Intracisternal cyclodextrin ameliorates neurological dysfunction, increases survival time, and stops Purkinje cell death in feline Niemann–Pick type C1 disease

Mucopolysaccharidosis IIIB (MPS IIIB; Sanfilippo syndrome type B) is an autosomal recessive lysosomal disorder caused by a marked decrease in alpha-N-acetyl-glucosaminidase (NAGLU) enzyme activity which leads to the build-up of abnormal amounts of heparan sulfate (HS) in the brain and other organs. At present there is no treatment for this disorder. Recent scientific studies have indicated a possible defect in the blood–brain barrier (BBB) in mice with MPS IIIB and in patients withMPS IIIA and IIID. A detailed study of the nature and integrity of the BBB is crucial to understand the pathogenesis of structural and functional brain abnormalities in MPS IIIB patients. We evaluated BBB integrity and structural brain abnormalities in MPS IIIB patients using CSF-AI and multimodal MRI. Five Caucasian MPS IIIB patients (4 males, 1 female) with classic severe phenotype between 6 and 8 years of age were enrolled. Their mean age at the time of diagnosis of MPS IIIB was 2.4 years. A blood sample and CSF sample (by lumbar puncture) were obtained for determination of CSF-AI. DCE-MRI (Dynamic Contrast Enhanced-MRI) images were obtained before, during, and after intravenous injection of gadoterate meglumine (Dotarem®) contrast agent for determination of blood plasma volume, BBB transfer coefficient (Ktrans, reflecting BBB permeability) and the tissue MRI relaxation time, T1 (reflecting tissue physical properties). Exploratory biomarkers such as HS (in serum, urine, and CSF) and hepatocyte growth factor (HGF) levels in CSF were also evaluated in these patients. CSF-AI ranged between 5.5 to 11.3 in 4 out of 5 patients (upper limit of normal 4.9) with CSF-AI for the fifth patient below the upper limit of normal. DCE-MRI results showed Ktrans values in grey and white matter that were very low and similar to those previously reported in adult healthy brain, and T1 values in white matter that were comparable to normal volunteers of similar age. Other key findings from the MRI included cerebral atrophy, increased skull thickness and abnormal areas of white matter hyperintensity (Fig. 1). Exploratory biomarkers showed substantial increase in HS levels in CSF, serum and urine, and an increase in HGF in CSF (compared to normal range). In MPS IIIB patients, there is evidence of mild BBB leakage based on the CSF-AI findings; these findings are reflected in the absence of clear evidence for BBB leakage on MRI. MRI volumetric measurements were robust and showed global and tissue-specific atrophy in these patients. Thesefindingsmay have implications forMPS IIIB disease pathogenesis.