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					                                       The Early Origins of


                          Autism      New research into the causes
                                   of this baffling disorder is focusing
                                           on genes that control
                                      the development of the brain


                                                       by Patricia M. Rodier




                                A                 utism has been mystifying scientists for more than
                                                   half a century. The complex behavioral disorder
                                                    encompasses a wide variety of symptoms, most of
                                          which usually appear before a child turns three. Children
                           with autism are unable to interpret the emotional states of others, failing
                           to recognize anger, sorrow or manipulative intent. Their language skills
                           are often limited, and they find it difficult to initiate or sustain conversa-
                           tions. They also frequently exhibit an intense preoccupation with a single
                           subject, activity or gesture.
                             These behaviors can be incredibly debilitating. How can you be included
                           in a typical classroom if you can’t be dissuaded from banging your head on
                           your desk? How can you make friends if your overriding interest is in cal-
                           endars? When children with autism also suffer from mental retardation— as
                           most of them do— the prognosis is even worse. Intensive behavioral therapy
                           improves the outcome for many patients, but their
                                                                                     SEVEN-YEAR-OLD WITH AUTISM
                           symptoms can make it impossible for them to live in-      reaches for a soap bubble during play-
                                                                                     time at the Eden Institute, a school for
                           dependently, even if they have normal IQs.                children with autism in Princeton, N.J.

56   Scientific American   February 2000                                             Copyright 2000 Scientific American, Inc.
                                           JUSTINE PARSONS




Copyright 2000 Scientific American, Inc.
                                                                              AUTISM’S EFFECTS include changes to the brain stem, the re-
                                                                               gion just above the spinal cord (left). The brain stem of a per-
                                                                                  son with autism is shorter than a normal brain stem (be-
                                                                                    low): the structures at the junction of the pons and the
                                          CEREBRUM                                    medulla (such as the facial nucleus and the trapezoid
                                                                                        body) are closer to the structures of the lower medulla
                                                                                         (the hypoglossal nucleus and the inferior olive). It is
                                                                                          as though a band of tissue were missing. The brain
                      THALAMUS                                                             stem of a person with autism also lacks the superior
                                                                                            olive and has a smaller-than-normal facial nucleus.
                                                                                             Such changes could occur only in early gestation.
                       MIDBRAIN




                        PONS

                                                                                                                            TRAPEZOID
                                                                                         TRAPEZOID                              BODY
                                                                                           BODY                         FACIAL
                                                             SUPERIOR OLIVE                                             NUCLEUS
                                                             FACIAL NUCLEUS


                                                              HYPOGLOSSAL
                                                                  NUCLEUS                                                        0.2-MILLIMETER
                 CEREBELLUM                    MEDULLA                                          1.1-MILLIMETER                     SEPARATION
TERESE WINSLOW




                                                                                                  SEPARATION
                                                                                              INFERIOR OLIVE                    INFERIOR OLIVE

                               BRAIN STEM                                            NORMAL BRAIN STEM                   BRAIN STEM OF
                                                                                                                      PERSON WITH AUTISM

