The Genetics of Autism

[Guest guest]

The Genetics of Autism

SUSAN E. FOLSTEIN, M.D., JONATHAN HAINES, PH.D., AND SUSAN L. SANTANGELO, SC.D.

Autism

is a neurodevelopmental disorder that is defined, not by its etiology

or neural mechanism, but by a unique and strange cluster of behaviors

that are usually evident in the first year of life: the inability to

form normal, reciprocal social relationships; abnormal (or no) language

development, with particular difficulties with social communication

(pragmatics) and abstractions; and repetitive, restricted interests and

behaviors.

While

abnormal social interaction is most commonly noticeable during the

first year of life, as many as 30 percent of cases become manifest

after 18-24 months of normal or near-normal development. Intelligence

varies from well within the normal range to profoundly retarded, with

about 75 percent of affected individuals having measured intelligence

in the mentally retarded range (below an IQ of 70). On the Wechsler

Scales, autistic persons, regardless of overall IQ, do relatively well

on the subtests that tap rote memory (digit span) and some

visuo-spacial tasks (block design and object assembly). They do poorly

on subtests that tap verbal abstractions and sequencing (picture

arrangement and comprehension) .

Many

children improve as they grow older, but social interaction rarely

becomes normal. Prognosis is related most closely to the level of

language development .Seizures may develop, particularly after puberty

in those autistic individuals with moderate to severe mental

retardation. Numerous biochemical studies have found increased levels

of whole blood and platelet serotonin, and one has suggested decreased

central serotonin responsiveness . Other neurotransmitter systems have

also been implicated, but have not been consistently replicated.

A

number of the children have larger than average heads, with some in the

macrocephalic range (above the 98th percentile of head circumference)

..On MRI, this increased head circumference has been shown to be

attributable to increased brain volume, more temporal-parietal than

frontal . Only a few autopsy studies have been done, but they

consistently demonstrate small neurons in several limbic nucleii and

decreased numbers of Purkinje cells in the cerebellar hemisphere .

Although some MRI studies (but not others) have suggested abnormalities

in the cerebellar vermis, this has not been confirmed by neuronal

counts of vermis in autopsy specimens . Together, the MRI and autopsy

findings suggest abnormal neural development in the limbic cortex and

cerebellar hemispheres. The prevalence of autism is between 5/10000 and

10/10000, depending on how broadly or narrowly the diagnostic criteria

are interpreted.

KNOWN ETIOLOGIES

The

majority of cases are of unknown etiology, but there are a few

disorders in which autism may occur more commonly than by chance, and

about 10 percent of cases have some discernable etiology . However, an

accurate measure of the expected level of random chance co-occurrence

is somewhat difficult to decide because of the frequent overlap between

autism and mental retardation. The fragile X (FRAX-A) mutation is found

in about 3 percent of unselected autism cases. Autism is very frequent

in tuberous sclerosis cases that are severely mentally retarded . The

disorder was said to be commonly associated with untreated

phenylketonuria (PKU), but the rate was never firmly established, and

the reported cases of autism with PKU were not well enough described to

be sure of this claim . Currently, untreated cases of PKU are rarely

seen, so that the association can no longer be studied in developed

countries. Similar difficulties surround the reported association with

congenital rubella.

Numerous

studies have been carried out to investigate the relationship between

autism and prenatal and perinatal problems. Compared with IQ-matched

controls, autistic individuals have a very small rate of untoward

events. Compared with sibling controls, they are often reported to have

a slight but significant increase in the occurrence of a

less-than-optimal prenatal and perinatal course. This optimality score

is based on the unweighted sum of all events that have been reported to

be risk factors in other studies, including both minor (for example,

primiparity) and major (low Apgar score at 5 minutes, for instance)

events.

Because

autistic children are often only children, primiparity is common. When

primiparity is omitted from the tally of the optimality score or

accounted for in a multivariate analysis , the differences between

autistic individuals and their siblings are no longer significant. It

is possible that relatively minor pre- and perinatal difficulties may

have a negative impact when they occur on a vulnerable genetic

background , but it has not yet been possible to test this hypothesis.

