Yet gene scans do not suggest a primary abnormality in the X or Y 23rd chromosome

The phenomenon of genomic imprinting may explain these puzzling findings

GENOMIC IMPRINTING

Certain genes in the sperm or egg are altered according to the sex of the parent

Hence called imprinted genes

Imprinted genes often contain instructions for genes on other chromosomes

Imprinting seems to a sort of genetic war between the sexes - often involves one sex silencing genes from the other sex

And there can be abnormalities in this process which do NOT involve clear abnormalities in the affected chromosome

THE EVIDENCE FOR PROTECTIVE GENOMIC IMPRINTING IN AUTISM, IMPRINTING THE X-CHROMOSOME, AND THE MALE BRAIN: EXPLAINING SEX DIFFERENCES IN THE LIABILITY TO AUTISM. D.H. Skuse,Pediatric Research,47:9-16, 2000.

The author looked at girls with Turner's Syndrome, a genetic abnormality in which one of the two X-chromosomes is missing

Found that when such girls had the maternal, but not paternal X-chromosome, they showed autism spectrum disorders

CONCLUSION:

WHEN familial genes for autism are present, they are inhibited by the patern X-chromosome, always present in normal girls, never in normal boys

But this inhibition occurs in other chromosomes NOT the sex chromosome

THE POTENTIAL ROLE FOR ANIMAL RESEARCH INTO THE GENETIC MECHANISMS OF AUTISM

Increasingly we can use genetically-altered mice to mimic any human genetic abnormality

Thus findings such as the above can lead to testing of such hypotheses in mouse genetic models

Foundation for Biomedical Research, FBR Facts,Vol. VII, No. 4, November 2000

Mighty Mice: Genetically Tweaked to Save Human Lives,Some very special rodents are revolutionizing disease research

On October 16, 2000 a team of researchers at the National Institutes of Health (NIH) announced that they had achieved a decades-long goal of genetically engineering mice to develop Burkitt's lumphoma, a rare but deadly cancer that attacks children and AIDS patients. Previous attempts to engineer Burkitt's mice failed, but the scientists, led by Herbert C. Morse III, M.D., finally found the proper genetic mix by creating a "mini-gene" that reproduces the cancer just as it occurs in people.

Scientists have much more to learn about how other genetic mutations, environmental factors, and infectious agents, such as teh Epstein-Barr virus, work together to cause Burkitt's lymphoma and other cancers. But studying the Burkitt's mice will lead to new understandings about why some people are predisposed to lymphoma, while other people develop other cancers.

"The only way to find this out is to invest basic research into mouse models of cancer," noted team member Siegfried Janz, M.D. of teh National Cancer Institute.

The development of genetically altered mice is one of the most remarkable steps forward in the history of disease research. Like the Pied Piper in reverse, these mice are leading us to a brighter future; one in which new medicines may treat or even cure many of the diseases and health disorders that currently plague mankind.

NEUROANATOMICAL ABNORMALITIES IN AUTISM

THERE IS INCREASING EVIDENCE FOR FOCAL NEUROANATOMICAL ABNORMALITIES IN AUTISM

EXAMPLE: NEUROANATOMICAL AND NEUROCOGNITIVE DIFFERENCES IN A PAIR OF MONOZXYGOUS TWINS DISCORDANT FOR STRICTLY DEFINED AUTISM. W.R. Kates et al.,Annals of Neurology,43-782-791, 1998.

In this study, the affected twin had MRI abnormalities not seen in the unaffected twin in:

Cerebellar vermis

Amygdala

Caudate nucleus

Will briefly review other studies suggesting abnormalities in the autistic cerebellum and amygdala

AUTISM AND THE CEREBELLUM

IMAGING AND NEUROHISTOLOGICAL STUDIES REVEAL ABNORMALITIES IN THE CEREBELLUM IN AUTISM

These abnormalities are seen throughout the cerebellum, but are most pronounced in the midline cerebellar vermis

Histological analysis of the few autistic brains which have come to autopsy has shown consistent abnormalities in this brain region

MRI studies show stunting of the vermis, despite a few cases of (equally pathological) enlargement of the vermis

OTHER NEUROLOGICAL DISORDERS INVOLVING CEREBELLAR STUNTING:

ANIMALS MODELS OF AUTISM INVOLVING CEREBELLAR DAMAGE

AN ANIMAL MODEL OF AUTISM: BEHAVIOURAL STUDIES IN THE GS GUINEA-PIG. J. Caston et al.,European Journal of Neuroscience,10:2677-2684, 1998.

THE GS GUINEA-PIG IS A STRAIN WITH GENETIC ABNORMALITIES IN THE VERMIS

Behavioral testing revealed a syndrome not unlike human autism, including:

Stereotyped motor behavior

Reduced exploration

Marked inability to shift attention

Reduced social interactions

The same French group has recently reported that rats with neonatal removal of hte cerebellar vermis show behavioral traits resembling autism.(EFFECTS OF EARLY MIDLINE CEREBELLAR LESION ON COGNITIVE AND EMOTIONAL FUNCTIONS IN THE RAT. S. Bobee et al., Behavioural Brain Research, 112:107-117, 2000)

Clearly this approach holds promise for developing animal models of autistic abnormalities, if not autism per se.

