Re: Autoimmune Link In Juvenile Batten Disease

[Guest guest]

Cheryl,

Thought you might be interested in this message I recently posted on ABMD list,

they are different, but there are some similarities. Both ultimately inhibit

conversion of Glutamate to GABA, but immunologically differ.

--------------------------------------------------------------------------------

Your message stated: " 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. " and also; " in

this disorder have an

immune reaction that disables an important enzyme in the brain. "

This is what I posted:

--------------------------------------------------------------------------------

Glutaric aciduria does have some interesting info that we might learn from,

below is part of a discussion of the neurodegeneration associated with it. See

the bold type.

--------------------------------------------------------------------------------

The cause of acute neurodegeneration in type 1 glutaric acidemia is unknown. The

accumulation of glutaric and 3-hydroxyglutaric acid in basal ganglia have been

implicated in the inhibition of glutamic decarboxylase activity responsible for

the synthesis of g -amino butyric acid (GABA).11 Glutamate toxicity has been

considered to be due to repeated depolarization of glutamate receptors in basal

ganglia.12 In most patients with type 1 glutaric acidemia, the acute

degeneration of basal ganglia occurs after a viral illness. This observation has

led to the hypothesis of quinolinic acid toxicity as the cause of neural

degeneration.13 Glutaryl coenzyme A dehydrogenase, the defective enzyme in type

1 glutaric acidemia, is responsible for the breakdown of L-tryptophan, as well

as L-lysine and its derivatives. A block in glutaryl coenzyme A dehydrogenase

might shunt tryptophan catabolism to the alternate kynurenine pathway. When

viral infections provoke the syntheses of a and b interferons, a well-known

effect of these compounds is to induce indolamine-2, 3-dioxygenase, which would

then lead to the formation of quinolinic acid, a well-established neurotoxin.13

http://www.kfshrc.edu.sa/annals/182/97-216.html

--------------------------------------------------------------------------------

To further explain some of this, since they don't make it clear; indolamine-2,

3-dioxygenase converts tryptophan to quinolinic acid, which for example has been

demonstrated to be 100 times more potent at stimulating the glutamate receptors

than glutamate itself (in rats). Ouinolinic acid then goes towards Kynurenine

then towards niacin>niacinamide,and NAD etc. This probable indolamine-2,

3-dioxygenase activity is compatible with reduced plasma tryptophan in autism

(as I think has been discussing). I don't think Glutaryl coenzyme A

dehydrogenase is associated with the tryptophan>>serotonin pathway, but instead

is used to metabolise tryptophan for energy. As I mentioned earlier, GPL labs

state: " Some of the other biochemical abnormalities common in autism include

elevated uracil and elevated glutaric

acid.(http://www.greatplainslaboratory.com/test1.html) " . It is not clear

however if there is a relationship between GABA synthesis and glutaric acid

levels being demonstrated by the findings of elevated GABA in autistic blood

samples as was discussed on this list some months back. One possibility might be

that true Glutaryl coenzyme A dehydrogenase deficiency might manifest with much

greater elevation of glutaric acid, and the level seen in autism is not nearly

as significant or as capable of causing inhibition of glutamic

decarboxylase/GABA synthesis.

Jon.

PS. This was included on the site above. Treatment includes a low protein diet

to avoid tryptophan and lysine.

--------------------------------------------------------------------------------

The case presented suggests that type 1 glutaric acidemia is a prenatal onset

disease, as evidenced by the macrocephaly and by the pathognomonic brain MRI

findings of the disease at birth. In a fetus in whom the disease was prenatally

detected and an elective abortion performed, significant histologic

abnormalities were found in the brain tissue.10 Since the disease is potentially

treatable, these observations raise the possibility of prenatal treatment of a

diseased fetus by riboflavin and carnitine administration to the

mother.http://www.kfshrc.edu.sa/annals/182/97-216.html

--------------------------------------------------------------------------------

Autoimmune Link In Juvenile Batten Disease

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.

_________________________________________________________________

Send and receive Hotmail on your mobile device: http://mobile.msn.com

Responsibility for the content of this message lies strictly with

the original author, and is not necessarily endorsed by or the

opinion of the Research Institute.

[Guest guest]

Hi Jon,

I can see the similarities. What is interesting is how the abnormalities

are viewed. It really reminds me of what is going on in the world of

autism. Everyone agrees that our children have all types of abnormalities,

but they look at them in different ways.

What immediately catches my eye (from the point of view) is the viral

trigger. Then the discussion of interferons leading to other effects. When

my younger son had his bloodwork, his elevated interferon was one of the

indicators that we were looking at some type of chronic viral problem. By

treating the viral component we took care of the elevated interferon and the

downstream effects. We also try to have more protein in his diet so his

body has the building blocks necessary to function properly.

What is exciting about so much of the research coming out is the change in

focus. We are beginning to find out that even disorders like Batten Disease

and Rett syndrome have an autoimmune component. Just think how many people

could potentially be helped if we gain access to the immune modulators.

Cheryl

>From: " Jon " <jerseybean@...>

>Reply-

>< >

>Subject: Re: Autoimmune Link In Juvenile Batten Disease

>Date: Sat, 1 Jun 2002 22:16:54 +0100

>

>Cheryl,

>

>Thought you might be interested in this message I recently posted on ABMD

>list, they are different, but there are some similarities. Both ultimately

>inhibit conversion of Glutamate to GABA, but immunologically differ.

>

>-------------------------------------------------------------------------------\

-

>

>Your message stated: " 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. " and also; " in this disorder have an

>immune reaction that disables an important enzyme in the brain. "

>

>This is what I posted:

>

>-------------------------------------------------------------------------------\

-

>

>Glutaric aciduria does have some interesting info that we might learn from,

>below is part of a discussion of the neurodegeneration associated with it.

>See the bold type.

>

>-------------------------------------------------------------------------------\

-

>

>The cause of acute neurodegeneration in type 1 glutaric acidemia is

>unknown. The accumulation of glutaric and 3-hydroxyglutaric acid in basal

>ganglia have been implicated in the inhibition of glutamic decarboxylase

>activity responsible for the synthesis of g -amino butyric acid (GABA).11

>Glutamate toxicity has been considered to be due to repeated depolarization

>of glutamate receptors in basal ganglia.12 In most patients with type 1

>glutaric acidemia, the acute degeneration of basal ganglia occurs after a

>viral illness. This observation has led to the hypothesis of quinolinic

>acid toxicity as the cause of neural degeneration.13 Glutaryl coenzyme A

>dehydrogenase, the defective enzyme in type 1 glutaric acidemia, is

>responsible for the breakdown of L-tryptophan, as well as L-lysine and its

>derivatives. A block in glutaryl coenzyme A dehydrogenase might shunt

>tryptophan catabolism to the alternate kynurenine pathway. When viral

>infections provoke the syntheses of a and b interferons, a well-known

>effect of these compounds is to induce indolamine-2, 3-dioxygenase, which

>would then lead to the formation of quinolinic acid, a well-established

>neurotoxin.13 http://www.kfshrc.edu.sa/annals/182/97-216.html

>

>-------------------------------------------------------------------------------\

-

>

>

>To further explain some of this, since they don't make it clear;

>indolamine-2, 3-dioxygenase converts tryptophan to quinolinic acid, which

>for example has been demonstrated to be 100 times more potent at

>stimulating the glutamate receptors than glutamate itself (in rats).