EVIDENCE FOR GENETIC ETIOLOGY

Among

the vast majority of cases with unknown cause, there is clear evidence

for a genetic etiology. First, even though the recurrence risk is about

6 percent to 8 percent , this is between 60 and 160 times what would be

expected by chance based on the population prevalence of 5-10 per

10,000. Second, population-based twin studies have consistently found a

very large difference between the monozygotic (MZ) and dizygotic (DZ)

concordance rates. Twin pairs are said to be concordant when both are

affected with the disorder or trait under study. Based on summing the

results of three population-based twin studies, the MZ concordance rate

is about 60 percent while the DZ rate is 0 percent . While the MZ

pairwise concordance rate is quite high, the DZ rate would be expected

to equal to the sibling recurrence risk of 6 percent to 8 percent. The

lack of any concordant DZ pairs is most likely a Type II error since

the total number of DZ pairs studied is only 30 and the chance of

observing no concordant DZ pairs is 16 percent.

Thus,

heritability is estimated to be very high, accounting for more than 90

percent of the total variance. However, the pattern of transmission in

families does not conform to any simple genetic mechanism. Genetic

models, based on the results of twin and family studies, suggest that

the disorder is most likely caused by the interactive effect of several

genes, at least three . However, it is unknown whether all autism is

caused by the same set of genes (perhaps say four to six) or whether

there may be a larger number that combine in different ways. The latter

is thought possible because of the wide variation in intelligence and

language. In addition, there is a possibility that in some small

subsets of families, autism may be transmitted by a single gene,

possibly one that is not expressed in everyone who has the gene (that

is, a gene with reduced penetrance)

NON-AUTISTIC FAMILY MEMBERS

Because

of the severe social deficits, autistic individuals rarely have

children, so that parents of autistic children are rarely autistic

themselves. Nevertheless, parent-child pairs are known to exist.

Although the majority of autistic individuals also have mental

retardation, most studies of parents and siblings of autistic children

have not found any increase in the rate of mental retardation among the

first-degree relatives, as compared with first-degree relatives of

controls .

There

are, however, some traits and disorders that do distinguish the parents

and siblings of autistic children from controls. These traits are

reminiscent of autism, but generally do not cause impairment or

handicap and often have adaptive value . Several studies have found

higher rates of developmental reading and language disorders and

pragmatic language deficits. Compared with controls, some parents and

siblings are socially reticent and others have for-preference fixed

routines or difficulties with change in routines.

Finally,

autism parents, more often than controls, have anxiety disorders and

probably recurrent mood disorders. In most cases, the onset of these

conditions preceded the birth of their autistic child. These findings

have been interpreted as possibly representing manifestations of some

of the individual genes that are hypothesized to interact to cause

autism. There has been one report of an association in parents between

whole blood serotonin levels and a questionnaire measure of depression

and a questionnaire measure of obsessive compulsive symptoms

CANDIDATE GENES

Any

number of genes expressed in the central nervous system during fetal

life and in the first two years post-natally could be candidates for

causing autism. Because of the blood serotonin findings and the trophic

role of serotonin in neural development, genes relating to serotonin

and its metabolism and receptors are the genes that have been most

carefully scrutinized. There are two reports of association between

polymorphisms in the serotonin transporter gene and autism. In this

gene, there is a common polymorphism in the promotor region that may

have functional significance on transcriptional efficiency and

serotonin uptake. While both studies reported convincing p-values, one

found an association with the longest repeat sequence, and the other

with the short sequence, so at this point the findings are not easily

interpretable. Studies of some other serotonin-related candidate genes

have been negative.

A

French group, in the course of studying several candidate genes

involved in monoaminergic metabolism (which yielded negative results),

also tested for association between the c-Harvey-ras (H-RAS) gene and

autism with positive findings, which they have replicated . While HRAS

is best known as an oncogene, it also plays a role in neural

development.

There

is a fairly large body of literature, mainly by one research group,

demonstrating a range of immunological and immunogenetic differences

between autistic individuals and normal, ethnically matched controls.