AUTISM AND THE AMYGDALA

THE AMYGDALA:

Is buried in the posterior temporal lobe

Virtually everything we know about the amygdala comes from animal experiments:

This area is critical for linking sensory stimuli to emotional and motivational content

Plays an important role in complex social behavior

THE AMYGDALA IN AUTISM

EVIDENCE FOR DAMAGE TO THE AMYGDALA IN AUTISM:

Identical twin study already referenced showed selective stunting of amygdala in the autistic twin

Tuberous sclerosis is associated with autism in those with growths in the temporal lobe (ASSOCIATION OF TUBEROUS SCLEROSIS OF TEMPORAL LOBES WITH AUTISM AND ATYPICAL AUTISM. P.F.Bolton and P.D. Griffiths, Lancet, 349:392-395, 1997)

Autism is accompanied by damage to this region:

Shown in histopathological studies

See in brain scans (e.g., MRI VOLUMES OF AMYGDALA AND HIPPOCAMPUS IN NON-MENTALLY RETARDED AUTISTIC ADOLESCENTS AND ADULTS. E.H. Aylward et al.,Neurology,53:2145-2150, 1999).

Functional amygdalar abnormalities in autistic social cognition revealed in a recent study: SOCIAL INTELLIGENCE IN THE NORMAL AND AUTISTIC BRAIN: AN fMRI STUDY. S. Baron-Cohen, et al., European Journal of Neuroscience, 11:1891-1898, 1999).

Study showed that in controls, the ability to correctly interpret human emotions from pictures of eyes required activation of the amygdala.

High-functional autistics (Asperger Syndrome) had problems with this task, and did not activate the amygdala in processing such information.

ANIMAL MODELS OF THE AMYGDALA THEORY OF AUTISM

BASIC RESEARCH: WE HAVE ALREADY NOTEAD THAT ANIMAL RESEARCH IS RESPONSIBLE FOR OUR UNDERSTANDING OF THIS REGION

SPECIFIC ANIMALS MODELS OF AUTISM:

Another French group has suggested that lesions of the amygdala in monkeys produce autistic deficits(THE CONTRIBUTION OF MEDIAL TEMPORAL LOBE STRUCTURES IN INFANTILE AUTISM: A NEUROBEHAVIORAL STUDY IN PRIMATES. J. Bachevalier and P.M. Merjanian, in Bauman ML and Kemper TL (Eds), THE NEUROBIOLOGY OF AUTISM, Johns Hopkins Press, pp 146-169, 1994).

NEUROBEHAVIORAL TERATOGENS AND AUTISM

PAT RODIER, A LEADING NEUROBEHAVIORAL TERATOLOGIST, HAS SUGGESTED THAT:

AN INCREASED INCIDENCE OF AUTISM IN THALIDOMIDE-EXPOSED INFANTS WITH EAR NOT LIMB ABNORMALITIES SUGGESTS A VERY EARLY DEVELOPMENTAL WINDOW OF VULNERABILITY FOR AUTISM

NEUROHISTOLOGY SUGGEST ABNORMALITIES IN MOTOR NUCLEI OF THE AUTISTIC BRAINSTEM

Moebius syndrome, for example, involves over-expression of autism in children with facial paralysis and eye movement deficits due to problems in brainstem motor nuclei similar to those reported above

PRENATAL EXPOSURE TO VALPROIC ACID CAUSES A FETAL ANTICONVULSANT SYNDROME WITH AUTISTIC FEATURES (A CLINICAL STUDY OF 57 CHILDREN WITH FETAL ANTICONVULSANT SYNDROMES. S.J.Moore et al., Journal of Medical Genetics, 37:489-397, 2000)

ANIMALS MODELS: Rodier and others have shown that in rats, prenatal valproate exposure on the 12th day of gestation causes stunting of cerebellar vermis and brainstem motor nuclei suggestive of autism

PRENATAL VITAMIN A EXPOSURE AND AUTISTIC-LIKE BRAIN DAMAGE

THE A VITAMINS ARE AMONG THE MOST POTENT OF ALL NEUROBEHAVIORAL TERATOGENS

In humans, very early exposure can result in mental retardation, as yet poorly characterized

Dr. Jane Adams, who studies birth defects in children exposed to potent synthetic vitamin A compounds ("retinoids") in utero, has been collaborating with me in studies of the neurbehavioral consequences of such exposure in rats

FINDINGS TO DATE:

NEROPATHOLOGY: Exposure on or around the 12th day of gestation:

Selectively stunts cerebellar vermis

Also stunts the inferior olive, a major brainstem cerebellar relay nucleus

Stunting of inferior olive is also reported in histological examination of autistic brains

BEHAVIOR:

Exposed neonates have problems with the righting reflex, recently also reported in neonatal autistic children (MOVEMENT ANALYSIS IN INFANCY MAY BE USEFUL FOR EARLY DIAGNOSIS OF AUTISM. P.Teitelbaum et al., Proceedings of the National Academy of Sciences, 95:13982-13987, 1998)

STRAIN AND TREATMENT

Such animals also show abnormalities in the dopamine system, including a reduction in the behavioral response to amphetamine and cocaine

Dopaminergic abnormalities may explain autistic stereotypes

Research funded in part by the National Alliance for Autism Research (NAAR) is ongoing, and will examine:

Detailed neuroanatomical abnormalities

Social behavior in these rats

Abnormalities in running wheels suggesting excessive emotional upset to outside interference

CONCLUSIONS:

THERE ARE ALREADY A NUMBER OF ATTRACTIVE ANIMAL MODELS OF AT LEAST CERTAIN NEUROLOGICAL ASPECTS OF AUTISM

FUNDING FOR SUCH ANIMAL REASEARCH IS ALL BUT NON-EXISTENT IN THE USA

And cannot be expected to improve without major increases in overall federal funding levels of the NIH and the NSF.

Coupled with constant political pressure on funding sources from groups such as this:

THE "ANIMAL RIGHTS" MOVEMENT: A SECOND THREAT TO ANIMAL MODELS IN AUTISM

Recent successful legal challenges by Animal Rightists to small rodent laboratories could well make my continuing research impossible. See article.

It is critical for patient advocacy groups to support animal research at the national and local levels

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