            I became involved in the search for         long sought to pinpoint exactly when          in describing its symptoms. The biologi-
         autism’s causes relatively recently—and        the disorder begins. Previous speculation     cal basis for autism, however, has been
         almost by accident. As an embryologist, I      had focused on late gestation or early        elusive— an unfortunate circumstance,
         previously focused on various birth de-        postnatal life as the time of origin, but     because such an understanding could en-
         fects of the brain. In 1994 I attended a re-   there was no evidence to back up either       able researchers to identify the leading
         markable presentation at a scientific con-      hypothesis. The connection with tha-          risk factors for autism and possibly to
         ference on research into birth defects.        lidomide suddenly threw a brilliant new       design new treatments for the condition.
         Two pediatric ophthalmologists, Marilyn        light on the subject. It suggested that          By examining the inheritance of the
         T. Miller of the University of                                                               disorder, researchers have shown that
         Illinois at Chicago and Ker-                                                                 autism runs in families, though not in a
         stin Strömland of Göteborg
         University in Sweden, de-
                                                 At least 16 of every                                 clear-cut way. Siblings of people with
                                                                                                      autism have a 3 to 8 percent chance of
         scribed a surprising outcome
         from a study investigating
                                               10,000 babies are born                                 being diagnosed with the same disor-
                                                                                                      der. This is much greater than the 0.16
         eye motility problems in vic-
         tims of thalidomide, the
                                               with autism or one of its                              percent risk in the general population
                                                                                                      but much less than the 50 percent
         morning-sickness drug that
         caused an epidemic of birth
                                                  related disorders.                                  chance that would characterize a genet-
                                                                                                      ic disease caused by a single dominant
         defects in the 1960s. The                                                                    mutation (in which one faulty gene in-
         study’s subjects were adults who had           autism originates in the early weeks of       herited from one parent is sufficient to
         been exposed to the drug while still in the    pregnancy, when the embryo’s brain and        cause the disorder) or the 25 percent
         womb. After examining these people,            the rest of its nervous system are just be-   chance that would characterize a single
         Miller and Strömland made an observa-          ginning to develop. Indeed, Miller and        recessive mutation (in which a copy of
         tion that had somehow eluded previous          Strömland’s work convinced me that the        the faulty gene must be inherited from
         researchers: about 5 percent of the            mystery of autism could soon be solved.       each parent). The results fit best with
         thalidomide victims had autism, which is                                                     models in which variants of several
         about 30 times higher than the rate                        Genetic Factors                   genes contribute to the outcome. To
         among the general population.                                                                complicate matters further, relatives of
            When I heard these results, I felt a
         shock of recognition, a feeling so pow-
         erful that I actually became dizzy and
                                                        A      t least 16 of every 10,000 babies
                                                                is born with autism or one of its
                                                          related disorders [see box on page
                                                                                                      people with autism may fail to meet all
                                                                                                      the criteria for the disorder but still
                                                                                                      have some of its symptoms. Although
         began to hyperventilate. In the effort to      60]. Since autism was first identified in       these relatives may have some of the
         identify autism’s causes, researchers had      1943, scientists have made great strides      gene variants linked to autism— what-

          58      Scientific American February 2000                                                                  The Early Origins of Autism
                                                         Copyright 2000 Scientific American, Inc.
Thalidomide Timeline
Age of embryo (days)      20     21    22     23    24    25     26     27    28     29     30    31    32    33     34    35    36
                           MISSING EARS                     SMALL EARS AND OTHER EAR MALFORMATIONS
    Damage caused




                                                                                                                                               JOHNNY JOHNSON
     by thalidomide                         MISSING OR SMALL THUMBS                                    THUMBS WITH AN EXTRA JOINT
         exposure at
                                                                      STUNTED ARMS
           this time
                                                                                     STUNTED LEGS

BIRTH DEFECTS caused by thalidomide vary depending on when the mother was ex-
posed to the drug (above). A 1994 study showed that thalidomide victims with autism
had ear anomalies and normal limbs, suggesting that the drug triggered the disorder 20 to




                                                                                                                                              PETIT FORMAT/NESTLE/SCIENCE SOURCE
24 days after conception, when the embryo’s nervous system is starting to form (right).