>Ouinolinic acid then goes towards Kynurenine then towards

>niacin>niacinamide,and NAD etc. This probable indolamine-2, 3-dioxygenase

>activity is compatible with reduced plasma tryptophan in autism (as I think

> has been discussing). I don't think Glutaryl coenzyme A dehydrogenase

>is associated with the tryptophan>>serotonin pathway, but instead is used

>to metabolise tryptophan for energy. As I mentioned earlier, GPL labs

>state: " Some of the other biochemical abnormalities common in autism

>include elevated uracil and elevated glutaric

>acid.(http://www.greatplainslaboratory.com/test1.html) " . It is not clear

>however if there is a relationship between GABA synthesis and glutaric acid

>levels being demonstrated by the findings of elevated GABA in autistic

>blood samples as was discussed on this list some months back. One

>possibility might be that true Glutaryl coenzyme A dehydrogenase deficiency

>might manifest with much greater elevation of glutaric acid, and the level

>seen in autism is not nearly as significant or as capable of causing

>inhibition of glutamic decarboxylase/GABA synthesis.

>

>Jon.

>

>PS. This was included on the site above. Treatment includes a low protein

>diet to avoid tryptophan and lysine.

>

>-------------------------------------------------------------------------------\

-

>The case presented suggests that type 1 glutaric acidemia is a prenatal

>onset disease, as evidenced by the macrocephaly and by the pathognomonic

>brain MRI findings of the disease at birth. In a fetus in whom the disease

>was prenatally detected and an elective abortion performed, significant

>histologic abnormalities were found in the brain tissue.10 Since the

>disease is potentially treatable, these observations raise the possibility

>of prenatal treatment of a diseased fetus by riboflavin and carnitine

>administration to the

>mother.http://www.kfshrc.edu.sa/annals/182/97-216.html

>-------------------------------------------------------------------------------\

-

>

> Autoimmune Link In Juvenile Batten Disease

>

>

> 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.

>

>

>

>

>

>

> _________________________________________________________________

> Send and receive Hotmail on your mobile device: http://mobile.msn.com

>

>

>

> Responsibility for the content of this message lies strictly with

> the original author, and is not necessarily endorsed by or the

> opinion of the Research Institute.

>

>

>

[Guest guest]

Thanks Cheryl,

I wasn't aware of autoimmune presentation in Retts, I'm trying to think of a

connection to MECP2 mutation, not having made one, I presume there are

possibilities since it otherwise is responsible for gene transcription

repression. I have a lead on that which I'm trying to push (BTW), since some

mothers have reported improvements in their girls when given antibiotics, and

some of them work by repressing mamalian transcription too. If you know anyone

who could advance this then I'd be glad to send what I have so far.

The answer may be in the files section, but I'm not very clear on just what is

expected of these immune modulators. I don't suppose they are going to be

steroids but whatever they are, would they not carry equal risk? It seems a bit

like having your cake AND eating it, on one hand you have chronic viral loading

that probably results in increased cytokines, and on the other you run the risk

of weakening defences against further infection. One thing that interferon does

do is prevent further viral infection, so whilst it might be an ideal to reduce

it in one respect, you are dropping your guard in another. Aren't

immune-modulators simply immune-suppressants by another name? I Hope I don't

have the wrong end of the stick!

Jon.

Autoimmune Link In Juvenile Batten Disease

>

>

> 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.

>

>

>

>

>

>

> _________________________________________________________________

> Send and receive Hotmail on your mobile device: http://mobile.msn.com

>

>

>

> Responsibility for the content of this message lies strictly with

> the original author, and is not necessarily endorsed by or the

> opinion of the Research Institute.

>

>

>

[Guest guest]

Jon,

Although the focus has been on the MECP2 mutation, recently there was

research on autoantibodies.

-----------------------------------------------------------------------

Brain Dev 2001 Dec;23 Suppl 1:S113-S117 Related Articles, Books, LinkOut

Brain-directed autoantibodies levels in the serum of Rett syndrome patients.

Klushnik TP, Gratchev VV, Belichenko PV.

Laboratory of Molecular Biochemistry, National Mental Health Research

Center, 115522, Moscow, Russia

Increased titer of brain-directed autoantibodies (AAB) may represent a risk

for brain development in children with Rett syndrome (RTT). The aims of this

work were to study the levels of brain-directed AAB, mainly nerve growth

factor (NGF) and S-100 protein AAB, to analyze morphological features of

brain labeling by AAB produced in RTT patients, and to correlate with

clinical manifestation. The increased titer of anti-NGF AAB, but not of

anti-S100 AAB has been determined in the blood of RTT patients. The blood

from five RTT girls was investigated repeatedly (two to four times) within

0.5-3 years. In these RTT patients the level of anti-NGF AAB was stable, not

depending on the stage of illness, so individual stability of anti-NGF AAB

levels have been detected. However, the negative correlation between the

level of these AAB and severity of disease has been found: girls with the

milder course of illness (with relative preservation of speech and locomotor

functions, later disease onset, and later development of regressive

symptoms) were characterized by the higher levels of AAB. The study also

revealed immunohistochemical labeling of neuronal population with serum from

RTT patients. Serum AAB from RTT cases labeled the cytoplasm and apical

dendrites of pyramidal neurons in the neocortex and hippocampus, neurons in

basal ganglia and brain stem, but not in the cerebellum of rats. Our results

show the presence of brain-directed AAB in blood serum of RTT patients,

which suggests an autoimmune component in pathogenesis of RTT.

PMID: 11738855 [PubMed - as supplied by publisher]

------------------------------------------------------------------------

(me again)

It's possible that antibiotics are actually addressing an infection that is

triggering autoimmunity. It is also known that antibiotics can have other

effects. If I remember correctly, Erythromycin increases cytokines like

IL-6 and IL-10. Biaxin has been found to increase IL-10. I think IL-6 can

be both immune stimulating or supressive and IL-10 is more of an immune down

regulator. I haven't run across info on other antibiotics (I haven't

actively searched, either) but it wouldn't surprise me if they have other

effects besides working against bacterial infections.

The immune modulators work in a way completely different than what is

available now. Instead of stimulation or suppression, they actually balance

the immune system. The body is able to deal with infections properly and

they also appear to have direct effects against viruses. There are at least

a half a dozen that are already developed and can become available after

appropriate trials for are completed. VIP is a good example of the

positive effects possible from an immune modulator. The immune modulator

needed for a particular person would depend on their abnormalities, not the

diagnosis.

