Natural history of cognitive development in neuronopathic mucopolysaccharidosis type II (Hunter syndrome): Contribution of genotype to cognitive developmental course

Abstract

The natural history of cognitive growth in the neuronopathic form of Mucopolysaccharidosis type II (MPS II) is not well defined especially their patterns of development and decline. The ability to predict the developmental course of the neurologically impaired patient is necessary to assess treatment outcomes aimed at the brain. Thirteen intravenous enzyme replacement therapy-treated Japanese patients with neuronopathic MPSII who had mutation analysis were followed on one standard measure of cognitive development over time. Six children in Group MS had missense mutations and 7 children in Group NT had null type mutations such as deletions, recombination with the pseudogene, and nonsense mutations. The patients as a whole demonstrated cognitive growth until about 36–42 months of age, followed by a plateau in development. The mean age equivalent score at age 3 was similar to that at age 6. While the decline was slow for the entire group, the patients in Group NT showed a more rapid decline than those in Group MS. Two patients with deletions showed decline to a very low level by age 5. The long plateau in cognitive development in patents with MPS II was substantiated and was consistent with other studies. This is the first demonstration that different mutation types within the neuronopathic MPS II patients are associated with different rates of decline. We also were able to identify the chronological age before which a trial would need to start in order to maintain cognitive growth and a ceiling beyond which a relatively normal outcome would not be likely.

Impact of intracerebroventricular enzyme replacement therapy in patients with neuronopathic mucopolysaccharidosis type II

“…DAs in each patient were compared with 13 Japanese patients with neuronopathic MPS II treated with intravenous idursulfase (n = 13). 4 In the one patient in group MS (patient E), the DA from the screening period up to week 52 was similar to the least-squares means of the historical control group but then increased up to week 100 ( Figure 2 A). In the patients in group NT (other than patient F), the DA either was similar to or increased above the least-squares means for the historical control group ( Figure 2 B).…”

“…The secondary endpoint, DA in a total of three areas, is presented at each time point for each patient and as the mean of all patients. DAs in each patient were compared with 13 Japanese patients with neuronopathic MPS II treated with intravenous idursulfase, 4 defined as patients with severe MPS II and etiological mutation of the IDS gene who received only intravenous idursulfase and had two or more KSPD evaluations collected before the study. Least-squares means calculated by a linear mixed-effects model in the reference group were used for comparison with patients in this study.…”

“… 3 Neuronopathic MPS II can be further divided into two groups based on the genetic mutation: group MS is characterized by missense mutations and is presumed to have slight residual enzyme activity, and group NT is considered to have null type mutations, such as deletions, recombination with pseudogene, and nonsense mutations. 4 The patients in group NT show a more rapid decline than do those in group MS. 4 …”

Therapy-type related long-term outcomes in mucopolysaccaridosis type II (Hunter syndrome) – Case series

“…The boy presented as Case 2 was four years old and the oldest of our cohort at presentation, with evident cognitive impairment. At that age, the plateau or gradual cognitive decline is expected, according to natural history studies [ 26 , 27 ]. With the genotype-phenotype relationship, a severe course of the disease was expected, and limited effectiveness of ERT was predicted.…”

Gene Therapy for Mucopolysaccharidosis Type II—A Review of the Current Possibilities

“…In the case of missense mutations, some may lead to a severe phenotype but most likely predisposed to the attenuated form. Due to the heterogeneity, in many cases, it is difficult to determine the exact genotype/phenotype correlation and predict the nature of development in a particular patient [ 13 , 17 ].…”