ever they may be— for some reason the         sure in utero. All their subjects—




                                                                                                                                              Photo Researchers, Inc.
genetic factors are not fully expressed       Swedish adults born in the late 1950s
in these individuals.                         and early 1960s— exhibited some of the
   Studies of twins in the U.K. confirm        malformations for which thalidomide
that autism has a heritable component         is infamous: stunted arms and legs, mis-
but suggest that environmental influ-          shapen or missing ears and thumbs,
ences play a role as well. For example,       and neurological dysfunctions of the
if genetic factors alone were involved,       eye and facial muscles. Because scien-         bryo as knowing when it happened. In
monozygotic (identical) twins, who            tists know which organs of the embryo          the case of thalidomide-induced autism,
share the same genes, should have a           are developing at each stage of preg-          the critical period is much earlier than
100 percent chance of sharing the same        nancy, they can pinpoint the exact days        many investigators would have guessed.
diagnosis. Instead, when one twin has         when a malformation can be induced:            Very few neurons form as early as the
autism, the second twin has only a 60         the thumb is affected as early as day 22       fourth week of gestation, and most are
percent chance of being diagnosed with        after conception, the ears from days 20        motor neurons of the cranial nerves, the
the same disorder. That twin also has         to 33, and the arms and legs from days         ones that operate the muscles of the eyes,
an 86 percent chance of having some of        25 to 35. What made the new study so           ears, face, jaw, throat and tongue. The
autism’s symptoms. These figures indi-         exciting for me was Miller and Ström-          cell bodies of these neurons are located
cate that other factors must modify the       land’s discovery that most of the              in the brain stem, the region between the
genetic predisposition to the disorder.       thalidomide victims with autism had            spinal cord and the rest of the brain. Be-
                                              anomalies in the external part of their        cause these motor neurons develop at
      The Embryology of Autism                ears but no malformations of the arms          the same time as the external ears, one
                                              or legs. This pattern indicated that the       might predict that the thalidomide vic-

S      everal environmental risk factors
       are already known. In utero expo-
sure to rubella (German measles) or to
                                              subjects had been injured very early in
                                              gestation—20 to 24 days after concep-
                                              tion— before many women even know
                                                                                             tims with autism would also suffer from
                                                                                             dysfunctions of the cranial nerves. Miller
                                                                                             and Strömland confirmed this predic-
birth defect–causing substances such as       they are pregnant.                             tion— they found that all the subjects
ethanol and valproic acid increases the          For embryologists, nothing tells us so      with autism had abnormalities of eye
chances that autism will develop. Peo-        much about what happened to an em-             movement or facial expression, or both.
ple with certain genetic diseases, such
as phenylketonuria and tuberous scle-
rosis, also have a greater chance of de-
veloping autism. None of these factors,
however, is present frequently enough
to be responsible for many cases. Fur-
thermore, most exposures to diseases
or hazardous substances would be like-
ly to affect both members of a pair of
twins rather than just one. Some of the
environmental influences must be more
                                                                                                                                           COURTESY OF SUSAN L. HYMAN




subtle than those identified so far. Re-
searchers do not know how the multi-
ple factors combine to make some peo-
ple display symptoms while allowing
others to escape them. This variation
makes the search for autism’s causes es-
pecially difficult.                            CHILD WITH AUTISM is normal in appearance, at least to the untrained eye. But he
   In their 1994 study Miller and Ström-      has a few physical anomalies characteristic of the disorder. The corners of his mouth are
land added another environmental con-         low compared with the center of his upper lip, and the tops of his ears flop over (left).
tributor to autism: thalidomide expo-         His ears are a bit lower than normal and have an almost square shape (right).

The Early Origins of Autism                                                                 Scientific American February 2000          59
                                               Copyright 2000 Scientific American, Inc.
                                                                                                                                                                            The Spectrum of Autism Disorders

                                                                                                                                          A     diagnosis of autism requires that the patient exhibit abnor-
                                                                                                                                                  mal behaviors in three categories [see list at right] and
                                                                                                                                          have especially notable deficits in the category of social interac-
                                                                                                                                                                                                                opment is followed by regression to severe disability, and Rett
                                                                                                                                                                                                                syndrome,a progressive neurological disorder that occurs only
                                                                                                                                                                                                                in females.
                                                                                                                                          tion. In addition, clinicians have identified several related disor-      Although many scientists have long known that autism is an
                                                                                                                                          ders that share some of the behavioral features of autism but         inherited disease, recent family studies by Peter Szatmari’s
                                                                                                                                          have different emphases or additional symptoms.For example,           group at McMaster University in Ontario suggest that it is the
                                                                                                                                          Pervasive Development Disorder, Not Otherwise Specified                spectrum of symptoms that runs in families rather than a sin-
                                                                                                                                          (PDD-NOS) denotes patients who miss fulfilling the autism cri-         gle diagnosis. For example, a child with autism may have a
                                                                                                                                          teria in one of the three categories. As is true of autism, PDD-      brother with Asperger syndrome,or a woman with autism may
                                                                                                                                          NOS includes patients with the whole range of IQs. Asperger           have a nephew with PDD-NOS. These family studies strongly
PHOTOGRAPHS BY JUSTINE PARSONS; SOURCE FOR ”DIAGNOSTIC CATEGORIES”: DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS (DSM-IV)