Cheryl

----------------------------------------------------------------------

FROM OMIM

Vasoactive intestinal peptide (VIP) is present not only in gastrointestinal

tissues but also in neural tissues, possibly as a neurotransmitter, and

exhibits a wide variety of biologic actions.

Vasoactive intestinal peptide is a neuropeptide present in the lymphoid

microenvironment that elicits a broad spectrum of biologic functions,

including the modulation of innate and adaptive immunity, and shows a

predominant antiinflammatory action. VIP promotes TH2 differentiation and

inhibits TH1 responses by regulating macrophage costimulatory signals and

probably IL12/IFN-gamma production. In collagen-induced arthritis, a murine

model for rheumatoid arthritis, Delgado et al. (2001) administered VIP daily

or on alternate days for 2 weeks. Treatment with VIP significantly reduced

incidence and severity of arthritis in this model, completely abrogating

joint swelling and destruction of cartilage and bone. The therapeutic effect

of VIP was associated with downregulation of both inflammatory and

autoimmune components of the disease. Delgado et al. (2001) concluded that

VIP is a viable candidate for the development of treatments for rheumatoid

arthritis.

Troger et al. (2001) investigated neurotransmitter behavior in the

streptozotocin-induced diabetic rat retina. They found reduction of

substance P (162320) and VIP, in contrast to the previously established

elevations in GABA and glycine in the early stages of diabetic retinopathy.

The authors stated that the reductions in substance P and vasoactive

intestinal polypeptide are noteworthy for the following reasons: first, both

peptides are known to modulate excitability of inner retinal neurons;

second, the reductions might be the result of excitotoxin damage.

>From: " Jon " <jerseybean@...>

>Reply-

>< >

>Subject: Re: Autoimmune Link In Juvenile Batten Disease

>Date: Sun, 2 Jun 2002 22:53:11 +0100

>

>Thanks Cheryl,

>

>I wasn't aware of autoimmune presentation in Retts, I'm trying to think of

>a connection to MECP2 mutation, not having made one, I presume there are

>possibilities since it otherwise is responsible for gene transcription

>repression. I have a lead on that which I'm trying to push (BTW), since

>some mothers have reported improvements in their girls when given

>antibiotics, and some of them work by repressing mamalian transcription

>too. If you know anyone who could advance this then I'd be glad to send

>what I have so far.

>

>The answer may be in the files section, but I'm not very clear on just what

>is expected of these immune modulators. I don't suppose they are going to

>be steroids but whatever they are, would they not carry equal risk? It

>seems a bit like having your cake AND eating it, on one hand you have

>chronic viral loading that probably results in increased cytokines, and on

>the other you run the risk of weakening defences against further infection.

>One thing that interferon does do is prevent further viral infection, so

>whilst it might be an ideal to reduce it in one respect, you are dropping

>your guard in another. Aren't immune-modulators simply immune-suppressants

>by another name? I Hope I don't have the wrong end of the stick!

>

>Jon.

_________________________________________________________________

Join the world’s largest e-mail service with MSN Hotmail.

http://www.hotmail.com

[Guest guest]

Cheryl - your note mid-page probably explains why Dr G recommends using

erythromicin or Biaxin if antibiotics indicated.

Have used a brand called Klacid here - clarythromicin - observed improved

focus during this time.

Re: Autoimmune Link In Juvenile Batten Disease

>Date: Sun, 2 Jun 2002 22:53:11 +0100

>

>Thanks Cheryl,

>

>I wasn't aware of autoimmune presentation in Retts, I'm trying to think of

>a connection to MECP2 mutation, not having made one, I presume there are

>possibilities since it otherwise is responsible for gene transcription

>repression. I have a lead on that which I'm trying to push (BTW), since

>some mothers have reported improvements in their girls when given

>antibiotics, and some of them work by repressing mamalian transcription

>too. If you know anyone who could advance this then I'd be glad to send

>what I have so far.

>

>The answer may be in the files section, but I'm not very clear on just what

>is expected of these immune modulators. I don't suppose they are going to

>be steroids but whatever they are, would they not carry equal risk? It

>seems a bit like having your cake AND eating it, on one hand you have

>chronic viral loading that probably results in increased cytokines, and on

>the other you run the risk of weakening defences against further infection.

>One thing that interferon does do is prevent further viral infection, so

>whilst it might be an ideal to reduce it in one respect, you are dropping

>your guard in another. Aren't immune-modulators simply immune-suppressants

>by another name? I Hope I don't have the wrong end of the stick!

>

>Jon.

_________________________________________________________________

Join the world’s largest e-mail service with MSN Hotmail.

http://www.hotmail.com

Responsibility for the content of this message lies strictly with

the original author, and is not necessarily endorsed by or the

opinion of the Research Institute.

[Guest guest]

He has said that he likes to use this class of antibiotics because instead

of directly killing bacteria, they help the body to do it itself. Many

antibiotics directly kill bacteria. The good bacteria is killed right along

with the bad. Then you have the potential for losing control of yeast

suppression.

>From: " R M " <rmwilson@...>

>Reply-

>< >

>Subject: RE: Autoimmune Link In Juvenile Batten Disease

>Date: Mon, 3 Jun 2002 23:17:26 +0800

>

>Cheryl - your note mid-page probably explains why Dr G recommends using

>erythromicin or Biaxin if antibiotics indicated.

>Have used a brand called Klacid here - clarythromicin - observed improved

>focus during this time.

>

> Re: Autoimmune Link In Juvenile Batten Disease

> >Date: Sun, 2 Jun 2002 22:53:11 +0100

> >

> >Thanks Cheryl,

> >

> >I wasn't aware of autoimmune presentation in Retts, I'm trying to think

>of

> >a connection to MECP2 mutation, not having made one, I presume there are

> >possibilities since it otherwise is responsible for gene transcription

> >repression. I have a lead on that which I'm trying to push (BTW), since

> >some mothers have reported improvements in their girls when given

> >antibiotics, and some of them work by repressing mamalian transcription

> >too. If you know anyone who could advance this then I'd be glad to send

> >what I have so far.

> >

> >The answer may be in the files section, but I'm not very clear on just

>what

> >is expected of these immune modulators. I don't suppose they are going to

> >be steroids but whatever they are, would they not carry equal risk? It

> >seems a bit like having your cake AND eating it, on one hand you have

> >chronic viral loading that probably results in increased cytokines, and

>on

> >the other you run the risk of weakening defences against further

>infection.

> >One thing that interferon does do is prevent further viral infection, so

> >whilst it might be an ideal to reduce it in one respect, you are dropping

> >your guard in another. Aren't immune-modulators simply

>immune-suppressants

> >by another name? I Hope I don't have the wrong end of the stick!

> >

> >Jon.

>

>

>

>

>_________________________________________________________________

>Join the world’s largest e-mail service with MSN Hotmail.

