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Stella M. Davies The first successful studies of hematopoietic cell transplantation for the treatment of any disease were performed for the treatment of a genetic disorder, severe combined immunodeficiency.1 This transplantation established proof of principle that engraftment of hematopoietic stem cells was possible and could correct a genetic disorder. Children with immunodeficiencies were obvious subjects for these investigations because they have a limited capacity to reject a graft, and the early successes were a result of an emerging understanding of HLA typing. Use of hematopoietic cell transplantation therapy for indications other than immunodeficiencies has required the development of immunosuppressive and myeloablative therapies. These strategies have extended the applicability of hematopoietic cell transplantation to individuals with intact immune systems, and it has been shown that achievement of engraftment from related and unrelated HLAmatched donors is possible in that setting also. Currently, most hematopoietic cell transplantations are performed to treat hematologic malignancies. Over the last 20 years, however, there has been a growing body of literature describing the application of allogeneic transplantation to correct inborn errors of metabolism. In these disorders, a single gene defect leads to the absence of a key protein, which leads to the clinical phenotype of disease. Allogeneic hematopoietic cell transplantation provides a means of replacing the missing protein, potentially improving the clinical phenotype. The most significant experience has been in the treatment of mucopolysaccharidoses and leukodystrophies, although case reports have described transplantation therapy for many other genetic disorders. This chapter reviews the development and current status of hematopoietic cell transplantation for genetic immunodeficiencies, mucopolysaccharidoses, and leukodystrophies, discusses its use for less frequent disorders, and describes future directions for the field.

IMMUNODEFICIENCIES SEVERE COMBINED IMMUNODEFICIENCY Severe combined immunodeficiency (SCID) is a rare syndrome of profoundly impaired cellular and humoral immune system function.2 Although both X-linked recessive and autosomal recessive forms of SCID are recognized, the X-linked form is the most frequent. Patients with X-linked SCID typically have very low numbers of T cells and natural killer (NK) cells, whereas B cells are often found in relatively high numbers even though specific antibody responses are deficient. The true incidence of severe immunodeficiencies is not known; however, they are estimated to occur in approximately 1 of every 10,000 live births. Infants with SCID have lymphopenia, and recognition of this abnormality can lead to early diagnosis. The lymphocytes of these babies are functionally abnormal and fail to proliferate in vitro or on challenge with mitogens, antigens, or allogeneic cells. Typically, levels of immunoglobulin are low or undetectable, thymus-dependent areas of the spleen are devoid of lymphocytes, and usually lymph nodes and tonsils are absent. SCID

requires immediate treatment. Unless hematopoietic cell transplantation or, in a small number of cases, gene therapy succeeds, death occurs during infancy. Early reports of transplantation for the treatment of SCID involved the use of HLA-matched family member donor cells, and current data indicate excellent outcomes with this therapy. A review of hematopoietic cell transplantation therapy for immunodeficiencies at Duke University covering a period of more than 16.5 years demonstrated that all 12 recipients of HLAidentical donor grafts were surviving.3 The majority of patients with SCID do not have an HLA-match related donor available. Alternative approaches (e.g., T-cell-depleted HLA haploidentical parental hematopoietic cell transplantation, and the identification of unrelated donors from registries) have been used aggressively. The use of haploidentical grafts has the advantage of almost immediate availability, and availability for essentially all infants, since the mother or father of the child can be a donor. This strategy has the disadvantage of delayed, sometimes incomplete, immune system recovery as a consequence of the aggressive T-cell depletion that is needed to reduce the risk of graft-versus-host disease (GVHD). Buckley and colleagues3 reported outcomes in 77 infants with SCID receiving T-cell-depleted HLA-haploidentical parental grafts at Duke University. Sixty of the 77 patients (78%) were surviving 3 months to 16.5 years after transplantation. T-cell function became normal about 3 to 4 months after transplantation, and the majority of long-term survivors had normal T-cell function with all the T cells in the blood being of donor origin. B-cell function remained abnormal in many of the recipients of haploidentical marrow, and most of these patients continue to receive intravenous immunoglobulin as support. A large multicenter series of hematopoietic cell transplantation therapy for immunodeficiencies has been reported from Europe.4 This study included data from 37 centers in 18 countries that participated in a European registry for stem cell transplantation for SCID and other immunodeficiency disorders. The registry includes 1082 transplantations performed in 919 patients; 566 transplantations were performed in 475 SCID patients. One hundred four SCID patients receiving an HLA-identical related donor transplantation were included in this series, and the survival rate was 77%. Of note, the analysis showed that similarly positive outcomes could be achieved with unrelated donor cells, with a survival rate of 81% in recipients of genotypically identical related donor cells, 72% in phenotypically identical related donors, and 63% in phenotypically matched unrelated donors. Encouragingly, significant improvements in survival after HLA-identical and -nonidentical hematopoietic cell transplantations have occurred over time (Fig. 94-1). A Cox regression multivariate analysis of risk factors for mortality showed only the age at the time of transplantation and the use of trimethoprim-sulfamethoxazole prophylaxis as having a significant effect on survival after transplantation from a related HLA-identical donor. Younger age was associated with an improved prognosis, with survival of 85% at 3 years in patients who underwent transplantation at an age of less than 6 months. Survival for patients receiving an HLA-mismatched graft was 54%. SCID phenotype had an effect on survival after HLA-nonidentical

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Figure 94-1 Cumulative probability of survival in patients with severe combine immunodeficiency disease, according to donor source (related or unrelated) and HLA matching and year of transplantation. (From Antoine C, Muller S, Cant A, et al: Long-term survival and transplant of haemopoietic stem cells for immunodeficiencies: Report of the European experience, 1968-99. Lancet 361:553-560, 2003.)

stem cell transplantation. Patients with SCID without B cells had a poorer prognosis than patients with SCID with B cells, in accord with a previous report.5 In the HLA-nonidentical setting, the use of a myeloablative conditioning regimen had a positive effect on survival in patients with SCID without B cells but did not reach significance in other SCID groups. Independent predictors of increased mortality in SCID patients given a graft from a related HLAmismatched donor included the SCID without B cells phenotype, absence of a protected environment, and presence of pulmonary infection before transplantation. The study of Antoine and associates4 explored a center-size effect, segregating data from experienced centers (50 or more procedures). In the more experienced centers, the survival rate after HLAnonidentical transplantation was significantly better (57% versus 43%; P = .009). Moreover, the frequency of acute GVHD decreased over time after haploidentical transplantation, from 35% to 40% before 1996 to 22% thereafter (P < .009), perhaps because more effective methods of T-cell depletion are now used. This might contribute to the observed improvements in survival over time.

