03.08>> Batten Disease    
What A Difference A Gene Makes  

Human beings have about 40,000 genes. Hard as it is to believe, sometimes a defect in a single gene can lead to devastating consequences. This is the case of a rare childhood genetic disorder known as Batten Disease, which currently has no treatment and is inevitably fatal. But researchers are making breakthroughs in the understanding of Batten Disease, finding knowledge that may someday lead to treatments and cures...

Imagine for a moment a disease so brutal that it can kill a healthy child by the time the child is a teenager. This is not an infection or something you can catch. It is a genetic defect known as Batten Disease.

On its 46 chromosomes, the human body has about 40,000 genes that provide the instructions for making proteins. These proteins are involved in every single process that goes on in the body, including, for example, respiration. We inherit genes from both our mother and father. As humans, we are diploid organisms, which means that we inherit one copy of each gene from each parent, so we have two copies of every gene.

But not every gene is perfect; some are defective. And the average person inherits 3 defective copies of genes out of the total number of 40,000 genes. This is not usually harmful, because each person has two copies. If one copy is defective, there is always the other one.

Batten Disease

Batten Disease is the most common inherited childhood neurodegenerative disease, though it is relatively rare – occurring in 2 to 4 out of every 100,000 births in the US.

A person with Batten Disease will appear normal until around age five years, when the child will start to have vision loss. Despite trips to the optometrist for glasses, eventually the child’s eyesight will fail completely and the child will go blind. Soon the child will experience cognitive decline; for example, unable to write or read Braille any more. Then he or she will begin shaking and having epileptic seizures. Eventually the child’s walking will break down and the child will have to use a wheelchair or be bedridden. Batten Disease is fatal in all cases and there are currently no cures and there are no treatments that will halt the progression of the disease or slow it down.

You’d think that a disease as heartbreaking as Batten Disease must be caused by many defective genes. But Batten Disease comes from a single defective gene, a gene called CLN3.

Here’s how it works: A person with only one defective copy of CLN3 gene will not have the disease, but will be a carrier. If both parents are carriers and the child unluckily inherits two bad copies of the CLN3 gene – one from each parent – then that child does not have a good CLN3 gene, and is positive for Batten Disease. [For those who studied genetics in Biology class, Batten Disease is an autosomal recessive disease, meaning both parents contribute the defective gene and that defective gene resides on a non-sex chromosome. With two carrier parents in this situation, the child has a 1-in-4 chance of getting the disease.]

Current Research

Dr. David Pearce is perhaps the man most knowledgeable about Batten Disease in the world. He has been studying the disease in his laboratory for over ten years. Dr. Pearce was a researcher in a biochemistry laboratory when he first read about Batten Disease. “It was time for me to branch out, and my research at the time lent itself to the disease,” said Dr. Pearce. His research was studying the biochemical functions of yeast. As it turns out, the CLN3 gene has been with us as far back as yeast on the evolutionary tree. After preliminary studies on yeast, Dr. Pearce moved on to mice. “Unfortunately with a juvenile neurological disorder such as Batten Disease,” he said, “we have to use a mammalian model.”

Dr. Pearce used a mouse model that did not have the CLN3 gene, just like the real Batten Disease children. These mice are called knockout mice because one of the genes has been “knocked out.” These mice develop some of the same symptoms as the children with Batten Disease. Dr. Pearce and his researchers study the brains of these mice in order to figure out what happens with the disease as it progresses.

One way to test cognitive abilities in mice is to use the log-rolling test. This test uses a metal rod that rolls in the water. The mice walk on the rod and it will spin faster and faster until eventually the mice fall off. Mice with Batten Disease will fall off much sooner than normal mice because of their decreased cognitive function.

Through their studies, Dr. Pearce and his lab found the brain cells of the mice with Batten disease are overexcited. What does this mean? To understand it, let’s understand how brain cells communicate with each other. [Note: visitors to the What A Year! website can get more information on how brain cells communicate in several of our stories: Autism 12/07, Multiple Sclerosis 01/08, Epilepsy 02/07, and Parkinson’s Disease 11/06.]

