Sanfilippo syndrome compromises blood-brain barrier, leads to brain damage

A study into the effects of Sanfilippo Syndrome type B (MPS III B) has found that the barrier responsible for protecting the brain from the entry of harmful blood-borne substances is structurally and functionally damaged by the devastating disease. University of South Florida researchers identified damage in specific brain structures involved in the pathology of MPS III B, one of four Sanfilippo syndromes, all of which are inherited diseases of metabolism.

The study, using a mouse model of MPS III B, has been published online in the journal PLoS One. Before this study, little was known about the integrity of the blood-brain barrier in this disease. (www.plosone.com)

"These new findings about blood-brain barrier structural and functional impairment in MPS III B mice, even at early disease stage, may have implications for disease pathogenesis and should be considered in the development of treatments for MPS III B," said study lead author Svitlana Garbuzova-Davis, PhD, an assistant professor in the Department of Neurosurgery and Brain Repair at the University of South Florida.

Sanfilippo syndrome type B is caused by a deficiency in the Naglu gene, the gene responsible for producing an enzyme needed to degrade heparan sulfate. Naglu-deficient mice show progressive deterioration of movement, vision and hearing. Neurons in various parts of the brain - including the olfactory bulb, cortex, thalamus, amygdala, and other areas - are affected by the disease. Consequently, patients with MPS III B experience a variety of pathological brain changes.

"Among our findings was that endothelial cells and other cells comprising the blood-brain barrier are damaged, resulting in vascular leakage," said Dr. Garbuzova-Davis. "This compromise may lead to destruction of the fragile central nervous system equilibrium."

Dr. Garbuzova-Davis and her co-researchers also reported that the "insult to blood-brain barrier integrity" likely comes from accumulated storage products within the endothelial cells, which are primary cellular components of the BBB. The authors noted that it is possible that blood-brain barrier dysfunction occurred before, or concurrent with, the appearance of neuropathological changes in MPS III B.

"Interestingly, more capillary leakage was seen in some brain structures, such as the hippocampus, in early symptomatic mice than in late symptomatic mice," Dr. Garbuzova-Davis said. "We speculate that the regions of the brain differ in metabolic functional activity, especially in growing animals, and higher activity may require more substantial exchanges of nutrients and metabolic activity. If the blood-brain barrier is already weakened in these areas, more vascular leakage may occur."

The authors report that capillary endothelial cell dysfunction may accelerate neuropathological changes in MPS III B by potentially allowing harmful blood-borne soluble substances, including neurotoxins, to enter the central nervous system.

"Alternatively, damaged endothelial cells may alter specific mechanisms for transport of various solutes across the blood-brain barrier," said Paul Sanberg, PhD, DSc, executive director of USF Center of Excellence for Aging and Brain Repair and co-author of the paper. "In this scenario, neural cells might suffer the dual effects of reduced nutrition and increased metabolite levels, impairing central nervous system function."

The researchers concluded that determining the evolution of blood-brain barrier dysfunction in MPS III B is important for both understanding how the disease progresses and for developing therapies. One possibility for blood-brain barrier repair is replacement of affected endothelial cells with endothelial progenitor cells from bone marrow or umbilical cord blood. Because a microaneurysm was noted in the brain of a mouse modeling MPS III B, the authors also suggest that special attention be given to the possibility of cerebral hemorrhage in MPS III B patients caused by weakened integrity.