>http://www.hotmail.com

>

>

>

>Responsibility for the content of this message lies strictly with

>the original author, and is not necessarily endorsed by or the

>opinion of the Research Institute.

>

>

>

[Guest guest]

Thanks Cheryl,

It certainly looks as if the NGF autoantibodies are a good thing so far as Retts

is concerned. Possibly it makes up for the inadequate repression by defeating

the stimulus (NGF).

You may have seen the first (edited) abstract, but here it is anyway:

--------------------------------------------------------------------------------

Rett syndrome is caused by mutations in X-linked MECP2, encoding

methyl-CpG-binding protein 2.

Using a systematic gene screening approach, we have identified mutations in the

gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the

cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the

mammalian genome and mediates transcriptional repression through interaction

with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21

sporadic patients, we found 3 de novo missense mutations in the region encoding

the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift

and a de novo nonsense mutation, both of which disrupt the transcription

repression domain (TRD).

--------------------------------------------------------------------------------

Knowing that antibiotics can mess with transcription, and that mothers were

reporting improvements while using them it seems to make sense that antibiotics

could be used to treat Retts.

Brief snippet and example of an extensive report:

Inhibitors of nucleic acid synthesis or function [back to list]

The antibiotics that interfere with DNA and RNA synthesis can be divided into 3

groups

1.. Those that interrupt nucleotide metabolism, usually by interference with

nucleotide synthesis or interconversion

2.. Those that prevent the DNA acting as a template for replication or

transcription, either by physically blocking access or by breaking up the strand

- generally not specific enough to be used as antimicrobial drugs

3.. Those which directly inhibit the enzymes involved in nucleic acid

synthesis

The first thing to remember at this point is that relatively few such inhibitors

can tell the difference between bacterial and mammalian nucleotide synthesis.

Obviously, this would be important in the treatment of a patient. <SNIP>

The tetracyclines are a group of bacteriostatic antibiotics which inhibit both

70s and the mammalian 80s ribosomes, although the bacterial 70s ones are more

sensitive. This is due to their ability to reach higher concentrations within

bacterial cells. They act on protein synthesis by blocking the binding of

aminoacyl tRNA molecules at the A site.

(More on these and links at the very bottom of this post, this list does not

seem to allow bold or underlined text)

--------------------------------------------------------------------------------

I'm going to sneak some more of my response in your text, and will denote it

with *.

Re: Autoimmune Link In Juvenile Batten Disease

>Date: Sun, 2 Jun 2002 22:53:11 +0100

>

>Thanks Cheryl,

>

>I wasn't aware of autoimmune presentation in Retts, I'm trying to think of

>a connection to MECP2 mutation, not having made one, I presume there are

>possibilities since it otherwise is responsible for gene transcription

>repression. I have a lead on that which I'm trying to push (BTW), since

>some mothers have reported improvements in their girls when given

>antibiotics, and some of them work by repressing mamalian transcription

>too. If you know anyone who could advance this then I'd be glad to send

>what I have so far.

>

>The answer may be in the files section, but I'm not very clear on just what

>is expected of these immune modulators. I don't suppose they are going to

>be steroids but whatever they are, would they not carry equal risk? It

>seems a bit like having your cake AND eating it, on one hand you have

>chronic viral loading that probably results in increased cytokines, and on

>the other you run the risk of weakening defences against further infection.

>One thing that interferon does do is prevent further viral infection, so

>whilst it might be an ideal to reduce it in one respect, you are dropping

>your guard in another. Aren't immune-modulators simply immune-suppressants

>by another name? I Hope I don't have the wrong end of the stick!

>

>Jon.

------------------------------------------------------------------------------

Rett syndrome is caused by mutations in X-linked MECP2, encoding

methyl-CpG-binding protein 2.

Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030,

USA.

Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder

and one of the most common causes of mental retardation in females, with an

incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to

develop normally until 6-18 months of age, then gradually lose speech and

purposeful hand use, and develop microcephaly, seizures, autism, ataxia,

intermittent hyperventilation and stereotypic hand movements. After initial

regression, the condition stabilizes and patients usually survive into

adulthood. As RTT occurs almost exclusively in females, it has been proposed

that RTT is caused by an X-linked dominant mutation with lethality in hemizygous

males. Previous exclusion mapping studies using RTT families mapped the locus to

Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have

identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding

protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG

dinucleotides in the mammalian genome and mediates transcriptional repression

through interaction with histone deacetylase and the corepressor SIN3A (refs

12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in

the region encoding the highly conserved methyl-binding domain (MBD) as well as

a de novo frameshift and a de novo nonsense mutation, both of which disrupt the

transcription repression domain (TRD). In two affected half-sisters of a RTT

family, we found segregation of an additional missense mutation not detected in

their obligate carrier mother. This suggests that the mother is a germline

mosaic for this mutation. Our study reports the first disease-causing mutations

in RTT and points to abnormal epigenetic regulation as the mechanism underlying

the pathogenesis of RTT.

PMID: 10508514 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------------

Brief snippet and example of an extensive report:

Inhibitors of nucleic acid synthesis or function [back to list]

The antibiotics that interfere with DNA and RNA synthesis can be divided into

3 groups

1.. Those that interrupt nucleotide metabolism, usually by interference with

nucleotide synthesis or interconversion

2.. Those that prevent the DNA acting as a template for replication or

transcription, either by physically blocking access or by breaking up the strand

- generally not specific enough to be used as antimicrobial drugs

3.. Those which directly inhibit the enzymes involved in nucleic acid

synthesis

The first thing to remember at this point is that relatively few such

inhibitors can tell the difference between bacterial and mammalian nucleotide

synthesis. Obviously, this would be important in the treatment of a patient.

One exception to this is the synthesis of tetrahydrofolic acid, which is a

donor of one-carbon units at several points in the synthesis of both purine and

pyrimidine nucleotides. As can be seen in the diagram below, the synthesis of

THFA is different in bacteria compared to mammals. This gives possibilities for

antibiotic attack without endangering your patient. This is where the first

widely used antibiotics, the sulphonamides, acted. These are structural

analogues of p-aminobenzoic acid and act as false substrates for the

dihydropteroate enzyme.

Similarly, the 2,4-diaminopyrimidines competitively inhibit the bacterial

dihydrofolate reductase enzymes but are specific enough to the bacteria enzyme

not to affect the mammalian one.

>>Snip>>

The aminoglycoside-aminocyclitol group, which includes a number of

old-favourites such as streptomycin, neomycin, gentamycin and kanamycin, bind to

different areas of the ribosome causing the initiation complex either not to

form or inhibiting translocation of the growing peptide from the A site to the P

site.

Chloramphenicol is another well-known antibiotic that binds to the 70s

ribosome, seeming in this case to inhibit the peptidyltransferase reaction,

which forms the peptide bonds between amino acid residues.

