FW: CAN's Overview of Autism Research

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CAN's Overview of Autism Research

FEAT DAILY NEWSLETTER Sacramento, California http://www.feat.org

" Healing Autism: No Finer a Cause on the Planet "

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March 1, 2000 Search www.feat.org/search/news.asp

Also: Repligen and Cure Autism Now Form Research Funding Partnership

What’s New, What’s Old and What’s Next 1998-2000: Overview of Autism

Research

By Portia Iversen

[This review of autism research is from the premiere issue of the Cure

Autism Now newsletter, Advances. Portia Iversen is a founder of CAN and is

a parent to an autistic child. There is some technical language.]

http://www.canfoundation.org/

After forty years in the desert, major change has been underway in the

field of autism research. The past two years in particular, have seen a

major increase in autism research. Significant new data are beginning to

accumulate, laying the ground work for discovering the causes, treatments

and a cure for autism.

Autism research is increasing, both in the number of studies being

conducted and in their scope and variety of approaches. We expect to see

this trend continue and as scientific efforts continue to accelerate, we

will experience the first medical breakthroughs in our understanding of the

causes of autism and the development of treatments and a cure.

The following is a sampling of important autism research conducted

over the past two years, which may be of particular interest to parents.

Note: The inclusion or omission of any study in this review does not

constitute an opinion as to its relevance, importance or validity.

Continued Evidence of Serotonin Involvement in Autism Dr. Diane

Chugani* of Wayne State University, Detroit has provided us with important

new information through the use of PET scanning techniques on the abnormal

capacity for serotonin synthesis in the brains of autistic children and

adults.

While the children appear to have decreased serotonin levels, adults

show increased levels. This data suggest that humans undergo a period of

high brain serotonin synthesis capacity during childhood and that the

developmental process may be disrupted in autistic children.

In a striking finding, n Leboyer* from the Faculte Jussieu in

Paris reports on whole blood serotonin and plasma beta-endorphin in autistic

probands and their first-degree relatives.

Whole blood serotonin is known to be elevated in autistic subjects and

could be a possible marker of genetic liability to autism. The author

confirms the previously reported familiality of hyperserotoninemia in autism

as mothers (51%), fathers (45%) and siblings (87%) have elevated levels of

serotonin and mothers (53%) also show elevated levels of C-ter-beta-EP-ir.

In other serotonin-related research, DeLong of Duke University

has completed a study on the use of low-doses of serotonin reuptake

inhibitors (SSRI) in young children with autism.

Twenty-two of the 37 children who underwent fluoxetine treatment had a

beneficial treatment response that was sustained during continuing treatment

for 13 - 33 months (mean 21 months). Those children with positive response

showed behavioral, language, cognitive, affective and social improvements.

In still another study involving SSRIs, Dr. D. Branford of the

Southern Derbyshire Mental Health Trust in Derby, England undertook a

retrospective case-note analysis of 37 adults with autism. The subjects were

prescribed one of two selective serotonin re-uptake inhibitor

antidepressants (fluoxetine or paroxetine). The SSRIs proved to be of no

benefit for 15 subjects (40%) and led to a deterioration in nine additional

cases (25%). However, some reduction of perseverative and maladaptive

behaviors was achieved in 13 cases (35%).

A number of other pharmaceuticals have recently been under

investigation for use in autism. Risperidone was investigated by Dr.

R. Nicolson of the University of Toronto in his study titled, “An open

trial of risperidone in young autistic children.” Eight of the 10 children

were considered to be responders. Dr. C.J. McDougle of Indiana University

School of Medicine conducted a 12-week double-blind placebo-controlled study

of risperidone in 31 adults with autistic spectrum disorders.

This study concluded that risperidone was superior to the placebo in

reducing repetitive behavior, aggression, anxiety or nervousness,

depression, irritability and the overall behavioral symptoms of autism. Nine

(60%) of 15 patients who received treatment with open-label risperidone

following the double-blind placebo phase responded. In another recent

report, Dr. A. Zuddas from the University of Cagliari, Italy, reports that

risperidone is an effective and relatively safe drug for long-term treatment

of behavioral disruption in autistic children and adolescents.

Dr. Hollander,* from the Seaver Autism Research Center at the

Mount Sinai School of Medicine, N.Y. conducted an open, retrospective

clinical study with venlafaxine and evaluated its effect on core symptoms of

autism as well as associated features of ADHD. He reports that Venlafaxine

was effective in low dosages (mean, 24.37 mg/day; range, 6.25 to 50 mg/day)

and was well tolerated.

