Autoimmune Link In Juvenile Batten Disease

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Source: NIH/National Institute Of Neurological Disorders And Stroke

(http://www.ninds.nih.gov/)

Date: Posted 5/23/2002

Study Finds Autoimmune Link In Juvenile Batten Disease

For years, researchers have tried to determine how the defective gene in

juvenile Batten disease leads to the seizures, mental impairment, and other

symptoms of this devastating childhood disorder. A new study shows that mice

lacking the gene that is altered, or mutated, in this disorder have an

immune reaction that disables an important enzyme in the brain. The study

also found signs of this reaction in children with Batten disease. The

finding provides a new clue about how Batten disease may damage the nervous

system and could lead to treatments for the disorder.

The study is the first to find evidence that the immune system plays a role

in Batten disease. The immune attack inactivates an enzyme called glutamic

acid decarboxylase 65 (GAD65) that normally converts one neurotransmitter

called glutamate into another, called gamma-aminobutyric acid or GABA. The

loss of the enzyme's activity leads to an excess of glutamate in the brain.

" The bottom line is that these children have an autoimmune response to a

protein (GAD65) that is important for neurological function, " says A.

Pearce, Ph.D., of the University of Rochester School of Medicine and

Dentistry in New York, who led the study. The study was funded in part by

the National Institute of Neurological Disorders and Stroke (NINDS) and

appears in the June 1, 2002, issue of Human Molecular Genetics.*

Juvenile Batten disease is a fatal, inherited childhood neurodegenerative

disorder that results from mutations in a gene called CLN3. Symptoms of this

disorder usually appear between the ages of 5 and 10 and may include vision

problems, seizures, personality and behavior changes, slow learning, or

clumsiness. Over time, affected children suffer mental impairment, worsening

seizures, and progressive loss of sight and motor skills. The disease is

usually fatal by the late teens or twenties. Juvenile Batten disease is the

most common of a group of disorders called neuronal ceroid lipofuscinoses,

or NCLs. NCLs are characterized by a buildup of pigments called lipofuscins

in the body's cells.

In the new study, Dr. Pearce and colleagues examined two strains of mice in

which the CLN3 gene is disabled, or " knocked out. " The CLN3 knockout mice

develop symptoms that resemble those seen in human Batten disease. The

researchers found an autoantibody (immune system protein) that inhibits

GAD65 in the bloodstreams of these mice. Autoantibodies are generated when

the immune system mistakenly begins attacking the body's own proteins. The

mice also had elevated levels of glutamate, reduced GAD enzyme activity, and

an abnormal condition called reactive astrocytosis in the brain. Reactive

astrocytosis is a proliferation of star-shaped cells called astrocytes and

typically occurs after the brain is damaged in some way. Gene analysis

showed that the CLN3 knockout mice also had changes in the activity of

several genes linked to the production and use of glutamate.

To see if children with Batten disease had an autoimmune reaction like the

one seen in the mice, the researchers tested blood from 20 individuals with

the disease. They found that all of the children with Batten disease had

autoantibodies to GAD65, while children without the disease did not have

this autoantibody. " We tested a lot of children with Batten disease, and all

of them have this antibody, so it is clearly some sort of clue as to what's

going on in this disease, " says Dr. Pearce. Postmortem brain tissue from

another child who died with juvenile Batten disease showed both reactive

astrocytosis and reduced GAD levels compared to individuals without the

disease.

" This is the first study to show autoimmunity in a pediatric

neurodegenerative disorder of genetic origin, " says Giovanna Spinella, M.D.,

a pediatric neurologist from NINDS. " The finding also illustrates how

studying rare disorders can provide new ways of understanding disease

processes that may be applicable in a broader sense. "

Previous studies have shown that GABA-producing neurons are lost early in

the course of Batten disease. Since these neurons frequently contain GAD65,

their loss may result from the immune reaction to this enzyme. The excess of

glutamate also may lead to neuron death through a process called

excitotoxicity, in which neurons die because they become overstimulated. The

resulting neuron loss may lead to the learning impairments, movement

problems, and other neurological symptoms of Batten disease. Because the

autoantibody prevents glutamate — which increases nerve signaling — from

being converted to GABA — which inhibits neuron activity — the autoimmune

reaction also provides a plausible explanation for the seizures that occur

in children with Batten disease, says Dr. Pearce. Researchers believe that

many seizure disorders result from neurotransmitter abnormalities that cause

too much nerve signaling.

The researchers do not yet know how the lack of CLN3 causes the immune

reaction, but they are planning additional studies to investigate that

question. One possibility is that the loss of CLN3 may interfere with the

function of GAD65 in a way that triggers the immune reaction, says Dr.

Pearce.

Autoantibodies to GAD have been detected in three other human diseases:

stiff person syndrome (SPS), cerebellar ataxia, and late-onset

insulin-dependent diabetes mellitus (IDDM). The autoantibodies in SPS and

cerebellar ataxia inhibit GAD activity, while those in IDDM do not. SPS and

cerebellar ataxia are adult-onset neurological disorders that cause

progressive muscle rigidity and spasms, symptoms that also occur in the late

stages of Batten disease. A recently reported clinical trial by NINDS

researchers found that immunotherapy significantly decreased stiffness and

spasms in patients with SPS. Since juvenile Batten disease is linked to the

same type of autoimmune response as SPS, immunotherapy may help to slow the

progression of Batten disease, says Dr. Pearce.

While the new findings are intriguing, more research is needed to determine

what the loss of the CLN3 gene does in the body and how the autoimmune

response may contribute to the symptoms and progression of juvenile Batten

disease, says Dr. Pearce. He and his colleagues are planning studies to

investigate these questions.

The NINDS is a component of the National Institutes of Health in Bethesda,

land, and is the nation's primary supporter of biomedical research on

the brain and nervous system.

*Chattopadhyay S, Ito M, JD, AI, Curran TM, Powers JM, Pearce

DA. " An Autoantibody Inhibitory to Glutamic Acid Decarboxylase in the

Neurodegenerative Disorder Batten Disease. " Human Molecular Genetics, June

1, 2002, Vol.11, No. 12, pp. 1421-1431.

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