We know of no systematic study that has found a higher rate of

autoimmune disorders in autistic children or their families. While some

of the immunogenetic findings have been replicated by the same research

group, it is not yet clear how they will be related other genetic and

etiological factors. A recent report suggests a positive association

between elevated blood serotonin and the major histocompatibility

haplotypes previously associated with autism . In addition, one Letter

to the Editor has suggested the possibility of some maternally

transmitted risk factor. In a review of her clinic sample, Lord found

that in families with two affected children, the second born almost

always had a lower IQ than the first born. No one has published an

attempt to replicate this finding, which suggests the possibility of an

interaction between a genetic vulnerability and a maternally

transmitted risk factor, perhaps immunogenetic in origin.

CHROMOSOMAL ABNORMALITIES AND GENETIC LINKAGE STUDIES

Over

a number of years, there have been reports of associations between

autism and chromosomal rearrangements, visible on karyotype, involving

many chromosomes. Most frequently reported are deletions and

duplications involving Chromosome 15q . Such findings suggest that

there may be one or more gene abnormalities in the area of overlap of

these rearrangements. This is being tested using genetic linkage

studies of families who have two children with autism. Prior to

screening the entire genome for autism-related genes, several groups

first investigated markers on chromosome 15. The three collaborating

sites of the Collaborative Autism Project (CAP) have independently

found evidence suggesting micro-rearrangements of chromosome 15q

markers in several families, perhaps as many as 10 percent of those

screened. There is some suggestion that these micro-rearrangements are

maternally inherited (CAP, unpublished).

One

group in the collaboration has reported a possible genetic linkage

using affected sib pairs, to chromosome 15 markers distal to the area

implicated in the Prader-Willi and Angelman's syndromes, and just

distal to the genes for some of the components of the GABA receptor

family . This finding has been confirmed using a different statistical

method . These investigators reported multi-allelic disequilibrium in

one of the GABA receptor genes using "trios," two parents and one

affected child. This gene cluster is just proximal to the area of

linkage reported by Pericak-Vance et al. and the markers showing

micro-rearrangements found by the CAP group; markers nearer the GABA

locus did not give positive lod scores. This region is currently under

intense scrutiny.

The

European Collaborative Linkage study of autism has completed their

first preliminary genome scan and reported a possible linkage between

autism and an area of chromosome 7. The study did not, however, find

linkage to markers on 15q. The chromosome 7 finding has not yet been

replicated, but several groups are analyzing this area of chromosome 7.

While

the several findings on Chromosome 15q 11-13 do not suggest precisely

the same location, this is not surprising or unexpected at this stage

of the investigations as it is very difficult to identify precisely the

location of genes that have a small effect in an oligogenic disorder.

Given the power needed to disentangle oligogenic conditions, the number

and size of families studied so far is very small. The convergence of

cytogenetic, linkage, and association data makes it highly likely that

there is a gene in this area on 15q relevant to autism.

CONCLUSIONS

Clearly,

autism is most often a strongly inherited disorder, most likely caused

by the interactive effects of several genes. While genes related to the

serotonin system are likely candidates, the findings to date are

unclear and more studies are needed. As the affected sibling pair

studies of the complete genome are completed, it is expected that

several more loci will be implicated. If some of these are genes of

small effect, replication may be difficult. There is converging

evidence, based on several different kinds of studies (chromosomal,

linkage, and association) of a locus on chromosome 15q 11-13.

Currently, several research groups are working to localize the area of

interest to an interval that is small enough to study more closely for

relevant genes

The Authors:

Dr. E. Folstein is Professor, Psychiatry at Tufts University School of Medicine.

She

can be contacted at New England Medical Center, 171 on Ave.,

Boston, MA 02111, USA. tel: , fax: e-mail: susan.folstein@...

Dr.

Haines is Associate Professor, Molecular Physiology &

Biophysics, and Director, Program in Human Genetics at Vanderbilt

University.

Dr.

Santangelo is Assistant Professor, Psychiatry at Tufts University

School of Medicine, and Adjunct Assistant Professor in Epidemiology at

Harvard School of Public Health.