Sanfilippo disease is a rare disorder caused by the failure of enzymes to break down specific kinds of complex carbohydrates, resulting in their accumulation in cells and often severe physical and neurological problems – and sometimes early death.
In a paper published in the March 4 issue of the Journal of Biological Chemistry, researchers at the University of California, San Diego School of Medicine, led by Jeffrey D. Esko, PhD, professor in the Department of Cellular and Molecular Medicine, describe the build-up of a novel secondary metabolite in Sanfilippo disease, a discovery that could improve understanding of the disease's pathology and refine diagnostic techniques.
Sanfilippo is one of a group of genetically inherited metabolic disorders called mucopolysaccharidoses, all of which involve the inability of different lysosomal enzymes to catabolize or break down glycosaminoglycans – complex sugar carbohydrates that help cells build skin, bone, cartilage, tendons and connective tissues.
"It's a very ordered sequence of degradation," said Esko, co-director of the Glycobiology Research and Training Center at UC San Diego. "Interference with any of the steps in the enzymatic process results in an accumulation of metabolites, which causes lyosomal dysfunction. Cells become constipated, leading to internal changes and dysfunction."
For patients with severe mucopolysaccharidosis, the consequences can be catastrophic. As incompletely degraded glycosaminoglycans accumulate in cells and tissues, they cause permanent, progressive damage that affects appearance, physical abilities, organ function and, most profoundly, mental development. Children with the disease can experience severe neuropathology and significant early mortality. It's estimated that 1 in 25,000 children in the United States have one of several forms of the disease. Some mucopolysaccharidoses can be temporarily treated with enzyme replacement therapies, but the body's blood-brain barrier blocks neurological benefit. There is no current cure.
"The three approved drugs on the market mask the genetic defect by supplementing the missing enzymes," said Esko. "They can help resolve storage in many organs, but not the brain because the enzymes do not cross the barrier. And they are very, very expensive."
In the new research, Esko and colleague William C. Lamanna, PhD, studied enzymatic activity in Sanfilippo patient fibroblasts, a type of cell most commonly found in connective tissues. They noted that defective enzymatic activity resulted in the accumulation of not just a glycosaminoglycan called heparan sulfate, but also a secondary metabolite called dermatan sulfate. Sanfilippo cells had levels of dermatan sulfate two- to five-fold higher than normal.
The combined accumulation of heparan sulfate with dermatan sulfate, researchers said, may explain some of the distinct pathological features of Sanfilippo disease. The emergence of dermatan sulfate as an additional biomarker for Sanfilippo disease could be useful in detection and diagnosis, though Esko said studies using patient tissue biopsies or blood or urine samples remain to be conducted.
"Right now, this discovery probably won't change the current therapy for Sanfilippo" said Lamanna, "but it does improve what we know about how the disease works and how to diagnose it."
The work follows related research published in 2010 in Molecular Therapy by Esko, Yitzhak Tor, PhD, UCSD Department of Chemistry and Biochemistry and Moores Cancer Center and colleagues that described a new type of targeting process for delivering modified enzymes to cells.
Co-authors of the JBC paper are Roger Lawrence and Stephane Sarrazin, both from the UCSD Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center.
Scott LaFee | EurekAlert!
Complementing conventional antibiotics
24.05.2018 | Goethe-Universität Frankfurt am Main
Building a brain, cell by cell: Researchers make a mini neuron network (of two)
23.05.2018 | Institute of Industrial Science, The University of Tokyo
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
24.05.2018 | Ecology, The Environment and Conservation
24.05.2018 | Medical Engineering
24.05.2018 | Physics and Astronomy