The macrolides are a family of mostly bacteriostatic antibiotics, including

erythromycin, which prevent protein synthesis by binding to the tRNA binding

site on the 50s ribosome, causing the tRNA molecules to dissociate from the

ribosomes.

The tetracyclines are a group of bacteriostatic antibiotics which inhibit both

70s and the mammalian 80s ribosomes, although the bacterial 70s ones are more

sensitive. This is due to their ability to reach higher concentrations within

bacterial cells. They act on protein synthesis by blocking the binding of

aminoacyl tRNA molecules at the A site.

Again, you can see that there are a number of possibilities for antibiotic

action at this level

http://www.sunderland.ac.uk/~hs0jsh/bio307/modes.htm#Inhibitors_of_nucleic_acid_\

synthesis

[Guest guest]

Jon, it's interesting how we take a different perspective on the Retts

research, transcription, etc. I was wondering if you would look at a few

things and let me know if it has any effect on your perspective. I'm just

curious and you seem to have a good researchers mind. Either way, I'll

still respond and you'll have a better idea of what I'm thinking about. If

you'd rather not, that's o.k. too.

Cheryl

NERVE GROWTH FACTOR; NGF

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=162030

Try to look at NRAS and the links it has for KRAS, HRAS...

BACULOVIRAL IAP REPEAT-CONTAINING PROTEIN 1; BIRC1

Alternative titles; symbols

NEURONAL APOPTOSIS INHIBITORY PROTEIN; NAIP

(towards the bottom you'll see mention of NGF)

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600355

AKT1

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164730

from this link make sure to click on RAF, PDGF, and.....

>From: " Jon " <jerseybean@...>

>Reply-

>< >

>Subject: Re: Autoimmune Link In Juvenile Batten Disease

>Date: Mon, 3 Jun 2002 20:39:40 +0100

>

>Thanks Cheryl,

>

>It certainly looks as if the NGF autoantibodies are a good thing so far as

>Retts is concerned. Possibly it makes up for the inadequate repression by

>defeating the stimulus (NGF).

>

>You may have seen the first (edited) abstract, but here it is anyway:

>

>-------------------------------------------------------------------------------\

-

>

>Rett syndrome is caused by mutations in X-linked MECP2, encoding

>methyl-CpG-binding protein 2.

>Using a systematic gene screening approach, we have identified mutations in

>the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as

>the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides

>in the mammalian genome and mediates transcriptional repression through

>interaction with histone deacetylase and the corepressor SIN3A (refs

>12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations

>in the region encoding the highly conserved methyl-binding domain (MBD) as

>well as a de novo frameshift and a de novo nonsense mutation, both of which

>disrupt the transcription repression domain (TRD).

>

>

>-------------------------------------------------------------------------------\

-

>

>Knowing that antibiotics can mess with transcription, and that mothers were

>reporting improvements while using them it seems to make sense that

>antibiotics could be used to treat Retts.

>

>Brief snippet and example of an extensive report:

>Inhibitors of nucleic acid synthesis or function [back to list]

>

>The antibiotics that interfere with DNA and RNA synthesis can be divided

>into 3 groups

>

> 1.. Those that interrupt nucleotide metabolism, usually by interference

>with nucleotide synthesis or interconversion

> 2.. Those that prevent the DNA acting as a template for replication or

>transcription, either by physically blocking access or by breaking up the

>strand - generally not specific enough to be used as antimicrobial drugs

> 3.. Those which directly inhibit the enzymes involved in nucleic acid

>synthesis

>The first thing to remember at this point is that relatively few such

>inhibitors can tell the difference between bacterial and mammalian

>nucleotide synthesis. Obviously, this would be important in the treatment

>of a patient. <SNIP>

>

>The tetracyclines are a group of bacteriostatic antibiotics which inhibit

>both 70s and the mammalian 80s ribosomes, although the bacterial 70s ones

>are more sensitive. This is due to their ability to reach higher

>concentrations within bacterial cells. They act on protein synthesis by

>blocking the binding of aminoacyl tRNA molecules at the A site.

>

>(More on these and links at the very bottom of this post, this list does

>not seem to allow bold or underlined text)

>-------------------------------------------------------------------------------\

-

>I'm going to sneak some more of my response in your text, and will denote

>it with *.

>

> Re: Autoimmune Link In Juvenile Batten Disease

>

>

> Jon,

> Although the focus has been on the MECP2 mutation, recently there was

> research on autoantibodies.

> -----------------------------------------------------------------------

> Brain Dev 2001 Dec;23 Suppl 1:S113-S117 Related Articles, Books, LinkOut

>

> Brain-directed autoantibodies levels in the serum of Rett syndrome

>patients.

>

> Klushnik TP, Gratchev VV, Belichenko PV.

>

> Laboratory of Molecular Biochemistry, National Mental Health Research

> Center, 115522, Moscow, Russia

>

> Increased titer of brain-directed autoantibodies (AAB) may represent a

>risk

> for brain development in children with Rett syndrome (RTT). The aims of

>this

> work were to study the levels of brain-directed AAB, mainly nerve growth

> factor (NGF) and S-100 protein AAB, to analyze morphological features of

> brain labeling by AAB produced in RTT patients, and to correlate with

> clinical manifestation. The increased titer of anti-NGF AAB, but not of

> anti-S100 AAB has been determined in the blood of RTT patients. The

>blood

> from five RTT girls was investigated repeatedly (two to four times)

>within

> 0.5-3 years. In these RTT patients the level of anti-NGF AAB was stable,

>not

> depending on the stage of illness, so individual stability of anti-NGF

>AAB

> levels have been detected. However, the negative correlation between the

> level of these AAB and severity of disease has been found: girls with

>the

> milder course of illness (with relative preservation of speech and

>locomotor

> functions, later disease onset, and later development of regressive

> symptoms) were characterized by the higher levels of AAB. The study also

> revealed immunohistochemical labeling of neuronal population with serum

>from

> RTT patients. Serum AAB from RTT cases labeled the cytoplasm and apical

> dendrites of pyramidal neurons in the neocortex and hippocampus, neurons

>in

> basal ganglia and brain stem, but not in the cerebellum of rats. Our

>results

> show the presence of brain-directed AAB in blood serum of RTT patients,

> which suggests an autoimmune component in pathogenesis of RTT.

>

> PMID: 11738855 [PubMed - as supplied by publisher]

> ------------------------------------------------------------------------

> (me again)

> It's possible that antibiotics are actually addressing an infection that

>is

> triggering autoimmunity.

>

> * I don't think they would be helping in that respect, if indeed

>antibiotics can tame autoimmunity since the authors state: " girls with the

>milder course of illness were characterized by the higher levels of AAB. " *

>

> It is also known that antibiotics can have other

> effects. If I remember correctly, Erythromycin increases cytokines like

> IL-6 and IL-10. Biaxin has been found to increase IL-10. I think IL-6

>can

> be both immune stimulating or supressive and IL-10 is more of an immune

>down

> regulator. I haven't run across info on other antibiotics (I haven't

> actively searched, either) but it wouldn't surprise me if they have

>other

> effects besides working against bacterial infections.

