D. J. andWijburg, F. A. (2010), Mucopolysaccharidosis type IIIA: Clinical spectrum and genotype–phenotype correlations. Ann Neurol., 68: 876887. doi: http://dx.doi.org/10.1002/ana.22092. doi:10.1016/j.ymgme.2014.12.131 129
Neurobehavioral outcomes in Sanfilippo syndrome typeB compared to type A
Kelly King, Alia Ahmed, Kyle Rudser, Robin Rumsey, Brianna Yund,
Igor Nestrasil, Michael Potegal, ChesterWhitley, Elsa Shapiro, University of Minnesota, Minneapolis, MN, USA
Previous research on Sanfilippo syndrome type A (mucopolysaccharidosis type III, MPS IIIA) indicates that children diagnosed with a rapidly progressing form (diagnosed before age 6) develop autism-like symptoms around age 4 and also begin to show signs of amygdala dysfunction manifest by decreased startle, orality, and loss of fear. We hypothesized that Sanfilippo syndrome type B (MPS IIIB) would have similar manifestations using the same neurobehavioral assessment protocol. Methods: Eleven patients with MPS IIIB were recruited from a natural history study (NCT01509768). All but one subject were over the age of 6 years, and that patient, under 2, was excluded. A comparison group of 9 patients was selected from a MPS
IIIA (NCT01047306) cohort who had the rapidly progressive form and who were matched for age (over 6). Another group of 8 MPS I patients were tested for comparison. Three measures were used:
Startle response in the Risk Room procedure, the Autism Diagnostic
Observation System (ADOS), and the Sanfilippo Behavior Rating
Scale (SBRS). Amygdala volumes were also obtained from manuallytraced MRI images. Results: All MPS III subjects were severely cognitively impaired. Behavioral observations suggested that MPS
IIIB patients were more verbal, and retained the ability to talk longer than MPS IIIA subjects. Three of 9 MPS IIIA patients startled in the
Risk Room test as did 2/10 MPS IIIB patients. In comparison, all MPS I controls startled. For the MPS IIIA group, the ADOS total score was 18.78 compared to 18.11 for MPS IIIB. Social and behavioral ADOS scores also demonstrated no significant differences. Small differences were seen on the SBRS. The onset of all abnormal behaviors was at an older age among MPS III patients compared to MPS I. The MPS IIIB patients expressed emotions more frequently compared to MPS IIIA; they appeared to be slightly more social, and had somewhat less fear and engaged in less risky behaviors and showed somewhat more fear of new people. These differences were small and the associated amygdala volumes also showed no differences. It should be noted that 4 patients were over age 22 compared to none of the MPS IIIA patients. Discussion and conclusions: Later onset of symptoms appears to differentiate MPS IIIA from IIIB. Because of a lack of recruitment of patients under age 6, we do not have data on how startle response, autism symptoms, and orality develop in MPS IIIB. Nevertheless, it can be concluded that MPS IIIA does not differ substantially from MPS IIIB on themeasures used for patients from ages 6 to 22 (supported by Shire and NIH U54NS065768). 1) Rumsey R, Rudser K, Delaney K, Ahmed A, Potegal M, Whitley
C, Shapiro E. (2014). Acquired Autistic Behaviors in Children with
MPS IIIA. Journal of Pediatrics. 164 (5), 1147–1151. 2) Potegal M,
Yund B, Delaney K, Ahmed A, Nestrasil I, Whitley C, Shapiro E (2013).
Mucopolysaccharidosis type IIIA presents as a variant of the Klüver–
Bucy Syndrome. Journal of Clinical and Experimental Neuropsychology. 35, 608–616. doi:10.1016/j.ymgme.2014.12.132 130
A study on the influence of glycosaminoglycan and growth factor interaction in mucopolysaccharidosis type I bone disease
Sandra D.K. Kingma, Tom Wagemans, Lodewijk IJlst, Ronald J.A.
Wanders, Frits A. Wijburg, Naomi van Vlies, Academic Medical Center,
Amsterdam, The Netherlands
Mucopolysaccharidosis type I (MPS I) is a lysosomal disorder characterized by deficient degradation of the glycosaminoglycans (GAG) heparan and dermatan sulfate (HS, DS). Progressive bone and joint disease are a major cause of morbidity in MPS I patients and no effective treatment is available yet. By elucidating the pathophysiological mechanisms underlying bone disease, new therapeutic targets could be identified. In the developing growth plate, chondrocytes undergo a process of proliferation, hypertrophy and differentiation, thereby leading to longitudinal growth. This process is regulated by the interaction between GAG and various growth factors (GFs), for instance
Indian Hedgehog (IHH) and fibroblast growth factors (FGFs). Alterations in GAG content of the extracellular matrix as a result of GAG accumulation, might lead to alterations in the complex interaction with
GFs. We hypothesized that altered interaction between GFs and accumulated GAG contributes to the pathogenesis of MPS I bone disease. In this study, binding betweenGAG and GFs, GF-signaling, bone growth and GAG and GF distribution in the growth plate were studied in MPS I cells and MPS I mouse bone. Fibroblasts were transduced into chondrocytes andGAG secreted into themediumwere isolated to study the binding capacity of control and MPS I GAG to FGF2. Healthy control
GAG bound FGF2, but FGF2-binding of MPS I GAG was not detectable.
Next, FGF2 signaling was studied in chondrocytes by analyzing protein levels of phosphorylated ERK (pERK). Higher pERK levels after FGF2 treatment were observed in MPS I chondrocytes, as compared to healthy control chondrocytes. Next, metatarsalia of 6-day-old wildtype (WT) and MPS I mice were cultured ex vivo and growth was measured.
After 5 days of treatment with FGF2, growth of MPS I bones was 7% (p b 0.05) increased, as compared toWT bones. Also, when normal GAG (isolated from porcine intestinal mucosa, obtained from Sigma) were added together with FGF2, a trend towards increased growth (10%, p = 0.09) of MPS I bones, as compared to WT, was observed. Staining with specific GAG antibodies to determine alterations in GAG content, revealed decreased abundance of sulfated HS domains and CS domains in MPS I growth plates, as compared to WT. IHH staining demonstrated that IHH, a key regulator of chondrocyte differentiation in the growth plate, was particularly abundant in proliferating chondrocytes in MPS I growth plates, rather than in hypertrophic chondrocytes as observed in WT growth plates. Because GF binding is highly dependent on GAG structure and sulfation, these results suggest that altered GF-function and distribution is likely caused by the accumulation of GAG inMPS I bone cells and extracellular matrix.