The use of umbilical cord blood for hematopoietic cell transplantation therapy for immunodeficiencies is currently being explored. Cord blood is an attractive stem cell source because the recipients are typically small; therefore, cell doses are likely to be adequate, and the product is immediately available. Knutsen and Wall6 reported the outcomes of umbilical cord blood transplantation in eight children with severe primary T-cell immunodeficiency disorders. Three patients had SCID, one had reticular dysgenesis, one had Nezelof syndrome, two had combined immunodeficiency, and one had Wiskott-Aldrich syndrome. In this series, the patients all received a preparative regimen of busulfan and cyclophosphamide, and all achieved complete donor chimerism, although one child needed a second transplantation after rejection of the initial graft. In this study, the early appearance of T-cell immunocompetence was observed, likely due to engraftment of memory T cells. In addition, there were normal proliferative responses to mitogens and alloantigens. The use of umbilical cord blood instead of the haploidentical stem cells approach has the advantage of more rapid and reliable reconstitution of immunosuppression. However, continuing follow-up of these patients will be necessary to evaluate long-term outcomes and to determine the optimal stem cell source for the treatment of patients with SCID. A number of studies have shown that the best outcomes in children with SCID are achieved with transplantation as early as possible. Kane and coworkers7 performed a retrospective review of patients with SCID who were referred and underwent transplantation in the neonatal period between 1987 and 1999 at a center in the United Kingdom. Thirteen patients received 18 hematopoietic cell transplantations. Stem cell sources included marrow (n = 4), umbilical cord blood (n = 1), parental T-cell-depleted haploidentical marrow (n = 10), and T-cell-depleted unrelated-donor marrow (n = 3). Patients were conditioned with busulfan and cyclophosphamide. All of the patients are surviving 6 months to 11.5 years after transplantation. Of note, five patients required additional hematopoietic cell infusions to achieve adequate and stable immune system recovery. Multiple hematopoietic cell infusions are not infrequent in transplantation therapy for SCID, particularly if grafts are given without a preparative regimen. Myers and associates8 also addressed the value of early transplantation in a report describing a subset of the Duke University experience reported by Buckley. This study compared immune system function in 21 SCID infants receiving transplantations in the neonatal period with that in 70 SCID infants receiving transplantations at an older age. Lymphocyte phenotypes, response to mitogens, immunoglobulin levels, and T-cell receptor circles were evaluated before transplantation and sequentially thereafter. Of the 21 SCID patients who underwent transplantation in the neonatal period, 95% were surviving. The infants who underwent transplantation in the neonatal period developed higher lymphocyte responses to phytohemagglutinin and higher numbers of CD3+ and CD45RA+ T cells in the first 3 years of life than those who received transplantations later. T-cell receptor circles peaked earlier and with higher values in the neonatal transplants than in the later transplants. These authors proposed that improved outcomes for SCID could be achieved with universal newborn screening for lymphopenia, so that children with SCID would be diagnosed early and transplantation could be performed under the most favorable circumstances. A logical extension of the reports describing an improved outcome with younger age at the time of transplantation has been the investigation of in utero transplantation for the treatment of SCID. Flake and colleagues9 reported the successful treatment of a fetus with X-linked SCID by in utero transplantation of paternal marrow cells enriched with hematopoietic cell progenitors by CD34+ cell selection. Three transabdominal injections of hematopoietic stem cells were given to the fetus in utero. At birth, the patient had no evidence of GVHD, and hematologic and immune system function appeared normal. Notwithstanding the success of this case, the clinical experience with in utero hematopoietic stem cell transplan-

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WISKOTT-ALDRICH SYNDROME Wiskott-Aldrich syndrome is a lethal hematologic disease primarily affecting the function of platelets and lymphocytes. It is an X-linked condition resulting from mutations in the WAS (also called WASP) gene at 11p11.22.16 Wiskott-Aldrich syndrome has a worldwide distribution with an estimated incidence of 4 per 1 million live male births. Although this is a single gene defect, variability in severity of the clinical syndrome within families and between unrelated individuals with identical mutations in the WAS gene suggest that prognosis for a given patient may be influenced by genetic background or environmental factors. Quantitative analysis of WAS production in lymphoid cells may predict clinical severity.17 The current mainstays of supportive care for Wiskott-Aldrich syndrome are splenectomy and intravenous immunoglobulin infusion.18,19 With these treatments, Wiskott-Aldrich syndrome patients remain at high risk of overwhelming sepsis due to an inherent deficiency of antibody production to polysaccharide antigens in combination with splenectomy. In addition, boys who do not achieve safe platelet counts are restricted in their activities. Immune system com-