To communicate with each other, brain cells send electric impulses from one neuron (brain cell) to the other. One neuron will get excited, fire a signal to the next neuron, and then inhibit (stop) itself until it gets another signal from a neighboring neuron. But if a neuron gets excited and remains excited, continually firing signals, the cells will eventually burn out and die, because neurons need to be able to switch off and have some down time from constant activation. Dr. Pearce suspects that a loss of brain cells may play a role in the degeneration of children with Batten Disease.

When a neuron fires a signal, it actually sends chemicals called neurotransmitters over the gap, or synapse, that separates the brain cells from one another. Dr. Pearce found that neurons in Batten Disease mice are over-sensitive to one particular neurotransmitter, called glutamate. Dr. Pearce and his team were able to stop Batten Disease degeneration in mice by inhibiting a specific glutamate receptor on the cell membranes of brain cells. They are still doing extensive research on mice, but hope to soon extend their research to clinical trials in humans.

Dr. Pearce and his researchers have also found an autoimmune component to Batten Disease. They found that mice with Batten disease make antibodies to their own proteins. Dr. Pearce hypothesized that these autoantibodies or self-antibodies lead to the body’s no longer recognizing itself, allowing an autoimmune response to occur. Dr. Pearce demonstrated the presence of these autoantibodies in children with Batten Disease.

To study the autoimmune aspects of Batten Disease, Dr. Pearce developed immunosuppressed mice. These mice did not have the ability to make these autoantibodies. Interestingly, the progression of Batten Disease was slowed in immunosuppressed mice. Dr. Pearce is now also studying immunosuppression in children with Batten Disease.

Dr. Pearce explains, “Batten Disease deals with many parts of the brain, and unfortunately I don’t envision this problem being solved by just one drug.” Dr. Pearce hopes drugs will eventually be available to slow the progression of the disease. For now, there are support groups around the world for the families of children with Batten Disease.

Dr. David Pearce is an Associate Professor of Biochemistry and Biophysics in the Center for Neural Development and Disease at the University of Rochester in New York and the scientific advisor for the Batten Disease Support and Research Association. Dr. Pearce completed his undergraduate and doctorate work in England before coming to the United States as a post-doctoral fellow. He chose science as a career because it was the easiest subject for him in school and also the most interesting.


Dr. Pearce and his lab team [enlarge]

Neuron Firing Animation
Neurons Firing

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What A Year! is a project of the Massachusetts Society for Medical Research.

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To Learn More

  • Chattopadhyay S., M. Ito, J. Cooper, A. Brooks, T. Curran, et al. An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Human Molecular Genetics 11 (2002): 1421-1431.
  • Kovacs A., D. Pearce. Attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile Batten disease. Experimental Neurology 209 (2008): 288-291. Epub 2007 Oct 25.
  • Kovacs A., J. Weimer, D. Pearce. Selectively increased sensitivity of cerebellar granule cells to AMPA receptor-mediated exitotoxicity in a mouse model of Batten disease. Neurobiology of Disease 22 (2006): 575-585. Epub 2006 Feb 17.
  • Lim, M., N. Alexander, J. Benedict, S. Chattopadhyay, S. Shemilt, et al. IgG entry and deposition are components of the neuroimmune response in Batten disease. Neurobiology of Disease 25 (2007): 239-251. Epub 2006 Oct 27.
  • Weimer, J., A. Custer, J. Benedict, N. Alexander, E. Kingsley, et al. Visual deficits in mouse model of Batten disease. Neurobiology of Disease 22 (2006): 284-293. Epub 2006 Jan 18.
  • Weimer, J., J. Benedict, Y. Elshatory, D. Short, D. Ramirez-Montealegre, et al. Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis. Brain Research 1162 (2007): 98-112.

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