Mucopolysaccharidosis type I subtypes. Presence of immunologically cross-reactive material and in vitro enhancement of the residual alpha-L-iduronidase activities.

Abstract

The enzymatic and immunologic properties of the defective residual a-L-iduronidase activities were investigated in fibroblast extracts from the three subtypes of mucopolysaccharidosis type I, Hurler (MPS IH), Scheie (MPS IS), and HurlerScheie (MPS IH-S) diseases. Using 4-methylumbelliferyl-a-L-iduronide (4MU-a-Id), the activities in fibroblast extracts from all three subtypes were less than 0.1% of normal. Rocket immunoelectrophoresis with monospecific rabbit anti-human a-L-iduronidase polyclonal antibodies, as well as immunoblots using a monoclonal antibody, revealed the presence of crossreactive immunologic material (CRIM) in extracts prepared from each subtype. When the samples were equalized for 8-hexosaminidase A activity, 38-105% of normal enzyme protein was detected. The sequential addition of cystamine, MgCl2 and pyridoxal phosphate increased the residual 4MU-a-Id activities in subtype extracts up to about 35% of normal mean fibroblast activity. Cystamine, MgC2 or pyridoxal phosphate alone enhanced the residual activities two-to fourfold, whereas the sequential addition of all three compounds was required for maximal effect. Of the six B6 vitamers evaluated, only the negatively charged forms, pyridoxamine (PLN), pyridoxamine phosphate (PNP), and pyridoxal phosphate (PLP), stimulated the residual activities. The addition of dermatan sulfate or heparan sulfate to the subtype extracts, followed by treatment with the effector compounds, similarly inhibited both the normal and enhanced MPS I activities. Heat inactivation experiments confirmed the fact that the mutant iduronidase activity was reconstituted and that the observed increase in enzymatic activity was not an artifact of the fluorogenic assay. These results suggest that the presence of certain thiol reducing agents, divalent cations and negatively charged B6 vitamers can alter the conformation of the mutant ac-L-iduronidase in vitro such that the hydrolysis of 4MU-a-Id is enhanced into the heterozygote range.

Characterization of the Defective ß-Glucuronidase Activity in Canine Mucopolysaccharidosis Type VII

“…Previously, we reported that the catalytic activities of two other lysosomal hydrolases which also de grade GAGs, a-L-iduronidase [23] and arylsulfatase B [24], also were enhanced by these effector molecules. These data suggest that the active sites of some lysosomal hydrolases may be maintained by the presence of essen tial sulfhydryl groups.…”

Immune response to intrathecal enzyme replacement therapy in mucopolysaccharidosis I patients

“…Patients with all forms of MPS I have unmeasurable endogenous α- l -iduronidase activity though those with attenuated disease may synthesize trace amounts of endogenous enzyme depending on the underlying genetic mutation (1,25). This cross-reactive immunologic material (CRIM) is recognized as self protein by the host immune system and its presence is thought to mitigate development of serum antibodies to intravenous recombinant human enzyme in CRIM-positive as compared to CRIM-negative subjects (18).…”

Pathogenesis and treatment of spine disease in the mucopolysaccharidoses

“…Since each subtype of MPS accumulates one or more particular types of GAGs, the chemical composition of these undegraded moieties most likely plays a role in causing specific disease manifestations. Disease severity may increase with the number of different accumulating GAG types; however, it is interesting to note that with MPS I, there are subtypes that are defined by varying disease severity [24, 25], indicating that there are factors beyond GAG type and level of accumulation that impact pathology.…”