                                                                                                                                          syndrome is used to describe patients with normal IQs and no          suggest that at least three of the diagnoses— autism,PDD-NOS
                                                                                                                                          evidence of language delay. Two much rarer diagnoses are              and Asperger syndrome— arise from some of the same inherit-
                                                                                                                                          Childhood Disintegrative Disorder,in which normal early devel-        ed factors.                                            — P.M.R.




                                                                                                                                       The next logical question was, “Are          ed backward more than 15 degrees—             fects the cranial nerves but also has sec-
                                                                                                                                     the cases of autism after thalidomide          are more common in children with              ondary effects on later brain develop-
                                                                                                                                     exposure similar to cases of unknown           autism than in typically developing           ment. That is, the injury to the brain
                                                                                                                                     cause, or are they different?” Aside           children, children with mental retarda-       stem might somehow interfere with the
                                                                                                                                     from their behavioral symptoms, peo-           tion or siblings of children with autism.     proper development or wiring of other
                                                                                                                                     ple with autism have often been de-            Dysfunctions of eye movement had              brain regions, including those involved
                                                                                                                                     scribed not only as normal in appear-          been associated with autism before the        in higher-level functions such as speech,
                                                                                                                                     ance but as unusually attractive. They         thalidomide study, and lack of facial         resulting in the behavioral symptoms of
                                                                                                                                     are certainly normal in stature, with          expression is one of the behaviors used       autism. Or perhaps the ear malforma-
                                                                                                                                     normal-to-large heads. The few studies         to diagnose the condition.                    tions and cranial nerve dysfunctions are
                                                                                                                                     that have tested nonbehavioral features                                                      only side effects of an injury that we
                                                                                                                                     of people with autism, however, have                 The Neurobiology of Autism              don’t understand. Whatever the true
                                                                                                                                     concluded that there are indeed minor                                                        situation may be, the anomalies in pa-
                                                                                                                                     physical and neurological anomalies in
                                                                                                                                     many cases, and they are the same ones
                                                                                                                                     noted in thalidomide-induced autism.
                                                                                                                                                                                    I   s it possible that all the symptoms
                                                                                                                                                                                        of autism arise from changes in the
                                                                                                                                                                                    function of the cranial nerves? Probably
                                                                                                                                                                                                                                  tients with autism of unknown cause
                                                                                                                                                                                                                                  were much the same as the anomalies
                                                                                                                                                                                                                                  in the thalidomide victims with autism.
                                                                                                                                     For example, minor malformations of            not. It is more likely that the nerve dys-    The conclusion was clear: many cases
                                                                                                                                     the external ears— notably posterior ro-       functions in people with autism reflect        of autism, if not all, are initiated very
                                                                                                                                     tation, in which the top of the ear is tilt-   an early brain injury that not only af-       early in gestation.