>

> *That sounds reasonable, though I have not looked at this much either,

>will have to go on my " Must do " list.*

>

> The immune modulators work in a way completely different than what is

> available now. Instead of stimulation or suppression, they actually

>balance

> the immune system. The body is able to deal with infections properly

>and

> they also appear to have direct effects against viruses. There are at

>least

> a half a dozen that are already developed and can become available after

> appropriate trials for are completed. VIP is a good example of the

> positive effects possible from an immune modulator. The immune

>modulator

> needed for a particular person would depend on their abnormalities, not

>the

> diagnosis.

>

> Cheryl

>

> *VIP is indeed noteworthy, I have looked at it in the past, but didn't

>associate it as an immune modulator. I'm curious now what the selection

>criteria will be for the immune modulators trials, will they be

>patient-specific or random? Will each drug only be given to

>patients/volunteers if it is predicted to treat a specific and already

>identified immune irregularity?

>

> Jon*

>

> ----------------------------------------------------------------------

> FROM OMIM

> Vasoactive intestinal peptide (VIP) is present not only in

>gastrointestinal

> tissues but also in neural tissues, possibly as a neurotransmitter, and

> exhibits a wide variety of biologic actions.

>

> Vasoactive intestinal peptide is a neuropeptide present in the lymphoid

> microenvironment that elicits a broad spectrum of biologic functions,

> including the modulation of innate and adaptive immunity, and shows a

> predominant antiinflammatory action. VIP promotes TH2 differentiation

>and

> inhibits TH1 responses by regulating macrophage costimulatory signals

>and

> probably IL12/IFN-gamma production. In collagen-induced arthritis, a

>murine

> model for rheumatoid arthritis, Delgado et al. (2001) administered VIP

>daily

> or on alternate days for 2 weeks. Treatment with VIP significantly

>reduced

> incidence and severity of arthritis in this model, completely abrogating

> joint swelling and destruction of cartilage and bone. The therapeutic

>effect

> of VIP was associated with downregulation of both inflammatory and

> autoimmune components of the disease. Delgado et al. (2001) concluded

>that

> VIP is a viable candidate for the development of treatments for

>rheumatoid

> arthritis.

>

> Troger et al. (2001) investigated neurotransmitter behavior in the

> streptozotocin-induced diabetic rat retina. They found reduction of

> substance P (162320) and VIP, in contrast to the previously established

> elevations in GABA and glycine in the early stages of diabetic

>retinopathy.

> The authors stated that the reductions in substance P and vasoactive

> intestinal polypeptide are noteworthy for the following reasons: first,

>both

> peptides are known to modulate excitability of inner retinal neurons;

> second, the reductions might be the result of excitotoxin damage.

>

>

_________________________________________________________________

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[Guest guest]

Amen Cheryl! Just think about all of the people who could have lives if the

immunemodulators work. That's the bottom line isn't it? Kathy NNY

[Guest guest]

Hi Cheryl,

We do seem to have quite different perspectives on this it is true, I would not

usually mount a defence for an autoimmune disorder, but in this case I am having

to make an exception. On the face of it I can see your perspective, but hidden a

little deeper in the text you directed me to it can be interpreted a little

differently.

Some background:

--------------------------------------------------------------------------------

Armstrong et al. (1995) systematically studied brains of 16 Rett girls ranging

in age from 2 to 35 years. They found no evidence that the pyramidal neurons in

Rett syndrome degenerate progressively with increasing age. Instead, they found

a striking decrease in the dendritic trees of selected cortical areas, chiefly

projection neurons of the motor, association, and limbic cortices. They

suggested that this may result in abnormalities of trophic factors.

http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?312750

--------------------------------------------------------------------------------

So there is an association with the link you gave, and here is an excerpt from

it:

--------------------------------------------------------------------------------

Using a neurite outgrowth assay in rat pheochromocytoma PC12 cells, they

observed that Naip overexpression impaired nerve growth factor (NGF)-induced

neurite outgrowth. The BIR motifs of Naip (residues 1-345) were not required for

this effect. However, the BIR domains of Naip were essential to prevent

apoptosis in PC12 cells after NGF deprivation or tumor necrosis factor-alpha

receptor (TNFAR; 191190) stimulation. Expression of full-length but not

BIR-deleted Naip protected against cell death. This correlated with reduced

activity of the cell death effector protease, caspase-3 (600636), in lysates of

Naip-PC12 cells. The authors hypothesized that dysregulation of cellular

differentiation and/or caspase suppression may contribute to motoneuron

dysfunction and cell death in spinal muscular atrophy where NAIP is mutated.

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600355

--------------------------------------------------------------------------------

Here is the basis of my alternative perspective; The MECP2 mutations commonly

demonstrated in Retts are to do with transcription repression. I chance that

this may well include the proforms of NGF, leading to an excess, and this might

not be matched by adequate conversion to NGF. The autoantibodies presumably will

not differentiate between pro-NGF or active NGF, and thus they will serve to

limit excessive pro-NGF. The difference between NGF & pro-NGF does seem to be an

important one; see text from your link denoted by " ** " :

Although proneurotrophins have been considered inactive precursors, Lee et al.

(2001) demonstrated that the proforms of NGF and the proforms of BDNF are

secreted and cleaved extracellularly by the serine protease plasmin (173350) and

by selective matrix metalloproteinases (MMP7, 178990; MMP3, 185250).** ProNGF is

a high-affinity ligand for p75(NTR) (NGFR; 162010), and induced

p75(NTR)-dependent apoptosis in cultured neurons with minimal activation of

TRK-alpha-mediated differentiation or survival**. The biologic action of

neurotrophins is thus regulated by proteolytic cleavage, with proforms

preferentially activating p75(NTR) to mediate apoptosis and mature forms

activating TRK receptors to promote survival.

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=162030

--------------------------------------------------------------------------------

This is the abstract from PubMed:

Regulation of cell survival by secreted proneurotrophins.

Lee R, Kermani P, Teng KK, Hempstead BL.

Division of Hematology, Department of Medicine, Weill Medical College of Cornell

University, 1300 York Avenue, New York, NY 10021, USA.

Neurotrophins are growth factors that promote cell survival, differentiation,

and cell death. They are synthesized as proforms that can be cleaved

intracellularly to release mature, secreted ligands. Although proneurotrophins

have been considered inactive precursors, we show here that the proforms of

nerve growth factor (NGF) and the proforms of brain derived neurotrophic factor

(BDNF) are secreted and cleaved extracellularly by the serine protease plasmin

and by selective matrix metalloproteinases (MMPs). **ProNGF is a high-affinity

ligand for p75(NTR) with high affinity and induced p75NTR-dependent apoptosis in

cultured neurons with minimal activation of TrkA-mediated differentiation or

survival. The biological action of neurotrophins is thus regulated by

proteolytic cleavage, with proforms preferentially activating p75NTR to mediate

apoptosis and mature forms activating Trk receptors to promote survival.**

PMID: 11729324 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

You may have detected a shift of opinion here however, I will explain.

