Biochemical and molecular analysis in a patient with the severe form of Hunter syndrome after bone marrow transplantation

Abstract

Hunter syndrome (mucopolysaccharidosis type II, or MPS II) results from a deficiency of iduronate‐2‐sulfatase (IDS) activity due to a primary genetic defect in the X‐chromosomal iduronate‐2‐sulfatase gene. We have studied a 10‐year‐old male, diagnosed with Hunter syndrome at age 2 years, who underwent bone marrow transplantation (BMT) at age 5 years. To evaluate the metabolic effect of BMT, biochemical and enzymatic studies were performed. Urinary glycosaminoglycans (GAGs) were quantitated, and iduronate‐2‐sulfatase activity was measured in serum, leukocytes, and liver homogenates. Decreased urinary glycosaminoglycan excretion and increased iduronate‐2‐sulfatase activity in serum and leukocytes were observed. Furthermore, molecular analysis was performed using reverse transcriptional polymerase chain reaction (RT‐PCR) sequencing and restriction enzyme assay. The patient was found to have a novel nonsense mutation, L279X (TTA to TGA) in exon 6 of the IDS gene, inherited from his mother. A comparison of the DNA contents of cultured skin fibroblasts prior to BMT with leukocyte DNA after BMT showed coexisting host mutant and donor normal alleles in post‐BMT leukocyte DNA. We postulate that the L279X mutation is a severe disease‐causing mutation for Hunter syndrome. © 1996 Wiley‐Liss, Inc.

Unrelated umbilical cord blood transplantation in infancy for mucopolysaccharidosis type IIB (Hunter syndrome) complicated by autoimmune hemolytic anemia

“…While BMT can correct the enzyme deficiency in marrow-derived cells but not other somatic cells, the enzymatic activity of these marrow-derived cells may be able to substantially reduce the total body burden of glycosaminoglycans either directly or indirectly by release of iduronate 2-sulfatase and subsequent uptake by other tissues through endocytosis. 10 The results in this patient are compatible with this hypothesis. One parameter of body burden of glycosaminoglycans is the quantity of glycosaminoglycans in urine, while the more sensitive 10 Clinically this patient has had regression of hepatomegaly.…”

“…10 The results in this patient are compatible with this hypothesis. One parameter of body burden of glycosaminoglycans is the quantity of glycosaminoglycans in urine, while the more sensitive 10 Clinically this patient has had regression of hepatomegaly. Follow-up over the next 10 years should indicate whether the transplant will prevent long-term organ dysfunction.…”

“…[9][10][11] This result has been also seen in other metabolic storage diseases with substantial CNS components. 12 Moreover, lifelong prevention of cardiac dysfunction (the most common cause of death in type IIB 8 ) has yet to be proven, although there has been a report of reversal of cardiac valvular abnormalities as measured by echocardiography in a 14-year-old boy with type IIB Hunter syndrome who underwent BMT.…”

“…8 In general, males with MPS IIB experience milder signs and symptoms with great variability in age of onset and severity. Transplantation using bone marrow, umbilical cord blood, or peripheral blood hematopoietic cells has been effective treatment for selected lysosomal and peroxisomal inherited metabolic storage diseases such as Hurler syndrome, [9][10][11] Maroteaux-Lamy, 12 X-linked adrenoleukodystrophy, 13 metachromatic leukodystrophy 14 and globoid-cell leukodystrophy. 15 Consideration of hematopoietic cell transplantation (HCT) and its implementation for these metabolic diseases must take into account the natural history of the disease and its status at HCT, likelihood of achieving stabilization or improvement in somatic and/or neuropsychologic parameters, and the probability of survival with the transplant.…”

“…8 Allogeneic BMT has been used to treat Hunter disease, but remains controversial since it often fails to reverse CNS impairment [9][10][11] and carries with it substantial early mortality and morbidity. Here, we report treatment of an infant with mucopolysaccharisosis type IIB with transplantation of unrelated umbilical cord blood cells and its complication by autoimmune hemolytic anemia.…”