Bone marrow transplantation for T−B− severe combined immunodeficiency disease in Athabascan-speaking native Americans

Abstract

Summary:A distinct form of autosomal recessive T − B − severe combined immunodeficiency disease occurs with a high frequency among Athabascan-speaking Native Americans (SCIDA), including Navajo and Apache Indians from the southwestern US and Dene Indians from the Canadian Northwest Territories. The SCIDA gene has been linked to markers on chromosome 10p although its identity and role in the pathogenesis of this disease are unknown. We report our experience in treating 18 Navajo and Dene children with SCIDA between 1984 and 1999; 16 underwent bone marrow transplants (BMT). All children were symptomatic within 2 months of birth, had the T − B − NK + SCID phenotype and 67% presented with oral and/or genital ulcers. Three children had evidence of maternal engraftment prior to transplant. Two children died shortly after diagnosis. Three children required more than one BMT and 12 are alive with T cell reconstitution at a median followup of 7 years. Three children developed normal B cell immunity, two of whom received ablative conditioning therapy with either radiation or busulfan. Three of the four children who died received therapy with either radiation or busulfan and two of eight long-term survivors who were also recipients of cytotoxic chemotherapy have failed to develop secondary teeth. These results demonstrate the efficacy of BMT in treating infants with this distinct form of SCID, although B cell reconstitution remains a problem even with HLAmatched donors. Without conditioning, T cell engraftment is likely when closely HLA-matched donors are used. With T cell depletion of haplocompatible marrow, conditioning with immunosuppressive therapy may be necessary; however, children with SCIDA who were treated with intensive immunosuppressive and

Hematopoietic stem cell transplantation for primary immunodeficiency disease

“…11 Unlike other forms of BÀ SCID, patients with Artemis deficiency have undergone HSCT with an excellent OS of 75%. 11 A new type of radiosensitive T þ SCID Rare forms of SCID are characterized by the selective absence of CD4 þ T cells (for example, HLA class II deficiency) or CD8 þ T cells (for example, ZAP70 deficiency). Due to partial T-cell function, children with these diseases are often diagnosed later than other patients with SCID.…”

CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

“…1,14 But, LIG4 syndrome patients, particularly compared to ART-SCID, generally have a poorer outcome. 5,[9][10][11]13,14 Multiple factors could be responsible for this, especially the general health of the patients prior to conditioning. Nevertheless, since compounds that can form DSBs are used during NHSCT, we sought to determine whether LigIV À/À deficiency could adversely hypersensitize individuals to such treatments.…”

“…6 Because of the central role played by NHEJ in V(D)J recombination all of these disorders initially present with moderate-to-severe combined immunodeficiency necessitating clinical intervention often culminating in BMT. 9 But, anecdotal (unpublished data) and evidence from other studies suggest that LIG4 syndrome patients are particularly poorly following BMT (Table 1). Indeed, there is only one detailed report of a successful BMT in LIG4 syndrome using NHSCT with a modified conditioning regimen.…”

“…12 This is in marked contrast to that of ART-SCID where NHSCT has been used successfully in these patients even before the underlying causative genetic defect was identified. 9,13,14 The reason for the difference in response in these two patient groups that display similar levels of radiosensitivity is unclear. To date, there has not been a report of BMT in XLF/Cernunnosdependent SCID.…”

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

“…Alternative regimes which avoid the use of DSB inducing agents have been developed for such patients and found to be highly efficient [100]. The long term outcome for Artemis deficient patients to BMT appears less positive than for other SCID conditions, and such knowledge can enhance the treatment pre and post BMT [65,101] Thus, providing an RS-SCID diagnosis can allow the optimisation of conditioning regimes as well as post transplantation care. Further, there appears to be an elevated incidence of lymphoid leukaemias in some of the RS-SCID patients.…”