Autoantibody Related to Deadly Children's Disease

An autoantibody has been found to be causally related to the molecular events underlying a rare children's disorder called Batten disease, according to study appearing in the June 1, 2002, issue of Human Molecular Genetics.

Batten disease is an inherited lysosomal storage disease that usually causes gradual mental retardation and death of the affected child by the early teens or twenties. The research showed that the autoantibody binds to and inhibits the enzyme glutamic acid decarboxylase (GAD65). Without GAD65, glutamate accumulates in neurologic tissue and eventually degrades brain function.

Dr. David Pearce and colleagues of the University of Rochester Medical Center Research (NY, USA) used a mouse model to study the CLN3 gene, which was known to be associated with Batten disease. They detected the presence of an autoantibody to glutamic acid decarboxylase (GAD65) in cln3-knockout mice serum that was associated with brain tissue but was not present in sera or brain of normal mice. The autoantibody to GAD65 had the ability to inhibit the activity of glutamic acid decarboxylase. Furthermore, brains from cln3-knockout mice had decreased activity of glutamic acid decarboxylase as a result of the inhibition of this enzyme by the autoantibody, resulting in brain samples from cln3-knockout mice having elevated levels of glutamate as compared with normal.

The study marks the first time researchers have linked Batten disease to a problem with the GAD65 enzyme. "It was a serendipitous discovery,” said Dr. Pearce. "Although it was not logical to test for an autoimmune component in Batten disease, we acted on a hunch, and it turned out to be very straightforward to find an autoantibody to GAD65.”

After the discovery of autoantibodies to GAD65 in mice, sera from 20 patients with the disease were tested. The antibody was found in all 20 of the samples but was not present in samples from people without the disease. "We finally have a mechanism for understanding the disease. We hope this opens the door to treatment some day,” said Dr. Pearce.




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