Improvement was noted in repetitive behaviors and restricted

interests, social deficits, communication and language function,

inattention, and hyperactivity. Venlafaxine is both a serotonin and

norepinephrine reuptake inhibitor.

Dr. P. G. Rossi, from the Neurological Institute, University of

Bologna, Italy, reports promising results in its study of Niaprazine, a

histamine H1-receptor antagonist with marked sedative properties. Niaprazine

was administered at 1 mg/kg/day for 60 days to 25 subjects with autistic

disorder.

A positive effect was found in 52% of patients, particularly on

hyperkinesia, unstable attention, resistance to change and frustration, mild

anxiety signs, heteroaggressiveness, and sleep disorders. No side effects

were observed. Because of its sedative effects and good tolerability,

niaprazine can be used as a first-choice drug to improve behavior and sleep

disorders in patients with autistic disorder.

In another study, McDougle and colleagues published results of a

clinical trial of Olanzapine treatment of children, adolescents, and adults

with pervasive developmental disorders. Eight patients with autistic

disorder or PDD were given olanzapine in an open-label, prospective fashion

for 12 weeks.

Seven of eight patients completed the 12-week trial, and six of the

completers were deemed clinical responders. Significant improvements in

overall symptoms of autism, motor restlessness or hyperactivity, social

relatedness, affectual reactions, sensory responses, language usage,

self-injurious behavior, aggression, irritability or anger, anxiety, and

depression were observed. Significant changes in repetitive behaviors were

not observed for the group.

A daily dose of olanzapine was 7.8 +/- 4.7 mg/day was given. No

evidence of extrapyramidal side effects or liver function abnormalities was

seen. Preliminary results suggest that olanzapine may be an effective and

well-tolerated drug in targeting core and related symptoms of PDDs in

children, adolescents, and adults.

Dr. Chez* published the results of a depakote (anticonvulsant)

and steroid trial. This was an open-label trial on a small group of children

with autism and PDD, many with EEG abnormalities. His paper suggests that

this may be a useful intervention in a subset of children with autism.

His data show that a subset of children with autism (which may be as

high as 50%) show abnormal EEG activity during sleep. In an earlier study,

Dr. Isabel Rapin* has attempted to further distinguish a subset of children

with autism who experience sudden and acute developmental and language

regression and to relate this phenomena to epileptiform activity.

Additional Biochemical Studies Emerge

Brain metabolites in the hippocampus-amygdala region and cerebellum in

autism were reported in an 1H-MR spectroscopy study by Dr. H. Otsuka and

co-investigators working at the University of Tokushima, Japan. They

examined 27 autistic patients and 10 normal children, using the STEAM

sequence. The N-acetyl aspartate (NAA) concentration was significantly lower

(P = 0.042) in autistic patients than in normal children.

In the further work of Chugani* from Wayne State University School of

Medicine, Detroit, she has published data that show that in autistic

children, N-acetyl-aspartate (NAA)levels are reduced compared to controls.

Plasma lactate levels were higher in the 15 autistic children.

Sulphation deficit in “low-functioning” autistic children was the

subject of a pilot study by Drs. Alberti and Waring. Alberti is located at

the Oasi Institute for Research on Mental Retardation and Brain Aging in

Troina, Italy. Waring is located in the U.K. The researchers investigated a

group of 20 autistic children and age-matched controls. Utilizing the

biochemical characteristics of paracetamol (tylenol) they evaluated by

high-performance liquid chromatography, the urine

paracetamol-sulfate/paracetamol-glucuronide ratio in all subjects following

administration of this drug. The PS/PG ratio in the group of autistic

subjects gave a significantly lower result than the control group.

Ted Page,* of the University of California, San Diego published two

separate reports over the past two years describing different purine-related

metabolic defects in subgroups of autistic patients. In the first paper,

Page and his colleague Nyhan, report: “A syndrome of seizures and pervasive

developmental disorder associated with excessive cellular nucleotidase

activity.” This syndrome presents with lack of language and social

interaction, truncal ataxia and seizures.

It is treatable with oral administration of uridine. It is currently

unknown what degree of overlap may exist between these patients and the

autistic population. CAN has funded the development of a rapid-screening

tool. Page and Colemen* report on purine metabolism abnormalities in a

hyperuricosuric subclass of autism, in their recent paper describing a

subclass of patients with classic infantile autism who have uric acid

excretion, which is >2 standard deviations above the normal mean.