plications of Wiskott-Aldrich syndrome are commonly managed by long-term corticosteroid therapy or, in extreme cases, by palliative organ transplantation for end-stage renal failure or liver disease.20,21 Development of lymphoma, usually in the second decade of life, is associated with poor outcomes. Two large registry series have described the outcome of hematopoietic cell transplantation for Wiskott-Aldrich syndrome patients. Filipovich and colleagues22 analyzed the combined outcomes reported to the IBMTR and the National Marrow Donor Program (NMDP). This study included 170 hematopoietic cell transplantations for Wiskott-Aldrich syndrome patients performed between 1968 and 1996. Fifty-five were from HLA-identical sibling donors, 48 from other relatives, and 67 from unrelated donors. The 5-year probability of survival for all subjects was 70%. Probabilities differed by donor type: 87% of recipients of HLA-identical sibling donor grafts survived as compared with 52% of recipients of other related donor grafts. Seventy-one percent of those receiving unrelated donor transplantations survived. Multivariate analysis indicated that boys older than 5 years had significantly lower survival rates when receiving transplants from related donors other than HLAidentical donors or from unrelated donors, compared with transplantations from HLA-identical sibling donors. Boys receiving an unrelated-donor transplantation before the age of 5 years had survival rates similar to those receiving HLA-identical transplantations (Fig. 94-2). Detailed data regarding chimerism and immune system reconstitution were not available in this multicenter registry series. Other studies have indicated that early mixed chimerism in WiskottAldrich syndrome patients is often stable because of a survival advantage for stem cells and hematopoietic precursors bearing the normal WAS gene.23 European registry data indicate similarly good results with genotypically identical transplantations.4 This study included 32 WiskottAldrich syndrome patients receiving a genotypically identical graft, and 81% were surviving. Survival was inferior for recipients of HLAmismatched related grafts, with 45% surviving (n = 43). Although data for Wiskott-Aldrich syndrome cases were not shown separately, for the non-SCID immunodeficiency patients, there was no difference in survival between recipients of genotypically HLA-identical and HLA-matched unrelated-donor transplantations. In this study, 75% of patients with unrelated donors were considered “HLAidentical” to their donors. The level of HLA typing, and the loci included to determine the level of match in the unrelated donor population are not stated in this report. Taken together, these data suggest that early hematopoietic cell transplantation using genotypically or phenotypically matched donor-recipient pairs is an excellent therapy for boys with WiskottAldrich syndrome. Transplantation before the age of 5 years is associated with the best outcome. These data should encourage earlier referral of suitable candidates for transplantation.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune system disorder characterized by fever, massive hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and central nervous system disease, commonly manifested as seizures.24 Historically, HLH has been categorized as primary or secondary. The primary form, also known as familial erythrophagocytic lymphohistiocytosis, typically has a symptomatic presentation at infancy, and inheritance is usually autosomal recessive. Secondary HLH is usually associated with Epstein-Barr virus infections and may manifest at an older age. The genetic basis for HLH has been established in a subset of patients, with approximately 25% of US patients showing a mutation in the perforin gene.25 Perforin is a protein that is expressed in the cytoplasmic granules of cytotoxic T cells and NK cells. Perforin may be principally responsible for the translocation of granzyme B from cytotoxic cells

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tation has been otherwise disappointing, and in most cases engraftment was not achieved. Touraine and colleagues10,11 also reported the treatment of one patient with bare lymphocyte syndrome and another patient with SCID by in utero transplantation of hematopoietic cells from fetal liver. Multiple prenatal and postnatal fetal liver transplantations were performed, and the evidence of engraftment in these two patients was limited. It was unclear that benefit was gained from the in utero component of the therapy. Additional work in this field will be needed for in utero transplantation to become an accepted therapy. The need for a preparative regimen prior to transplantation therapy for SCID is variable. Many patients with little residual NK cell or lymphocyte function will achieve engraftment without a preparative regimen. Avoiding the use of a preparative regimen significantly reduces the late effects of transplantation. No clinical test can categorically predict graft rejection. A common approach is to attempt engraftment in the absence of a preparative regimen, but to resort to hematopoietic cell infusion with a preparative regimen if engraftment fails. The greater the degree of HLA-mismatch between donor and recipient, the more difficulty there is likely to be in achieving engraftment and the greater the likelihood of need for a preparative regimen. An alternative to a full preparative regimen, suitable for children with significant organ dysfunction, is the use of a nonmyeloablative regimen. Amrolia and associates12 reported eight patients with severe immunodeficiency undergoing hematopoietic cell transplantation from HLA-matched unrelated (n = 6) or sibling (n = 2) donors. A nonmyeloablative preparative regimen was used that included fludarabine, melphalan, and antilymphocyte globulin. The patients all had severe organ deficiency that precluded transplantation with conventional conditioning. All patients had successful engraftment with predominantly donor chimerism, and the duration of neutropenia was brief. Significant acute GVHD did not develop, but one patient had limited chronic GVHD. One patient died of disease recurrence and three survived with stable mixed chimerism. All patients had good recovery of CD3+ T-cell numbers, and six of seven evaluable patients have normal phytohemagglutinin indices 1 year after transplantation. The rate of immune system reconstitution appears comparable to that of historical control subjects undergoing myeloablative protocols. This approach may provide an attractive option in the future. Transplantation with no conditioning regimen has been used widely since late adverse effects are reduced. However, this approach may result in graft failure, and the time course of T-cell reconstitution may be prolonged or limited in some patients.13,14 The use of a conditioning regimen appears to improve cell recovery in particular SCID phenotypes.15

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Figure 94-2 Probabilities of survival by donor type and recipient age for 170 patients receiving hematopoietic cell transplantations for the treatment of Wiskott-Aldrich syndrome. There was no significant difference in the risk of mortality after HLA-matched sibling-donor transplantations and after unrelated-donor transplantations in children younger than 5 years. A significantly worse rate of survival was associated with the use of related donors other than HLA-identical siblings, regardless of recipient age, and with use of unrelated donors in patients older than 5 years of age. (From Filipovich AH, Stone JV, Tomany SC, et al: Impact of donor type on outcome of bone marrow transplant for Wiskott-Aldrich syndrome: Collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood 97:1598-1603, 2001.)