                                                                                                                                     60     Scientific American February 2000                                                                    The Early Origins of Autism
                                                                                                                                                                                      Copyright 2000 Scientific American, Inc.
                                                disturbances— do sound like ones more           tween a number of neuroanatomical
                                                likely to originate in the brain regions as-    landmarks. I was surprised to discover
                                                sociated with basic functions. Further-         that my hypothesis was absolutely
Diagnostic Categories                           more, the most consistently observed ab-        wrong. Although the side-to-side mea-
                                                normality in the brains of people with          sures were indeed normal, the front-to-
Impairment of Social Interaction: Failure       autism is not a change in the forebrain         back measures were astonishingly re-
to use eye contact, facial expression or        but a reduction in the number of neu-           duced in the brain stem of the woman
gestures to regulate social interaction;        rons in the cerebellum, a large process-        with autism. It was as though a band of
failure to seek comfort; failure to develop     ing center of the hindbrain that has long       tissue had been cut out of the brain
relationships with peers.                       been known to have critical functions in        stem, and the two remaining pieces had
                                                the control of muscle movement.                 been knit back together with no seam
Impairment of Communication: Failure to            One reason for scientists’ confusion         where the tissue was missing.
use spoken language,without compensat-          about the brain regions involved in                For the second time in my life, I felt a
ing by gesture; deficit in initiating or sus-    autism may be that our assumptions              powerful shock of recognition. I heard a
taining a conversation, despite adequate        about where functions are controlled            roaring in my ears, my vision dimmed,
speech; aberrant language (for example,         are shaky. For example, the laboratory          and I felt as though my head might ex-
repeating a question instead of replying).      group led by Eric Courchesne of the             plode. The shock was not generated by
                                                University of California at San Diego           the unexpected result but by the realiza-
       Restricted and Repetitive Inter-         has shown that parts of the cerebellum          tion that I had seen this pattern of short-
       ests and Behaviors: Abnormally           are activated during certain tasks re-          ening before, in a paper that showed
       intense preoccupation with one           quiring high-level cognitive processing.        pictures of abnormal mouse brains.
       subject or activity; distress over       Another difficulty is that
       change; insistence on routines or        the symptoms of autism
       rituals with no purpose; repetitive
       movements,such as hand flapping.
                                                are so complex. If simpler
                                                behavioral abnormalities
                                                                                       Many cases of autism,
                                                could be shown to be di-
                                                agnostic of the disorder,
                                                                                    if not all,are initiated very
       BEHAVIORAL THERAPY for chil-
       dren with autism can help them
                                                researchers might have a
                                                better chance of identify-
                                                                                         early in gestation.
       lead happier lives as adults. Instruc-
       tors at the Eden Institute school        ing their source in the ner-
       carefully evaluate the symptoms of       vous system [see box on
       each child to draw up an appropri-       next page].                                     When I retrieved the article from the
       ate intervention plan. They often           In 1995 our research team had the            stacks of papers on my office floor, I
       engage the children in stimulating       opportunity to follow up on the                 found that the correspondence between
       play activities (far left). The insti-   thalidomide study by examining the              the brain I had been studying and the
       tute also provides supervised hous-      brain stem of a person with autism. The         mouse brains described in the article
       ing for adults with autism (left).       tissue samples came from the autopsy            was even more striking than I had re-
       The 37-year-old man pictured here        of a young woman who had suffered               membered. Both cases exhibited short-
       used videocassette spools to make
                                                from autism of unknown cause; she               ening of the brain stem, a smaller-than-
       the curtain behind his bed; his in-
       tense interest in these objects is a     had died in the 1970s, but fortunately          normal facial nucleus and the absence
       characteristic behavior of autism.       the samples of her brain tissue had been        of a superior olive. Additional features
                                                preserved. When we examined the                 of the mice were clearly related to other
                                                woman’s brain stem, we were struck by           anomalies associated with autism: they
                                                the near absence of two structures: the         had ear malformations and lacked one
      The region of the brain implicated        facial nucleus, which controls the mus-         of the brain structures controlling eye
   by the thalidomide study— the brain          cles of facial expression, and the superi-      movement.
   stem— is one that has rarely been con-       or olive, which is a relay station for au-         What had altered the brains of these
   sidered in studies of autism or in studies   ditory information. Both structures             mice? It was not exposure to thalidomide
   of other kinds of congenital brain dam-      arise from the same segment of the em-          or any of the other environmental factors
   age, for that matter. On a simplistic lev-   bryo’s neural tube, the organ that devel-       associated with autism but the elimina-
   el, neurobiologists associate the brain      ops into the central nervous system.            tion of the function of a gene. These were
   stem with the most basic functions:          Counts of the facial neurons in the             transgenic “knockout” mice, engineered
   breathing, eating, balance, motor coor-      woman’s brain showed only about 400             to lack the expression of the gene known
   dination and so forth. Many of the be-       cells, whereas counts of facial neurons         as Hoxa1 so that researchers could study
   haviors disturbed in autism, such as lan-    in a control brain showed 9,000.                the gene’s role in early development. The
   guage, planning and interpretation of           Overall, the woman’s brain was nor-          obvious question was, “Could this be
   social cues, are believed to be controlled   mal in size; in fact, it was slightly heav-     one of the genes involved in autism?”
   by higher-level regions of the brain, such   ier than the average brain. I hypothe-             The literature supported the idea that
   as the cerebral cortex and the hip-          sized that the brain stem was lacking           Hoxa1 was an excellent candidate for
   pocampus in the forebrain.                   only the specific neurons already identi-        autism research. The studies of knock-
      Yet some symptoms common in               fied— those in the facial nucleus and the        out mice showed that Hoxa1 plays a
   autism— lack of facial expression, hyper-    superior olive— and to test that idea I         central role in development of the brain
   sensitivity to touch and sound, and sleep    decided to measure the distances be-            stem. Groups in Salt Lake City and