Previously I proposed that the unregulated transcription might be further

upregulated by active NGF (A bit like no brakes, and a sticky gas pedal). Your

information leads me to consider that it might be due to an excessive production

of Pro-NGF that is not matched by conversion to active NGF. This is interesting

to consider, but a bit beyond my means to take any further. I'm stuck with the

identified mutations of MECP2 that are surely the underlying cause of Retts, and

a potential strategy that could improve the situation via an exogenous means of

transcription repression with or without NGF or autoantibodies as a factor.

I'm not sure I will have persuaded you otherwise and I welcome your input.

Jon.

Re: Autoimmune Link In Juvenile Batten Disease

>

>

> Jon,

> Although the focus has been on the MECP2 mutation, recently there was

> research on autoantibodies.

> -----------------------------------------------------------------------

> Brain Dev 2001 Dec;23 Suppl 1:S113-S117 Related Articles, Books, LinkOut

>

> Brain-directed autoantibodies levels in the serum of Rett syndrome

>patients.

>

> Klushnik TP, Gratchev VV, Belichenko PV.

>

> Laboratory of Molecular Biochemistry, National Mental Health Research

> Center, 115522, Moscow, Russia

>

> Increased titer of brain-directed autoantibodies (AAB) may represent a

>risk

> for brain development in children with Rett syndrome (RTT). The aims of

>this

> work were to study the levels of brain-directed AAB, mainly nerve growth

> factor (NGF) and S-100 protein AAB, to analyze morphological features of

> brain labeling by AAB produced in RTT patients, and to correlate with

> clinical manifestation. The increased titer of anti-NGF AAB, but not of

> anti-S100 AAB has been determined in the blood of RTT patients. The

>blood

> from five RTT girls was investigated repeatedly (two to four times)

>within

> 0.5-3 years. In these RTT patients the level of anti-NGF AAB was stable,

>not

> depending on the stage of illness, so individual stability of anti-NGF

>AAB

> levels have been detected. However, the negative correlation between the

> level of these AAB and severity of disease has been found: girls with

>the

> milder course of illness (with relative preservation of speech and

>locomotor

> functions, later disease onset, and later development of regressive

> symptoms) were characterized by the higher levels of AAB. The study also

> revealed immunohistochemical labeling of neuronal population with serum

>from

> RTT patients. Serum AAB from RTT cases labeled the cytoplasm and apical

> dendrites of pyramidal neurons in the neocortex and hippocampus, neurons

>in

> basal ganglia and brain stem, but not in the cerebellum of rats. Our

>results

> show the presence of brain-directed AAB in blood serum of RTT patients,

> which suggests an autoimmune component in pathogenesis of RTT.

>

> PMID: 11738855 [PubMed - as supplied by publisher]

> ------------------------------------------------------------------------

> (me again)

> It's possible that antibiotics are actually addressing an infection that

>is

> triggering autoimmunity.

>

> * I don't think they would be helping in that respect, if indeed

>antibiotics can tame autoimmunity since the authors state: " girls with the

>milder course of illness were characterized by the higher levels of AAB. " *

>

> It is also known that antibiotics can have other

> effects. If I remember correctly, Erythromycin increases cytokines like

> IL-6 and IL-10. Biaxin has been found to increase IL-10. I think IL-6

>can

> be both immune stimulating or supressive and IL-10 is more of an immune

>down

> regulator. I haven't run across info on other antibiotics (I haven't

> actively searched, either) but it wouldn't surprise me if they have

>other

> effects besides working against bacterial infections.

>

> *That sounds reasonable, though I have not looked at this much either,

>will have to go on my " Must do " list.*

>

> The immune modulators work in a way completely different than what is

> available now. Instead of stimulation or suppression, they actually

>balance

> the immune system. The body is able to deal with infections properly

>and

> they also appear to have direct effects against viruses. There are at

>least

> a half a dozen that are already developed and can become available after

> appropriate trials for are completed. VIP is a good example of the

> positive effects possible from an immune modulator. The immune

>modulator

> needed for a particular person would depend on their abnormalities, not

>the

> diagnosis.

>

> Cheryl

>

> *VIP is indeed noteworthy, I have looked at it in the past, but didn't

>associate it as an immune modulator. I'm curious now what the selection

>criteria will be for the immune modulators trials, will they be

>patient-specific or random? Will each drug only be given to

>patients/volunteers if it is predicted to treat a specific and already

>identified immune irregularity?

>

> Jon*

>

> ----------------------------------------------------------------------

> FROM OMIM

> Vasoactive intestinal peptide (VIP) is present not only in

>gastrointestinal

> tissues but also in neural tissues, possibly as a neurotransmitter, and

> exhibits a wide variety of biologic actions.

>

> Vasoactive intestinal peptide is a neuropeptide present in the lymphoid

> microenvironment that elicits a broad spectrum of biologic functions,

> including the modulation of innate and adaptive immunity, and shows a

> predominant antiinflammatory action. VIP promotes TH2 differentiation

>and

> inhibits TH1 responses by regulating macrophage costimulatory signals

>and

> probably IL12/IFN-gamma production. In collagen-induced arthritis, a

>murine

> model for rheumatoid arthritis, Delgado et al. (2001) administered VIP

>daily

> or on alternate days for 2 weeks. Treatment with VIP significantly

>reduced

> incidence and severity of arthritis in this model, completely abrogating

> joint swelling and destruction of cartilage and bone. The therapeutic

>effect

> of VIP was associated with downregulation of both inflammatory and

> autoimmune components of the disease. Delgado et al. (2001) concluded

>that

> VIP is a viable candidate for the development of treatments for

>rheumatoid

> arthritis.

>

> Troger et al. (2001) investigated neurotransmitter behavior in the

> streptozotocin-induced diabetic rat retina. They found reduction of

> substance P (162320) and VIP, in contrast to the previously established

> elevations in GABA and glycine in the early stages of diabetic

>retinopathy.

> The authors stated that the reductions in substance P and vasoactive

> intestinal polypeptide are noteworthy for the following reasons: first,

>both

> peptides are known to modulate excitability of inner retinal neurons;

> second, the reductions might be the result of excitotoxin damage.

>

>

_________________________________________________________________

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[Guest guest]

Jon, maybe our perspectives are not as far off as I thought. I think one of

the problems is that alot of the literature is not very clear.

What you've probably noticed is that most of what I post has to do with

cytokines, chemokines, neurotrophins, viruses, retroviruses, etc. These are

all factors discussed in neuroimmune/autoimmune disorders.

