Quality of life of Hurler syndrome patients after successful hematopoietic stem cell transplantation.

Hurler syndrome (HS) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Hematopoietic stem cell transplantation (HSCT) results in long-term survival, although with significant residual disease burden. How this residual disease affects the health-related quality of life is unknown. Therefore, we conducted a multicenter cohort study on functional and psychosocial health and compared the outcomes to normative data using the Child Health Questionnaire and Pediatric Outcomes Data Collection Instrument. Perception of care was evaluated by the Measure of Processes of Care questionnaire. Sixty-three HS patients receiving HSCT with at least 3 years of follow-up after HSCT were included. The influence of potential predictors was analyzed using linear regression analysis, and correlation analysis was performed using Spearman rank correlation. Functional health of transplanted HS patients was significantly diminished compared with normative data (median physical summary z score, -2.4 [range, -3.5 to -1.6]; median global functioning z score, -3.2 [range, -4.8 to -1.8]). Psychosocial health was comparable or only slightly reduced compared with healthy peers (median psychosocial summary z score, 0.15 [range, -0.7 to 0.8]). A higher obtained lysosomal enzyme level post-HSCT predicted for superior functional health. Overall, parents were satisfied with the care received. Functional health of transplanted HS patients appeared significantly more affected than psychosocial health. To improve functional health, the use of only noncarrier donors and striving to achieve full-donor chimerism, both resulting in higher enzyme levels, is advised. Assessing the health-related quality of life could play an important role in evaluating outcomes of HS patients receiving novel (cell) therapies, including autologous gene-transduced HSCT.

Cord blood is the optimal graft source for the treatment of pediatric patients with lysosomal storage diseases: clinical outcomes and future directions.

Initially used as an alternative hematopoietic stem cell source for patients without a human leukocyte antigen-matched bone marrow or peripheral blood stem cell donor, unrelated cord blood (UCB) is now the preferred donor source when hematopoietic stem cell transplantation (HSCT) is used to treat patients with lysosomal storage disorders (LSD). Without transplantation, these patients have serious progressive multi-system deterioration and premature death. UCB transplantation favorably alters the natural history of these diseases and prolongs survival. It primarily works through cellular enzyme replacement by healthy engrafted donor cells providing a continuous endogenous supply of enzyme throughout the body and, thorough engraftment of donor-derived microgial cells, in the central nervous system. HSCT in LSD, the majority performed in patients with mucopolysaccharidoses and leukodystrophies, is associated with remarkably high rates of engraftment and survival. Importantly, recipients of UCB, as compared with other donor sources, more often achieve full-donor chimerism and normalization of enzyme levels, which has been associated with superior long-term clinical prognosis. Additionally, UCB units are readily available, reducing time to transplantation and thereby providing access to transplant at young ages, another highly important predictor for long-term neuro-developmental function. For these reasons, UCB grafts are nowadays considered to be the optimal graft source for HSCT in patients with LSD.

Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines.

Allogeneic hematopoietic cell transplantation (HCT) is the only treatment able to prevent progressive neurodegenerative disease in a selected group of mucopolysaccharidosis (MPS) disorders. However, its use was historically limited by the high risk of graft failure and transplantation-related morbidity and mortality. Therefore, since 2005 new international HCT guidelines for MPS disorders were proposed. The survival and graft outcomes of MPS patients receiving HCT according to these guidelines in 2 European centers of expertise were evaluated. Two consecutive conditioning regimens were used, busulfan/cyclophosphamide or fludarabine/busulfan-based, both with exposure-targeted i.v. busulfan. A noncarrier matched sibling donor (MSD), matched unrelated cord blood (UCB), or matched unrelated donor (MUD) were considered to be preferred donors. If not available, a mismatched UCB donor was used. Participants were 62 MPS patients (56 MPS type I-Hurler, 2 MPS type II, 2 MPS type III, and 2 MPS type VI) receiving HCT at median age 13.5 months (range, 3 to 44). Forty-one patients received a UCB donor, 17 MSD, and 4 MUD. High overall survival (95.2%) and event-free survival (90.3%) were achieved with only low toxicity: 13.3% acute graft-versus-host disease aGVHD) grades II to IV and 14.8% chronic GVHD (1.9% extensive). A mismatched donor predicted for lower event-free survival (P = .04). A higher age at HCT was a predictor for both aGVHD (P = .001) and chronic GVHD (P = .01). The use of a mismatched donor was a predictor for aGVHD (P = .01). Higher rates of full-donor chimerism were achieved in successfully transplanted UCB recipients compared with MSD/MUD (P = .002). If complying with the international HCT guidelines, HCT in MPS patients results in high safety and efficacy. This allows extension of HCT to more attenuated MPS types. Because a younger age at HCT is associated with reduction of HCT-related toxicity, newborn screening may further increase safety.