They state these hyperuricosuric autistic individuals may comprise

approximately 20% of the autistic population. Their experiments show that de

novo purine synthesis is increased approximately four-fold in the

hyperuricosuric autistic patients. Although an enzyme defect responsible for

the accelerated purine synthesis was not identified, the abnormal ratio of

adenine to guanine nucleotides suggests a defect in purine nucleotide

interconversion.

A recently released study by J. Zhang et al, describes results of

analysis of compounds in the urine of autistic children with HPLC and mass

spectrometry. This study was the joint effort of Repligen Corporation and

University of land School of Medicine, Baltimore.

Urine samples were collected from 40 autistic children aged 3-12 and

44 healthy children and analyzed by HPLC-MS/MS. The most significant

difference in the two groups was a significant fraction (47%) of the

autistic patients with undetectable levels of 7-methylxanthine in their

urine. In a double-blind, placebo-controlled, crossover clinical study in 20

children the effect of placebo vs. secretin was evaluated on urinary

metabolites.

There was a significant increase in urinary 7-methylxanthine following

secretin, which was not observed following placebo administration. Four

autistic children who had no detectable levels of 7-methylxanthine at the

beginning of the study showed an increase of greater than 100-fold following

secretin.

On the Immunology Front

S. Mesahel, University of Birmingham U.K., published the results of a

study titled: Urinary Levels of Neopterin and Biopterin in Autism. Increased

neopterin levels are known to be associated with activation of the cellular

immune system. Reduced biopterins are essential for neurotransmitter

syntheses. In this study, both urinary neopterin and biopterin were raised

in the autistic children compared to controls and the siblings showed

intermediate values.

Serum auto-antibodies to brain in Landau-Kleffner variant (LKSV),

autism and other neurological disorders (OND) were reported by Anne Connolly

of St. Louis Children’s Hospital. Connolly’s results show lgG anti-brain

autoantibodies present in 45% of sera from children with LKSV, 27% with

autism and 10% with ONDs compared with 2% in healthy children. lgM

autoantibodies were present in 36% of sera from children with autism, 9%

with LKSV and 15% with ONDs compared with 0% of control sera.

The author concludes that the presence of these antibodies raises the

possibility that automimmunity plays a role in the pathogenesis of language

and social developmental abnormalities in a subset of children with these

disorders.

Zimmerman and Anne Comi of Hopkins Hospital report on

familial clustering of autoimmune disorders in autism. This research group

surveyed the families of 61 autistic patients and 46 healthy controls using

questionnaires. The mean number of autoimmune disorders was greater in

families with autism.

Forty-six percent had two or more members with autoimmune disorders.

Zimmerman purports that the increased number of autoimmune disorders

suggests that in some families with autism, immune dysfunction could

interact with various environmental factors to play a role in autism

pathogenesis.

DelGiudice-Asch* reports B lymphocyte antigen D8/17 (which can be

associated with a constellation of repetitive behaviors, sometimes referred

to as PANDAS: pediatric autoimmune neuropsychiatric disorder associated with

streptococcus), to be higher in 18 autistic patients than in 14 medically

ill controls.

The frequency of individuals with higher than normal levels of

D8/17-positive cells was significantly greater in the autistic patients

(78%) than controls (21%). The researchers believe that elevated D8/17

expression may serve as a marker for compulsion severity with autism.

Dr. Sudhir Gupta* located at the University of California, Irvine, is

still completing his double blind study of intravenous immunoglobulin (IVIG)

treatment in autistic children and we await the outcome of this important

study. In a related study, Audreyus

* * *

Repligen and Cure Autism Now Form Research Funding Partnership

Develop Assessment Tools for Clinical Trials of Autism Therapies

[From a company press release.]

http://www.northernlight.com/arun?sacl=uvmx4wYhw5iwa & sastdt=200102262305

Repligen Corporation and Cure Autism Now announced Wednesday that they

will collaborate to jointly fund research to develop new tools to measure

changes in the symptoms of autism in clinical trials. Cure Autism Now is a

leading private funding organization for autism research.

Research projects eligible for funding will include the development of

psychometric tools to measure changes in the social and communicative

aspects of autism and methods to quantify changes in the neurophysiological

deficits and other neurobehavioral abnormalities characteristic of autism.

The research will be carried through a series of grant awards to academic

centers with established expertise in psychometrics or neurophysiology.

>> DO SOMETHING ABOUT AUTISM NOW <<

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