Some of what I had you look at was related to what you mentioned about

antibiotics and how they can interfere with DNA,etc., because some of our

DNA is not necessarily of human origin. Some have been converted into

normal functional genes, some haven't. My question would be what has become

activated due to the MECP2 mutation? Your original thought about a sticky

gas pedal and no brakes may be correct.

(From link I've given you below, see: gene expression)

" It is currently believed that transcription factors are the last link in

the long chain of events beginning with binding of cytokines to their

specific receptors and ending with the cell- and tissue-specific expression

or repression of genes and the associated alterations in the functional

activities of a cell. "

The immune modulators have the ability to balance the immune system and

potentially could treat disorders like Rett. The way I understand it, the

immune profiling studies will involve measuring cytokines and separating the

participants into subgroups depending on their profile. The immune

modulator chosen would be based on the type of imbalance a person has.

NGF is a cytokine and one of the things it does is induce the synthesis of

VIP. If you look at this link on NGF you'll see some of what you mention

below. I try to stay away from this site because it is really easy to keep

clicking and before you know it you've spent way too much time reading, LOL.

I almost did that just getting the link for you. I learned something

new and interesting though. Right before the references it says: Increased

levels of anti-NGF antibodies have been found in the sera of HSV-infected

patients. I wonder what else is able to trigger the antibodies?

Here's the link to NGF and you'll find that they also have info on many of

the other things mentioned below. (you can access from bottom of page)

http://www.copewithcytokines.de/cope.cgi?005975

Cheryl

>From: " Jon " <jerseybean@...>

>Reply-

>< >

>Subject: Re: Autoimmune Link In Juvenile Batten Disease

>Date: Wed, 5 Jun 2002 23:59:59 +0100

>

>Hi Cheryl,

>

>We do seem to have quite different perspectives on this it is true, I would

>not usually mount a defence for an autoimmune disorder, but in this case I

>am having to make an exception. On the face of it I can see your

>perspective, but hidden a little deeper in the text you directed me to it

>can be interpreted a little differently.

>

>Some background:

>-------------------------------------------------------------------------------\

-

>

>Armstrong et al. (1995) systematically studied brains of 16 Rett girls

>ranging in age from 2 to 35 years. They found no evidence that the

>pyramidal neurons in Rett syndrome degenerate progressively with increasing

>age. Instead, they found a striking decrease in the dendritic trees of

>selected cortical areas, chiefly projection neurons of the motor,

>association, and limbic cortices. They suggested that this may result in

>abnormalities of trophic factors.

>http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?312750

>

>-------------------------------------------------------------------------------\

-

>

>So there is an association with the link you gave, and here is an excerpt

>from it:

>-------------------------------------------------------------------------------\

-

>

>Using a neurite outgrowth assay in rat pheochromocytoma PC12 cells, they

>observed that Naip overexpression impaired nerve growth factor

>(NGF)-induced neurite outgrowth. The BIR motifs of Naip (residues 1-345)

>were not required for this effect. However, the BIR domains of Naip were

>essential to prevent apoptosis in PC12 cells after NGF deprivation or tumor

>necrosis factor-alpha receptor (TNFAR; 191190) stimulation. Expression of

>full-length but not BIR-deleted Naip protected against cell death. This

>correlated with reduced activity of the cell death effector protease,

>caspase-3 (600636), in lysates of Naip-PC12 cells. The authors hypothesized

>that dysregulation of cellular differentiation and/or caspase suppression

>may contribute to motoneuron dysfunction and cell death in spinal muscular

>atrophy where NAIP is mutated.

>http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600355

>

>-------------------------------------------------------------------------------\

-

>

>Here is the basis of my alternative perspective; The MECP2 mutations

>commonly demonstrated in Retts are to do with transcription repression. I

>chance that this may well include the proforms of NGF, leading to an

>excess, and this might not be matched by adequate conversion to NGF. The

>autoantibodies presumably will not differentiate between pro-NGF or active

>NGF, and thus they will serve to limit excessive pro-NGF. The difference

>between NGF & pro-NGF does seem to be an important one; see text from your

>link denoted by " ** " :

>

>

>Although proneurotrophins have been considered inactive precursors, Lee et

>al. (2001) demonstrated that the proforms of NGF and the proforms of BDNF

>are secreted and cleaved extracellularly by the serine protease plasmin

>(173350) and by selective matrix metalloproteinases (MMP7, 178990; MMP3,

>185250).** ProNGF is a high-affinity ligand for p75(NTR) (NGFR; 162010),

>and induced p75(NTR)-dependent apoptosis in cultured neurons with minimal

>activation of TRK-alpha-mediated differentiation or survival**. The

>biologic action of neurotrophins is thus regulated by proteolytic cleavage,

>with proforms preferentially activating p75(NTR) to mediate apoptosis and

>mature forms activating TRK receptors to promote survival.

>http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=162030

>

>-------------------------------------------------------------------------------\

-

>

>This is the abstract from PubMed:

>Regulation of cell survival by secreted proneurotrophins.

>

>Lee R, Kermani P, Teng KK, Hempstead BL.

>

>Division of Hematology, Department of Medicine, Weill Medical College of

>Cornell University, 1300 York Avenue, New York, NY 10021, USA.

>

>Neurotrophins are growth factors that promote cell survival,

>differentiation, and cell death. They are synthesized as proforms that can

>be cleaved intracellularly to release mature, secreted ligands. Although

>proneurotrophins have been considered inactive precursors, we show here

>that the proforms of nerve growth factor (NGF) and the proforms of brain

>derived neurotrophic factor (BDNF) are secreted and cleaved extracellularly

>by the serine protease plasmin and by selective matrix metalloproteinases

>(MMPs). **ProNGF is a high-affinity ligand for p75(NTR) with high affinity

>and induced p75NTR-dependent apoptosis in cultured neurons with minimal

>activation of TrkA-mediated differentiation or survival. The biological

>action of neurotrophins is thus regulated by proteolytic cleavage, with

>proforms preferentially activating p75NTR to mediate apoptosis and mature

>forms activating Trk receptors to promote survival.**

>

>PMID: 11729324 [PubMed - indexed for MEDLINE]

>

>-------------------------------------------------------------------------------\

-

>

>You may have detected a shift of opinion here however, I will explain.

>Previously I proposed that the unregulated transcription might be further

>upregulated by active NGF (A bit like no brakes, and a sticky gas pedal).

>Your information leads me to consider that it might be due to an excessive

>production of Pro-NGF that is not matched by conversion to active NGF. This

>is interesting to consider, but a bit beyond my means to take any further.

>I'm stuck with the identified mutations of MECP2 that are surely the

>underlying cause of Retts, and a potential strategy that could improve the

>situation via an exogenous means of transcription repression with or

>without NGF or autoantibodies as a factor.

>

>I'm not sure I will have persuaded you otherwise and I welcome your input.

>

>Jon.

_________________________________________________________________

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thanks for the explanation, cheryl.

mary n