exclude voluntary units with known G6PD deficiency. 5 As shown in this case, G6PD-deficient UCB units are not at a disadvantage during engraftment, in the absence of oxidative stress. Exclusion of G8PD-deficient UCB donors therefore does not appear to be justified. Hence, we maintain our policy that G6PD deficiency should not be a consideration factor in selecting unrelated UBC for storage and donation. These observations are also in line with published results of HSCT from adult female donors heterozygous for G6PD deficiency, 6 where erythroid progenitors harboring the inactivated normal allele did not show any competitive engraftment disadvantage. In fact, stochastic skewing of X-chromosome inactivation might favor engraftment of HSC with the G6PD-deficient allele. 6 Finally, up to 10% of Chinese female newborns may be heterozygous for G6PD deficiency, which is not detectable by cord blood screening. It remains to be seen whether imbalanced skewing of X-chromosome inactivation might lead to G6PD deficiency after UCBT from female donors heterozygous for G6PD deficiency.

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supporting

confidence: 82%

mentioning

confidence: 99%

Engraftment of umbilical cord blood with glucose 6-phosphate dehydrogenase deficiency after double-unit unrelated cord blood transplantation

Au¹,

Lie²,

Lam³

et al. 2009

Bone Marrow Transplant

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“…A different situation is found in some X-linked anemias, where the age-related skewing leads to the manifestation of the disease in elderly female carriers. [27][28][29] These selection processes in X-linked disorders do not explain why the frequency of the age-related skewed X inactivation has been shown to be higher in females 455-60 years of age in several cross-sectional studies. 2,3,5 Likewise, these processes do not explain why females with low DS have higher mortality compared to those with a more skewed pattern.…”

Section: Discussionmentioning

confidence: 99%

Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons

Mengel‐From

Thinggaard²,

Christiansen³

et al. 2011

Eur J Hum Genet

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In mammalian females, one of the two X chromosomes is inactivated in early embryonic life. Females are therefore mosaics for two cell populations, one with the maternal and one with the paternal X as the active X chromosome. A skewed X inactivation is a marked deviation from a 50:50 ratio. In populations of women past 55-60 years of age, an increased degree of skewing (DS) is found. Here the association between age-related skewing and mortality is analyzed in a 13-year follow-up study of 500 women from three cohorts (73-100 years of age at intake). Women with low DS had significantly higher mortality than the majority of women who had a more skewed DS (hazard ratio: 1.30; 95% CI: 1.04-1.64). The association between X inactivation and mortality was replicated in dizygotic twin pairs for which the co-twin with the lowest DS also had a statistically significant tendency to die first in the twin pairs with the highest intra-pair differences in DS (proportion: 0.71; 95% CI: 0.52-0.86). Both results suggest that lower DS is associated with higher mortality. We therefore propose that age-related skewing may be partly due to a population selection with lower mortality among those with higher DS. European Journal of Human Genetics (2012) 20, 361-364; doi:10.1038/ejhg.2011.215; published online 7 December 2011Keywords: aging; sex; mortality INTRODUCTIONThe biological phenomenon of X-chromosome inactivation is observed in females across a variety of mammalian species. Females have two X chromosomes, of which either the maternal or the paternal X is inactivated in early embryonic life, at about the time of implantation. 1 Females are therefore mosaics for two cell populations, one with the maternal and one with the paternal X as the active X chromosome. Early in life the two cell populations are normally distributed around a 50:50 ratio. 2,3 In some females, one of the two cell populations is more abundant than the other and the value of the larger proportion is called the degree of skewing (DS), with DSZ50. DS¼50 is therefore a complete random X inactivation and DS¼100 is a completely skewed X inactivation. X inactivation is believed to occur randomly for each cell and to be permanent for all descendants of the cell. For women younger than 55-60 years of age, DS does not increase significantly with age in populations 2,3 or within the same individual. 4 However, DS increases considerably with age in cross-sectional studies of populations older than 55-60 years and this age association continues to increase in populations at the most advanced ages. 2,3,5 Most X-inactivation studies have been performed on peripheral blood cells, but a higher frequency of skewed X inactivation in elderly women has also been found in buccal swab cells. 6,7 Most X-inactivation studies use an indirect assay targeted to a methylation site and polymorphic sequence named the HUMARA assay. The representativeness of this indirect method for studying X inactivation has been questioned. Recently, however, skewing of X inactivation in aging women was co...

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“…Additionally, when the HSC donor is a G6PD heterozygous female, the extent of G6PD deficiency in the recipient following engraftment can differ from that in the original donor, due to possible skewing of X‐inactivation at the time of engraftment. Therefore, some authors recommend repeat G6PD screening approximately 6 months after transplantation for recipients of HSCs from female donors .…”

Section: Transfusion Medicine and Cellular Therapymentioning

confidence: 99%

Glucose‐6‐phosphate dehydrogenase deficiency in transfusion medicine: the unknown risks

et al. 2013

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The hallmark of glucose-6-phosphate dehydrogenase (G6PD) deficiency is red blood cell (RBC) destruction in response to oxidative stress. Patients requiring RBC transfusions may simultaneously receive oxidative medications or have concurrent infections, both of which can induce hemolysis in G6PD-deficient RBCs. Although it is not routine practice to screen healthy blood donors for G6PD deficiency, case reports identified transfusion of G6PD-deficient RBCs as causing hemolysis and other adverse events. In addition, some patient populations may be more at risk for complications associated with transfusions of G6PD-deficient RBCs because they receive RBCs from donors who are more likely to have G6PD deficiency. This review discusses G6PD deficiency, its importance in transfusion medicine, changes in the RBC antioxidant system (of which G6PD is essential) during refrigerated storage, and mechanisms of hemolysis. In addition, as yet unanswered questions that could be addressed by translational and clinical studies are identified and discussed.

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G6PD deficiency from lyonization after hematopoietic stem cell transplantation from female heterozygous donors

Cited by 7 publications

References 14 publications

Engraftment of umbilical cord blood with glucose 6-phosphate dehydrogenase deficiency after double-unit unrelated cord blood transplantation

Engraftment of umbilical cord blood with glucose 6-phosphate dehydrogenase deficiency after double-unit unrelated cord blood transplantation

Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons

Glucose‐6‐phosphate dehydrogenase deficiency in transfusion medicine: the unknown risks

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