Long-term functional outcomes of children with hurler syndrome treated with unrelated umbilical cord blood transplantation.

OBJECTIVES: Hurler syndrome is characterized by progressive multisystem deterioration leading to early death in childhood. This prospective study evaluated the long-term outcomes of patients with Hurler syndrome who underwent umbilical cord blood transplantation from unrelated donors. STUDY DESIGN: Only patients with Hurler syndrome who underwent umbilical cord blood transplantation between December 1995 and March 2006 (n = 25) and who were followed for at least 5 years (n = 19) were included in the analysis. The patients were longitudinally evaluated by a multidisciplinary team of specialists following a standardized protocol. RESULTS: Median age at transplantation was 15.9 months (range 2.1-35), and patients were followed up until a median age of 10.1 years (range 7.2-14.9). Overall survival was 80%. All successfully transplanted patients achieved full donor chimerism and normal enzyme levels, and all children continue to make gains in development. Gross motor function was the most affected area. Vision and hearing were compromised in a minority of the patients, with some requiring corneal transplant or hearing aids. Cardiopulmonary function improved. Some children required orthopedic surgery, but severe complications were prevented in most patients. Although longitudinal growth was lower than that of unaffected children, it was considerably higher than expected from the natural course of the disease. Head circumference normalized. Hydrocephalus was not observed at longer follow-up, and cerebral atrophy decreased over time. CONCLUSIONS: In this descriptive study of children with Hurler syndrome, unrelated umbilical cord blood transplantation was associated with improved somatic disease and neurodevelopment.

Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study.

Mucopolysaccharidosis type I-Hurler syndrome (MPS-IH) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Although hematopoietic cell transplantation (HCT) has been performed in these patients for more than 30 years, large studies on the long-term outcome of patients with MPS-IH after HCT are lacking. The goal of this international study was to identify predictors of the long-term outcome of patients with MPS-IH after successful HCT. Two hundred seventeen patients with MPS-IH successfully engrafted with a median follow-up age of 9.2 years were included in this retrospective analysis. Primary endpoints were neurodevelopmental outcomes and growth. Secondary endpoints included neurologic, orthopedic, cardiac, respiratory, ophthalmologic, audiologic, and endocrinologic outcomes. Considerable residual disease burden was observed in the majority of the transplanted patients with MPS-IH, with high variability between patients. Preservation of cognitive function at HCT and a younger age at transplantation were major predictors for superior cognitive development posttransplant. A normal α-l-iduronidase enzyme level obtained post-HCT was another highly significant predictor for superior long-term outcome in most organ systems. The long-term prognosis of patients with MPS-IH receiving HCT can be improved by reducing the age at HCT through earlier diagnosis, as well as using exclusively noncarrier donors and achieving complete donor chimerism.

Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning.

We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.

[Minocycline-induced autoimmune hepatitis]. / Auto-immuunhepatitis door minocycline.

BACKGROUND: Drug-induced autoimmune hepatitis is an acute and potentially severe side effect, particularly often reported after the long-term use of minocycline. The condition's characteristic biochemical findings are highly elevated transaminase levels, only mildly increased markers of cholestasis and bilirubin levels, an elevated IgG concentration and a high antinuclear antibody (ANA) titre. CASE DESCRIPTION: A 14-year-old girl developed autoimmune hepatitis due to the long-term use of minocycline for acne vulgaris. She presented with icterus and very high transaminase levels. The patient made a full recovery after the medication was discontinued. CONCLUSION: This type of autoimmune hepatitis can be differentiated from 'classic' autoimmune hepatitis by the patient's quick recovery after stopping the inducing drug and no relapse of the condition after the discontinuation of glucocorticoid therapy.