into target cells. Granzyme B can then migrate to the target cell nucleus and participate in triggering of apoptosis.26 The clinical features of HLH are due to widespread infiltration of the liver, spleen, marrow, and central nervous system with active lymphocytes and macrophages. The expansion of these cells represents a failure of regulation of the immune system response, in particular by NK cells. Flow cytometric analysis of perforin expression has been used to identify cases with perforin mutations.27 Characteristic but different abnormalities in patients with HLH associated with Epstein-Barr virus were also described in the same paper. The 5-year survival rate was 10.1% in an analysis of 122 HLH patients treated with chemotherapy alone.28 This registry report, however, describes a 66% 5-year survival rate for allogeneic hematopoietic cell transplantation recipients. The majority of these patients received transplants from HLA-matched sibling donors. The use of matched sibling donor marrow cells for transplantation raises the concern that the sibling donor might also have HLH. Differences in the age of onset of at least 3 years between siblings have been described. Patients as old as 17 years have presented with familial disease. Potential donors from affected families should be studied carefully for evidence of latent HLH. If similar outcomes can be achieved with unrelated donor hematopoietic cell transplantation, this might be a more attractive option. A survival rate of 44% was reported in HLH patients treated at two institutions receiving unrelated-donor hematopoietic cell transplantation (n = 16).29 This report also noted that survival was poor in patients not in clinical remission at time of transplantation, with only one of six patients surviving. These data emphasize the need to make the best possible attempt to achieve a remission prior to transplantation. A recent report of the treatment of HLH with a uniform chemotherapy and transplantation protocol (HLH 94) also supports the value of hematopoietic cell transplantation for patients with HLH.30 In 1994, the Histiocyte Society initiated a prospective international collaborative therapeutic study aimed at improving survival. One hundred thirteen patients younger than 15 years of age with persistent, recurring, or familial disease received a preparative regimen consisting of chemotherapy plus immunotherapy (etoposide, corticosteroids, cyclosporine), and, in selected patients, intrathecal methotrexate followed by hematopoietic cell transplantation. All patients either had an affected sibling or fulfilled the Histiocyte Society diagnostic criteria. At a median follow-up of 3.1 years, the estimated 3-year probability of survival was 55%, and in familial cases it was 51%. The 3-year probability of survival in those patients who underwent transplantation was 62%. This study indicated that survival in HLH patients had improved significantly and established the value of hematopoietic cell transplantation using related or unrelated donor stem cell sources as an important part of treatment.

MUCOPOLYSACCHARIDOSES MPS I (HURLER SYNDROME) The mucopolysaccharidoses (MPS) are a group of recessively inherited lysosomal storage diseases characterized by specific enzyme deficiencies, tissue accumulation of glycosaminoglycans leading to musculoskeletal deformities, organ involvement, and mental retardation of varying severity.31 Experience with hematopoietic cell transplantation therapy is greatest in cases of Hurler syndrome (MPS I), the prototypical MPS disease. MPS I is an autosomal recessive disorder caused by deficiency of lysosomal a-L-iduronidase. Affected children appear normal at birth but subsequently develop coarse facial features, hepatosplenomegaly, short stature, persistent rhinitis, corneal clouding, claw hands, coronary artery stenosis, hydrocephalus, progressive mental retardation, and a variety of welldefined musculoskeletal abnormalities known as dysostosis multiplex. Untreated patients will have progressive mental retardation with development of severe kyphosis. Such patients typically will die of cardiopulmonary insufficiency and/or complications of hydrocephalus. A 9-month-old boy was the first child treated with hematopoietic cell transplantation for MPS I in 1980.32 This patients is surviving 20 years later, fully engrafted with cells from his mother’s marrow, and has stable intelligence in the low normal range.33 This initial favorable experience has encouraged further investigation of transplantation therapy for MPS I. In the largest series reported to date, Peters and associates34 reported outcomes of hematopoietic cell transplantation for MPS I in 54 children using data collected by the Storage Disease Collaborative Study Group. The patients in this study had a median age of 1.8 years at the time of transplantation, with a range of 0.4 to 7.9 years. Transplantations were performed between 1983 and 1995. Thirty-nine of the 54 patients (72%) had engraftment after the first hematopoietic cell transplantation. This is a much lower frequency of engraftment than would be expected and indicates that patients with MPS 1 have particular difficulty with stem cell homing or adhesion. The actuarial probability of 5-year survival was 75% for recipients of genoidentical grafts and 53% for recipients of related HLA-mismatched donor grafts. Survival for all patients who achieved engraftment was 53%. This large study provided the opportunity for the authors to examine cognitive outcomes. Baseline and post-hematopoietic cell transplantation neuropsychological data were available for 26 of 30 engrafted survivors. Of 14 patients who underwent transplantation before 24 months of age, 9 demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, only 3 of 12 patients who underwent transplantation after 24 months of age

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progress. Typically, multiple surgeries are required in the first decade after transplantation.37,38 The management of children with MPS during transplantation can be complex. Cardiac involvement due to deposition of glycosaminoglycan in coronary arteries causing stenosis can lead to sudden death during anesthesia or cardiac failure secondary to cardiomyopathy.39,40 These manifestations improve significantly after engraftment is achieved. However, as the children grow, deposition of glycosaminoglycan in the poorly vascularized cardiac valves continues, despite the presence of donor enzyme. Some long-term transplantation survivors have required cardiac valve replacement. Patients with MPS commonly have deposition of glycosaminoglycan in the upper airway and can be particularly difficult to intubate.40,41 Belani and colleagues40 described 141 episodes of anesthesia in children with MPS. In children with MPS I, the incidence of odontoid dysplasia was 94%, and 38% demonstrated anterior C1-C2 subluxation, illustrating the need for great care during anesthesia. Intubation was noted to be more difficult, with the vocal cords frequently not visible, and there was a high frequency of airway obstruction after extubation. Two children required reintubation to support their airway. In this series, two inoperative deaths occurred secondary to severe and extensive coronary obstruction, and it was noted that cardiac catheterization may underestimate the degree of coronary stenosis. The ocular abnormalities associated with MPS may also progress after successful transplantation, and careful efforts to optimize vision with surgery or refraction are important to optimizing developmental progress.42 Life-long observation of all aspects of the child’s growth and development are essential to achieve the highest possible level of function, and significant improvements can be achieved with frequent and aggressive speech, physical, and occupational therapy.

