Long term disease burden post-transplantation: three decades of observations in 25 Hurler patients successfully treated with hematopoietic stem cell transplantation (HSCT)

Abstract

Background Mucopolysaccharidosis type I-Hurler syndrome (MPSI-H) is a lysosomal storage disease characterized by severe physical symptoms and cognitive decline. Early treatment with hematopoietic cell transplant (HSCT) is critical to the survival of these patients. While survival rates and short-term outcomes are known to be improved by HSCT, the long-term cognitive, adaptive and psychosocial functional outcomes of children with (MPSI-H) post-HSCT are not well documented. This manuscript focuses on retrospective long-term follow-up (7–33 years) of 25 MPSI-H patients, transplanted between 1986 and 2011. Results The median age at transplantation was 21 months (range 12–57 months). Except for one death, all successfully transplanted MPSI-H patients surviving at least 1 year after HSCT are alive to-date, with a median age of 21 years (range 8–36 years) at the last follow-up evaluation. A majority of HSCT grafts were bone marrow transplants (BMT), resulting in durable full chimerism in 18 (72%). Pre-HSCT, the onset of first symptoms occurred very early, at a median age of 3 months (range birth-16 months). The most prevalent symptoms before MPSI-H diagnosis involved progressive dysostosis multiplex; almost all patients suffered from hip dysplasia and thoracolumbar spine Kyphosis. Despite HSCT, considerable residual disease burden and ensuing corrective surgical interventions were observed in all, and at every decade of follow-up post HSCT. Late-onset psychiatric manifestations were significant (n = 17 patients; 68%), including depression in 13 patients at a median onset age of 18 years (range 13–31 years), hyperactivity and attention deficit disorder (n = 4), and multiple acute psychotic episodes (APE), independent of depression observed (n = 3) at a median onset age of 18 years (range 17–31 years). The adult Welscher Intelligence Scale results (n = 16) were heterogenous across the four scale dimensions; overall lower scores were observed on both working memory index (median WMI = 69.5) and processing speed index (median PSI = 65), whereas verbal comprehension index (median VCI = 79) and perceptual reasoning index (median PRI = 74) were higher. Conclusion With advanced treatment options, MPSI-H are living into 3rd and 4th decades of life, however not disease free and with poor adaptation. Residual disease (loss of mobility, limited gross and fine motor skills; low cognitive ability; suboptimal cardiopulmonary function, vision and hearing) negatively impacts the quality of life and psychosocial functioning of affected individuals.

Differences in MPS I and MPS II Disease Manifestations

“…Later in adolescence, there is also evidence that MPS I patients experience low self-esteem, depression, and social withdrawal. Recent work has also reported a high proportion of lateonset psychiatric manifestations, including depression, psychotic episodes (independent of depression), hyperactivity, inattention, and dementia that emerge approximately 15 years post-HSCT [131][132][133].…”

MPS I: Early diagnosis, bone disease and treatment, where are we now?

“…In 2014, Weisstein et al 97 studied the long term effects of HSCT in patients between 9 months and 2.5 years, and demonstrated that HSCT had no significant effect on MPS I bone disease. A more recent study was performed by Guffon et al 98 on long term disease burden in 25 severely affected MPS I patients that received HSCT between the age of 12‐57 months. Despite HSCT, all patients had significant residual skeletal disease and all patients needed corrective surgical intervention 98 .…”

“…A more recent study was performed by Guffon et al 98 on long term disease burden in 25 severely affected MPS I patients that received HSCT between the age of 12‐57 months. Despite HSCT, all patients had significant residual skeletal disease and all patients needed corrective surgical intervention 98 . Several other studies confirmed that skeletal abnormalities progress after HSCT 99,100 …”

Brazilian Consensus Guidelines for Hematopoietic Stem Cell Transplantation - Inborn errors of metabolismo

“…The use of haploidentical donors should also be avoided, except for X-linked forms or proved non-carrier relatives, parents are obligated heterozygotes. Myeloablative conditioning regimens are recommended, based on Busulfan (with pharmacokinetics), fludarabine, and thymoglobulini [8][9][10][11][12] .…”

“…Intense international collaboration during the last decade has identified predictors of clinical outcomes, including myeloablative conditioning, early timing of transplantation, and probably enzyme activity level in blood after HSCT. This has resulted in optimized transplantation protocols and 5-year survival rates > 90% 6,10,11 . The Brazilian government has approved HSCT with related and unrelated donors for patients with MPS I and II.…”