MPS I has an incidence of about one in 100,000 live births characterized by accumulation of excess heparan and dermatan sulfate due to deficient alpha-L-iduronidase enzyme activity [24
]. Damage to multiple organs occurs for the entire range of severity although children with MPS IH have earlier onset of symptoms and CNS effects. Although hydrocephalus, hearing and vision difficulties as well as severe motor involvement contribute to poor cognition and impaired language, the slowing and decline of cognitive and language development in MPS IH is thought to occur independently of these problems [25
]. Affected children develop normally in the first months of life; a slowing in cognitive development occurs at one year that accelerates and is evident by age 2 years [24
]. By age 3 years, without treatment most children with MPS IH are cognitively impaired. A correlation of −0.58 has been found between mental ability and age in untreated children [25
]. Median life expectancy without treatment is 5.3 with most children dying by 10 years of age [25
]. Unlike other forms of MPS, children with MPS IH do not have significant behavioral difficulties until late in their disease course [25
Hematopoietic cell transplant (HCT) arrests CNS deterioration and ameliorates disease in soft tissue [2
]. Survival and continued new learning in children with MPS IH has been demonstrated but with residual deficits [30
]. While previous studies have indicated steeper developmental growth curves in children transplanted under two years of age, many of these children continue to have difficulty in their school performance. Could it result from a combination of disease and HCT treatment effects on the brain?
MPS IA is characterized by later onset and less CNS involvement [28
]. Scheie syndrome has a late onset with no easily discernible effects on the CNS. Hurler-Scheie syndrome is an intermediate form with onset in middle childhood with learning difficulties of undetermined nature and severity. Children with MPS IA are treated with ERT; enzyme does not cross the blood brain barrier to any significant degree but no need for CNS treatment was assumed presumably because no decline in cognition was thought to be present. However, evidence for a high incidence of speech language problems [31
] and clinical observations indicating decline in cognitive skills suggests more cognitive involvement in MPS IA participants than previously considered [32
In this exploratory project, differences were hypothesized between MPS IH and MPS IA that might clarify abnormalities of brain structure and function due to disease severity or treatment.
Group Differences: The children with MPS IH did not differ from those with MPS IA in cognitive ability or memory; for both groups the mean IQ was about one standard deviation below the mean. The low mean IQ in the MPS IA group dispels any notion that their CNS is entirely intact. While long term cognitive and adaptive deficits in MPS IH are well known [30
], educational and vocational expectations may need to be altered for MPS IA with attention to their cognitive limitations. Four of 7 MPS IA participants had shunts for hydrocephalus. Three had cord compression in contrast to none of the MPS IH participants who presumably have decreased risk due to HCT. In such a small sample it is hard to determine the impact of these conditions, but future studies with a larger sample should consider their contribution to lowered cognitive ability.
TOVA d prime, a measure of signal detection and attention span, was significantly poorer in the MPS IH group (in the impaired range) compared to the MPS IA group (in the low average range). While omission and commission errors (both components of d prime), were two and one standard deviations lower for the MPS IH group compared to MPS IA group, respectively, group variability and small sample size may have contributed to the lack of statistical significance for these individual variables.
FA when controlled for age was significantly different between the MPS IH and the MPS IA groups with the former showing lower FA, suggesting poorer white matter integrity in the region of interest. MD was also significantly different with higher values indicating more diffusion in the MPS IH group. These results are consistent with other research in pediatric cancer patients8–10
indicating that patients who undergo HCT have long-term white matter compromise with decreased FA and white matter volumes. As we do not have normal controls, we cannot determine whether the MPS IA values are normal or fall between the normal and MPS IH values.
Relationship between DTI and neuropsychological results: For the combined sample, FA was significantly associated with TOVA d prime (attention), errors of omission, and variability. MD values were associated only with omission errors. Analyzing the groups separately indicated that the associations between DTI measures and measures of attention were driven primarily by the MPS IH group. The association of TOVA d prime and reaction time with FA in the MPS IH group was significant; poorer stimulus detection and slower reaction time were associated with lower FA in the corpus callosum. Poorer connectivity in the pathways that mediate visual attention and processing is likely. Inattention and inefficient processing have been described consistently by the parents of children with MPS IH, but not MPS IA.
While HCT can be life saving and prevent cognitive decline in MPS IH, risks to the CNS may exist from the treatment itself. In children with ALL treated with chemotherapy or HCT, presumably without a ‘brain disease,’ late treatment effects have been found in executive function, speed of processing, and decreased FA [5
HCT treatment requires ablation of the bone marrow with the use of chemotherapy, and sometime radiation. While the negative effects of radiation especially at greater than 1800 cGy are well known [35
], all but one of our patients had a brain-sparing protocol and was below 1400 cGY to minimize effects on cognition. To reduce the negative effects of the preparative regimen yet preserve the benefit of HCT to MPS IH patients, new protocols that are reduced in intensity offer hope of preserving cognitive function in these patients.
Medical risk factors were associated with FA across the whole group, although the association was stronger in the MPS IH group. The two participants with the most medical risk factors (4 and 5) had lowest TOVA scores and FA. Thus, in MPS IH, both disease severity and HCT treatment have a negative effect on attention functions which are associated with poor white matter integrity.
This study is limited by a small sample with resultant lack of power to detect differences, lack of control group, and a wide age range. In addition, we recognize that patients with attenuated MPS I are not a perfect comparison group. While they did not have HCT treatment, they had less severe disease. A comparison group with neither MPS nor HCT treatment would not have allowed us to examine either of those factors.
While obtaining larger samples in rare diseases is a challenge, we are currently conducting a confirmatory prospective longitudinal study with a larger sample as well as a control group to further explore the role of specific disease, treatment and risk factors in the long-term outcomes of children with MPS I.