MPS VI (MAROTEAUX LAMY SYNDROME) MPS-VI (Maroteaux-Lamy syndrome) is characterized by the defective degradation of dermatan sulfate due to the deficiency of N-acetyl galactosamine-IV-sulfatase.43 The clinical severity of MPS VI is highly variable, with a continuum from mildly affected to severely affected patients.44 Affected individuals typically have bony dysplasia hepatosplenomegaly, airway narrowing, deposition of dermatan sulfate on cardiac valves, and deposition of subcutaneous tissues leading to restriction in movement. MPS VI patients typically have a normal intellect, although cognitive deterioration, perhaps in association with hydrocephalus, can occur later in life. Patients usually die in their teens or early adult life, often of cardiopulmonary failure. Owing to the rarity of this disease and the variable phenotype, experience of transplantation in cases of MPS VI is limited. The first human hematopoietic cell transplantation for MPS VI was reported in 1984, when Krivit and colleagues45 described the outcome of sibling donor transplantation in a 13-yearold girl with a severe form of MPS VI. This patient had severe life-threatening upper airway obstruction leading to obstructive sleep apnea. A subsequent report of her clinical status 40 months later described resolution of the sleep apnea, improvement in hepatosplenomegaly, and improvement in range of motion due to resolution of the soft tissue changes.46 Of note, there was no radiographic improvement in the bone pathology and no increase in height. The patient had severe corneal clouding and this did not resolve, requiring corneal transplantation. Subsequent case reports have supported the observation that portions of the MPS VI phenotype will be improved by transplantation. Herskhovitz and colleagues47 described four patients who underwent transplantation for MPS VI with follow-up periods ranging between 1 and 9 years. The indications for transplantation were cardiomyopathy in three patients and severe obstructive sleep apnea in one. In all engrafted patients, facial features have become less coarse. Cardiac manifestations improved or remained stable, and three of the four patients

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showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with baseline Mental Developmental Indices (MDI) greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte a-L-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they received transplants from a donor with homozygous normal leukocyte a-Liduronidase enzyme activity, compared with a heterozygous carrier of MPS I. These data indicate the importance of early transplantation in children with MPS I (typically before 2 years of age) to optimize cognitive outcome. A companion paper to this series described the outcome of 40 children with MPS I receiving unrelated-donor hematopoietic cell transplantations.35 The children in this report were a median 1.7 years old (range, 0.9 to 3.2 years) and underwent transplantation between 1989 and 1994. Only 25 of the 40 patients achieved donor cell engraftment, again emphasizing the difficulty in engraftment in this patient population. An estimated 49% percent of patients were alive at 2 years. Sixty-three percent had evidence of allogeneic donor engraftment, and 37% had recovery of autologous hematopoiesis. When graft failure occurs in this population, autologous recovery of hematopoiesis is usual, rather than aplasia. Hematopoietic cell dose correlated with both donor engraftment and superior survival. Neither T-cell depletion of the marrow inoculum nor irradiation as part of the conditioning regimen influenced the incidence of engraftment, although the power of the study to identify an effect was modest. MDI were assessed before and after transplantation in 11 engrafted survivors in this study. Eight children had a baseline MDI of greater than 70 at the time of transplantation. Of these cases, six patients have shown stability in the age equivalence scores, and in two it was too early to evaluate. Four of the children were acquiring skills at a pace equal to or slightly below age peers and two children had shown either a plateau in their learning or extreme slowing in their learning process. Post-transplantation evaluation of engrafted children with baseline MDI less than 70 (typically older children) indicated that two children had shown deterioration in their developmental skills, and the remaining three children maintained their skills and were adding to them at a variable rate. The authors conclude from this study that MPS I patients with baseline MDI greater than 70 who achieve engraftment will have favorable long-term outcomes, with cognitive function close to or within the normal range. Again, these data emphasize the need for early transplantation in MPS I patients before there has been significant loss of cognitive function. The low frequencies of engraftment described in these studies are a common feature of transplantation for MPS I cases. A proportion of children who fail to engraft can be rescued with a second allogeneic transplantation. Grewal and coworkers36 described outcomes in 11 MPS I patients receiving a second transplantation after initial graft failure. The median age at second transplantation was 25 months (range, 16-45 months), and the median time from the first transplantation was 8 months (range, 4-18.5 months). The conditioning regimen consisted of cyclophosphamide and total body irradiation, with or without antithymocyte globulin. The source of hematopoietic cells was an unrelated donor in six cases, an HLA-matched sibling in four cases, and an HLA-mismatched related donor in one case. Five of the 11 grafts were T-cell depleted prior to infusion. Actuarial survival was 50% over 4 years. All surviving patients show sustained donor engraftment with normalization of a-L-iduronidase levels. Neuropsychological function stabilized after the second transplantation in three of five evaluable patients. Long-term follow-up after transplantation for MPS I shows that while donor cell engraftment can stabilize neurocognitive decline, continuing complications secondary to accumulation of glycosaminoglycans occur as the children mature. In particular, orthopedic abnormalities, including acetabular dysplasia, kyphoscoliosis, carpal tunnel syndrome, trigger finger, and genu valgum, tend to

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were being educated in mainstream schools. However, skeletal changes persisted or even progressed, although posture and joint stability improved and all the patients remained ambulatory and active. These data support the role of transplantation therapy in prolonging survival and improving the quality of life in MPS VI patients. However, careful selection of patients whose condition is likely to be improved by transplantation is necessary.