Dried blood spot analysis: an easy and reliable tool to monitor the biochemical effect of hematopoietic stem cell transplantation in hurler syndrome patients.

Hurler syndrome (HS), the most severe phenotype in the spectrum of mucopolysaccharidosis type I, is caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). At present, hematopoietic stem cell transplantation (HSCT) is the only treatment able to prevent disease progression in the central nervous system, and therefore considered the treatment of choice in HS patients. Because IDUA enzyme activities after HSCT have been suggested to influence the prognosis of HS patients, monitoring these activities after HSCT remains highly important. The use of dried blood spots (DBS) for enzyme analysis can be a useful alternative to the conventional leukocyte assay. Importantly, this method allows for convenient worldwide shipment, and can therefore be applied to monitor patients from larger areas of the world, or during large-scale international studies. Furthermore, this method requires only a minimal amount of blood. From 13 HS patients receiving HSCT, 36 paired whole blood and DBS samples were analyzed to assess leukocyte and DBS IDUA activities, respectively. To correct for potential interfering factors, simultaneous assay of the alpha-Galactosidase-A (AGA) activity was performed in the DBS samples and an IDUA/AGA ratio was calculated. A strong linear correlation was demonstrated between the DBS IDUA/AGA ratio and the leukocyte IDUA activity (r(2) = .875, P < .001). This correlation was applicable to all enzyme activities, including the activities measured early after HSCT as well as heterozygous activities because of mixed chimerism or the use of a carrier donor. These results demonstrate that the DBS method is reliable to monitor the biochemical effect of HSCT in HS patients.

Risk factor analysis of outcomes after unrelated cord blood transplantation in patients with hurler syndrome.

Allogeneic stem cell transplantation (SCT) is considered effective in preventing disease progression in patients with Hurler syndrome (HS). Unrelated umbilical cord blood (UCB) grafts are suggested as an alternative to bone marrow (BM) or peripheral blood stem cells (PBSC). We studied 93 HS patients receiving an UCB graft to analyze risk factors for outcomes. The median time from diagnosis to transplant was 4.6 months, median follow-up was 29 months, and median number of nucleated CB cells infused was 7.6 x 10(7)/kg. Most of the patients received 1 or 2 HLA disparate grafts, and the most frequently used conditioning regimen was cyclophosphamide + busulfan (Bu/Cy). All patients received anti-T cell antibody. At post transplant day +60, the cumulative incidence of neutrophil engraftment was 85%. A younger age at transplant and a higher CD34(+) dose at infusion were favorably associated with engraftment. With the exception of 2 patients, all engrafted patients achieved full and sustained donor chimerism. The 3-year event-free survival (EFS) and 3-year overall survival (OS) rates were 70% and 77%, respectively. In a multivariate analyses, use of Bu/Cy and a shorter interval from diagnosis to transplant were predictors for improved EFS rate (82% for patients transplanted within 4.6 months after diagnosis compared to 57% for the rest). Improved outcomes from early transplantation and immediate availability of CB unit lead us to conclude that CB transplantation is a beneficial option, which should be considered expediently for children with HS.

The clinical outcome of Hurler syndrome after stem cell transplantation.

Hurler syndrome (HS) is a severe inborn error of metabolism causing progressive multi-system morbidity and death in early childhood. At present, stem cell transplantation (SCT) is the only available treatment that can prevent central nervous system disease progression in HS patients. Although SCT has been shown to be effective for several important clinical outcome parameters, the reported clinical outcome after successful SCT is variable among HS patients and there are still some major limitations. This review will focus on the clinical outcome of HS patients after successful SCT, with particular emphasis on the long-term outcome and complications. In addition, factors that are suggested to contribute to the variable outcome are outlined, as well as the limitations of SCT in HS patients.