MPS II (HUNTER SYNDROME) MPS II is an X-linked disorder caused by deficiency of iduronate sulfatase enzyme activity.44 MPS II has a wide range of clinical severity, from the early-onset severe form (MPS IIA) to the milder later onset form (MPS IIB). Boys with MPS IIA exhibit significant somatic features such as coarse facial features, progressive hearing loss, hepatosplenomegaly, cardiomyopathy, dysostosis multiplex, macrocephaly, central nervous system deterioration, and neuropsychological impairments. As in cases of MPS I, changes reflect deposition of storage material. Neuropsychological consequences of MPS IIA are similar to those of MPS I except that behavioral abnormalities may be more marked. In general, male subjects with MPS IIB experience milder signs and symptoms with great variability in age of onset and severity, with survival as long as 40 years reported. The variable phenotype and life expectancy of patients with MPS II make the decision to submit a patient to the risks of transplantation very difficult. In addition, there are some reported cases of children who underwent transplantation for MPS II and who have suffered continuing neurologic deterioration despite achievement of adequate engraftment.48,49 Vellodi and coworkers49 described a series of 10 patients who underwent transplantation as treatment for Hunter’s syndrome. The donor was an HLA-identical sibling in two cases, an HLA-nonidentical relative in six cases, a volunteer unrelated donor in one case, and unknown in one case. Only 3 of the 10 patients survived more than 7 years post-transplantation. In two of these cases, there was a steady progression of a physical disability and mental handicap, although one patient maintained normal intellectual development with only mild physical disability. These authors and others have suggested there may be a role for transplantation in carefully selected boys with Hunter’s syndrome.50-53 This remains a controversial issue, and if such transplantations are undertaken, careful attention should be paid to the process of informed consent and to long-term follow-up to document the benefits achieved.54-57

MPS VII (SLY SYNDROME) MPS VII is an autosomal recessive disorder caused by an inherited defect in the lysosomal hydrolase b-glucuronidase. The enzyme defect causes accumulation of undegraded glycosaminoglycans. Approximately 40 cases of MPS VII have been reported worldwide, and there is considerable experience in transplantation of mouse models in this disease.58-60 Animal models have also been used in an investigation of brain-directed gene therapy with encouraging preliminary results.61 One detailed case report of transplantation in a 12-year-old girl with Sly syndrome has been published.62 This child had significant improvement in mobility and in apnea associated with upper airway obstruction after engraftment. Of note, the patient’s mental retardation was not reversed by transplantation, in agreement with the findings in animal models.63

LEUKODYSTROPHIES ADRENOLEUKODYSTROPHY X-linked adrenoleukodystrophy (ALD) is a demyelinating disorder of the central nervous system with highly variable clinical

presentation.64-67 The gene responsible for ALD encodes for a paroxysmal membrane protein, ALDP, which is a member of the ABC (ATP binding cassette) transporter superfamily.68 Individuals with ALD are deficient in lignoceroyl-CoA ligase, an enzyme needed for the degradation of very long chain fatty acids (VLCFA) and elevated VLCFA levels in blood, particularly C24 and C26, are useful in the diagnosis of ALD. Approximately half the individuals with a mutation in this gene will have the rapidly progressive childhood cerebral form of the disease that is associated with an inflammatory response in the brain. Boys with childhood onset cerebral adrenoleukodystrophy (COCALD) commonly experience rapid neurologic deterioration progressing to death 2 to 3 years after diagnosis, although a minority will survive for a prolonged period in a semivegetative state. Within the same kindred, however, 25% or more of individuals will have a milder form of the disease called adrenomyeloneuropathy (AMN). AMN progresses slowly, involves the spinal cord, and shows little or no inflammatory response. AMN is compatible with a near-normal life span. In addition, within the same kindred, individuals can be found who are carriers of a gene mutation who are asymptomatic or have Addison’s disease in isolation.64 The phenotypic variability of ALD and the discordance of severity within families makes the decision to offer a therapy that is associated with significant morbidity and mortality, such as hematopoietic cell transplantation, a difficult one.65 In addition, in symptomatic boys with COCALD, the rapid, often stepwise progression of the disease and the deterioration that can occur after transplantation may lead to severe disability even in children who are successfully engrafted. Identifying the benefits that can be achieved with hematopoietic cell transplantation for COCALD and identifying the optimal patients to treat with transplantation remains a challenge. It is desirable to identify boys destined to manifest COCALD at the earliest stage of their disease and offer transplantation. It is not desirable to offer transplantation to those destined to have AMN or isolated Addison’s disease. Data suggest that neuropsychological testing may predict early progression of a symptomatic case of COCALD.69 In addition, monitoring progression of lesions detected by magnetic resonance imaging, with scoring according to the Loes scale, may assist in patient selection.70 Although no large studies of hematopoietic cell transplantation for the treatment of ALD are reported, a recent study described the neurologic outcomes in 12 patients with COCALD who were followed for 5 to 10 years after transplantation.71 The findings indicated variable levels of improvement. Magnetic resonance imaging showed complete reversal of abnormalities in two patients and improvements in one. All patients who showed continued radiologic demyelination after transplantation were stabilized and remained unchanged thereafter. Motor function remained normal or was improved after transplantation in 10 patients, verbal intelligence remained within the normal range for 11 patients, and performance abilities were improved or were stable in 7. The authors concluded that hematopoietic cell transplantation had long-term beneficial effects when the procedure is done at an early stage of the disease. Identifying boys known to have ALD on the basis of elevated VLCFA levels at the start of the decline that will lead to symptomatic COCALD is an important goal in the continuing investigation of transplantation for ALD. Early diagnosis of ALD is commonly not possible for the first affected child in a family. Boys commonly present with behavioral difficulties and a decline in school performance that is mistaken for attention deficit disorder, and diagnosis is commonly delayed until gait abnormalities appear. Immunosuppressive approaches are currently being explored in boys with neurologic disease too far advanced to allow successful transplantation. Future transplantation series should continue careful monitoring of short- and long-term complications to ensure that the therapy gives maximum benefit and least harm.

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METACHROMATIC LEUKODYSTROPHY

GLOBOID CELL LEUKODYSTROPHY Globoid-cell leukodystrophy (GLD) is an autosomal recessive disease caused by diminished or absent activity of the lysosomal enzyme glucocerebrosidase.88 Globoid-cell leukodystrophy is characterized by progressive loss of central and peripheral myelin and by spasticity, dementia, and peripheral neuropathy.72 Globoid-cell leukodystrophy typically ends in progression to a chronic vegetative state and premature death. The most frequent form of GLD has its onset in early infancy and is rapidly progressive, typically leading to death within 2 years. The late-onset form begins in later childhood has a more insidious onset and progresses over several years to death. Data describing the outcome of transplantation therapy for GLD patients are sparse. Krivit and coworkers89 described five children with GLD treated with allogeneic hematopoietic cell transplantation. Four of the patients received marrow from an HLA-identical sibling and one was treated with unrelated umbilical cord blood with one HLA DR mismatch. Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by a return to normal glucocerebrosidase levels. In the four patients with later onset disease, the central nervous system deterioration was halted

and in the patient with the infantile form of the disease, diagnosed biochemically prior to development of symptoms, signs and symptoms of neurologic deterioration had not appeared by the time of reporting. Of note, some of the patients in this series achieved significant reversal of symptoms of GLD. This observation contrasts with the findings of most transplantation studies of metabolic disease in which halting of deterioration is achieved but few if any patients show gain in function. Transplantation in children with the rapidly progressive infantile form of GLD is controversial.90,91 Early transplantation reports described difficulty in achieving engraftment and early death from GVHD without reversal of symptomatic disease. Prompt transplantation in the immediate postnatal period or even in utero offers the possibility of reversal or control of disease. However, such investigations should be performed within the context of a carefully monitored clinical investigation because the long-term benefits are currently unknown.

OTHER DISEASES Additional case reports have described the role of hematopoietic cell transplantation in the treatment of patients with a range metabolic disorders, and successful outcomes of transplantation have been reported for patients with diseases such as alpha-mannosidosis, Wolman disease, and Niemann-Pick type 1A disease.57,75,92-95 In light of the small number of cases reported for these diseases, it is difficult to make firm recommendations about therapy. In addition, positive outcomes are more likely to be reported than negative outcomes. There is a continuing role for registries such as the IBMTR and disease-specific registries for reporting the outcomes of consecutive series of cases.

FUTURE DIRECTIONS Partial correction of clinical phenotype, as seen, for example, in patients with MPS I, is a significant limitation to the success of hematopoietic cell transplantation as therapy for metabolic diseases. Transplantation fails to deliver adequate levels of enzyme to areas of the body that are poorly vascularized, such as cardiac valves, bone, and cartilage. A potential strategy to address this problem is the use of mesenchymal as well as hematopoietic stem cells. Mesenchymal stem cells are cells with the potential to differentiate into mesodermal cells, such as cartilage and bone. Previous data have shown that after a hematopoietic cell transplantation, the stromal cells of the marrow remain of host origin.92,93 The addition of mesenchymal stem cells cultivated ex vivo might achieve donor cell engraftment, improve delivery of enzyme to bone and cartilage, and improve disease course. Additionally, animal models suggest that coinfusion of mesenchymal stem cells can facilitate engraftment of allogeneic cells and reduce GVHD.94,95 Although these studies are in their early stages, it has been shown that it is possible to grow mesenchymal stem cells ex vivo and infuse them without toxicity. Krivit and associates92 infused mesenchymal stem cells into children with MLD who had previously successfully undergone transplantation. In these children, peripheral neuropathy had progressed despite successful halting of the central nervous system disease by hematopoietic cell transplantation. Preliminary data indicate improvement in nerve conduction times after infusion of mesenchymal stem cells grown from the original hematopoietic cell donor. There will likely be significant continuing efforts in this area, using genetically modified and unmodified mesenchymal stem cells to attempt to optimize correction of the phenotype. An additional limitation of transplantation as therapy for metabolic disorders is, in general, the inability to reverse central nervous system damage that occurred before transplantation. A potential and

Transplantation

Metachromatic leukodystrophy (MLD) is an autosomal recessive inherited disorder caused by a deficiency of arylsulfatase A activity, which leads to accumulation of galactosyl sulfatide. The clinical symptoms vary depending on the patient’s age at onset of the disease.72 MLD can be classified clinically as infantile (onset at 6 months to 2 years), early juvenile (onset at 4 to 6 years), late juvenile (onset at 6 to 16 years), and adult (onset at more than 16 years of age). The juvenile or early onset presentations are characterized by progressive mental regression, loss of speech, quadriplegias, peripheral neuropathy, and death within a few years of onset. The adult onset forms are more typically associated with psychiatric symptoms, particularly in the early stages of the disease.73 Presentation commonly includes a change in personality, poor school or job performance, emotional instability, disorganized thinking, and impairment of memory. Diagnoses of hypomania, depression, or psychosis are common until additional clinical signs prompt magnetic resonance imaging examination that will show diagnostic white matter changes.74 Late-onset MLD can also manifest as polyneuropathy, because a progressive peripheral neuropathy is an important part of this disorder. In 1985, Bayever and associates75 reported transplantation for late infantile MLD using an HLA-identical sibling donor. In the 33 months after the procedure, there seemed to have been a halt in the progression of the patient’s neurologic deterioration. In 1990, Krivit and associates76 reported a second case of late infantile MLD with transplantation from a matched sibling donor. In this case, there also appeared to be a delay of progression of neurologic deterioration. Subsequent case reports support the belief that transplantation can retard the progression of disease.77-87 However, the peripheral neuropathy associated with MLD appears likely to progress even in the presence of full donor engraftment. Experience with transplantation in cases of adult-onset MLD remains limited. Case reports of this disorder also suggest a halting of neurologic deterioration, although there is no evidence of any gain in function after successful engraftment. Investigators are currently studying the role of umbilical cord blood transplantation for the treatment of the early-onset rapidly progressive infantile MLD. Identification and procurement of suitable donor cells can proceed more quickly with an umbilical cord blood source than with an adult volunteer unrelated donor. The umbilical cord blood approach remains an investigational procedure, because follow-up is too short to assess benefit.

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currently likely feasible approach to solving this problem is newborn screening for storage disorders to enable transplantation at the earliest possible time. A proposal has been made that newborn screening programs be performed using heel-stick cards currently used to screen for other disorders.96 Such a program would identify affected patients in the first month of life and allow early transplantation before severe central nervous system damage has occurred. An exciting alternative approach to hematopoietic cell transplantation for treatment of metabolic disorders is the use of gene therapy, in which autologous cells are transduced with a normal copy of the defective gene. This is an attractive approach because the issues of donor identification and GVHD are removed, and a large amount of preclinical work has been performed addressing the use of this strategy. Significant issues and technical questions still remain to be addressed, however, before gene therapy is a viable option in humans. Chief among these are the relative inefficiency of gene transduction and the challenges related to regulation of and durability of gene expression using these strategies. An additional challenge has arisen recently because the single example of successful use of human gene therapy, the treatment of children with SCID, has been associated with insertional leukemogenesis in a significant number of patients.97,98 With 3 years of follow-up, 2 of 10 children treated have a leukemia-like process, which represents a significant setback in the field of gene therapy. However, analysis of the insertion sites and better understanding of the biology of this event may show that this phenomenon is specific to this particular therapeutic approach. Further understanding of the mechanism by which this occurred is essential for the development of future gene therapy studies.

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Transplantation

42. Gullingsrud EO, Krivit W, Summers CG: Ocular abnormalities in the mucopolysaccharidoses after bone marrow transplant. Longer follow-up. Ophthalmology 105:1099-1105, 1998. 43. Litjens T, Brooks DA, Peters C, et al: Identification, expression, and biochemical characterization of N-acetylgalactosamine-4-sulfatase mutations and relationship with clinical phenotype in MPS-VI patients. Am J Hum Genet 58:1127-1134, 1996. 44. Winchester B, Vellodi A, Young E: The molecular basis of lysosomal storage diseases and their treatment. Biochem Soc Trans 28:150-154, 2000. 45. Krivit W, Pierpont ME, Ayaz K, et al: Bone-marrow transplant in the Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI): Biochemical and clinical status 24 months after transplant. N Engl J Med 311:16061611, 1984. 46. McGovern MM, Ludman MD, Short MP, et al: Bone marrow transplant in Maroteaux-Lamy syndrome (MPS type 6): Status 40 months after BMT. Birth Defects Orig Artic Ser 22:41-53, 1986. 47. Herskhovitz E, Young E, Rainer J, et al: Bone marrow transplant for Maroteaux-Lamy syndrome (MPS VI): Long-term follow-up. J Inherit Metab Dis 22:50-62, 1999. 48. McKinnis EJ, Sulzbacher S, Rutledge JC, et al: Bone marrow transplant in Hunter syndrome. J Pediatr 129:145-148, 1996. 49. Vellodi A, Young E, Cooper A, et al: Long-term follow-up following bone marrow transplant for Hunter disease. J Inherit Metab Dis 22:638-648, 1999. 50. Coppa GV, Gabrielli O, Zampini L, et al: Bone marrow transplant in Hunter syndrome (mucopolysaccharidosis type II): Two-year follow-up of the first Italian patient and review of the literature. Pediatr Med Chir 17:227-235, 1995. 51. Coppa GV, Gabrielli O, Zampini L, et al: Bone marrow transplant in Hunter syndrome. J Inherit Metab Dis 18:91-92, 1995. 52. Coppa GV, Gabrielli O, Cordiali R, et al: Bone marrow transplant in a Hunter patient with P266H mutation. Int J Mol Med 4:433-436, 1999. 53. Bergstrom SK, Quinn JJ, Greenstein R, et al: Long-term follow-up of a patient transplanted for Hunter’s disease type IIB: A case report and literature review. Bone Marrow Transplant 14:653-658, 1994. 54. Mullen CA, Chan KW: Ethical considerations in allogeneic hematopoietic cell transplant for children with slowly fatal conditions. Bone Marrow Transplant 26:1030-1031, 2000. 55. Mullen CA, Thompson JN, Richard LA, et al: Unrelated umbilical cord blood transplant in infancy for mucopolysaccharidosis type IIB (Hunter syndrome) complicated by autoimmune hemolytic anemia. Bone Marrow Transplant 25:1093-1097, 2000. 56. Peters C, Krivit W: Hematopoietic cell transplant for mucopolysaccharidosis IIB (Hunter syndrome). Bone Marrow Transplant 25:1097-1099, 2000. 57. Krivit W, Peters C, Dusenbery K, et al: Wolman disease successfully treated by bone marrow transplant. Bone Marrow Transplant 26:567-570, 2000. 58. Hofling AA, Vogler C, Creer MH, et al: Engraftment of human CD34+ cells leads to widespread distribution of donor-derived cells and correction of tissue pathology in a novel murine xenotransplant model of lysosomal storage disease. Blood 101:2054-2063, 2003. 59. Soper BW, Lessard MD, Vogler CA, et al: Nonablative neonatal marrow transplant attenuates functional and physical defects of beta-glucuronidase deficiency. Blood 97:1498-1504, 2001. 60. Sammarco C, Weil M, Just C, et al: Effects of bone marrow transplant on the cardiovascular abnormalities in canine mucopolysaccharidosis VII. Bone Marrow Transplant 25:1289-1297, 2000. 61. Brooks AI, Stein CS, Hughes SM, et al: Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectors. Proc Natl Acad Sci U S A 99:6216-6221, 2002. 62. Yamada Y, Kato K, Sukegawa K, et al: Treatment of MPS VII (Sly disease) by allogeneic BMT in a female with homozygous A619V mutation. Bone Marrow Transplant 21:629-634, 1998. 63. Bastedo L, Sands MS, Lambert DT, et al: Behavioral consequences of bone marrow transplant in the treatment of murine mucopolysaccharidosis type VII. J Clin Invest 94:1180-1186, 1994. 64. Moser HW, Moser AE, Singh I, et al: Adrenoleukodystrophy: Survey of 303 cases—biochemistry, diagnosis, and therapy. Ann Neurol 16:628-641, 1984. 65. Moser HW, Moser AB, Smith KD, et al: Adrenoleukodystrophy: Phenotypic variability and implications for therapy. J Inherit Metab Dis 15:645-664, 1992. 66. Moser HW: Clinical and therapeutic aspects of adrenoleukodystrophy and adrenomyeloneuropathy. J Neuropathol Exp Neurol 54:740-745, 1995. 67. Moser HW, Loes DJ, Melhem ER, et al: X-Linked adrenoleukodystrophy: Overview and prognosis as a function of age and brain magnetic resonance

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