   The Early Origins of Autism                                                                 Scientific American February 2000         61
                                                 Copyright 2000 Scientific American, Inc.
                                                                   A Simpler Symptom of Autism

                         S      cientists at York University and the Hospital for Sick Children
                                in Toronto have recently identified an autism-related behav-
                         ior that is much simpler than the array of behaviors that have tradi-
                                                                                                   watched lights flashing on video screens [see illustration below].
                                                                                                   The children ranged in age from four to seven.In the first test,each
                                                                                                   child was placed in front of a three-screen panel, and a flashing
                         tionally been used to diagnose the condition.Susan Bryson and her         light appeared on the middle screen. This stimulus prompted all
                         doctoral student Reginald Landry have found that children with            the children to focus their eyes on the flashes (a).Then the middle
                         autism respond abnormally to a task involving their reactions to vi-      screen went blank, and a flashing light appeared on the far-right or
                         sual stimuli.Because this mental activity is probably mediated by a       far-left screen of the panel. Both groups of children shifted their
                         primitive part of the brain— most likely the brain stem or the cere-      eyes to that screen (b). In the second test, however, the lights on
                         bellum, or both— the discovery has important implications for the         the middle screen kept flashing while the lights appeared on the
                         neurobiology of autism. Bryson and Landry’s work could also help          other screen.The children without autism shifted their eyes to fo-
                         clinicians develop a simpler way to test children for the disorder.       cus on the new stimulus (c),but the children with autism remained
                            In their study Bryson and Landry observed the reactions of two         “stuck”on the first stimulus and failed to turn their eyes to the new
                         groups of children, those with autism and those without it, as they       one (d).The two tests were repeated many times for each child.

                         a                                                  b                                                    c




                                              NORMAL CHILDREN                                     NORMAL CHILDREN                                      NORMAL
                                              AND CHILDREN                                        AND CHILDREN                                         CHILDREN
                                              WITH AUTISM                                         WITH AUTISM
DANIELS & DANIELS




                    London had studied different knockout           genes do, but most changes are likely to        or do nothing at all. Deviations from
                    strains with similar results. They found        be fatal, so they are rarely passed on to       the normal sequence in any part of a
                    that the gene is active in the brain stem       subsequent generations. Although many           gene can affect its performance, but the
                    when the first neurons are forming— the          other genes appear in several forms— for        vast majority of disease-causing varia-
                    same period that Miller and Strömland           example, the genes that encode eye col-         tions are in the protein-coding regions.
                    had identified as the time when thalido-         or or blood type—highly conserved genes         Thus, we began the search for variant
                    mide caused autism. Hoxa1 produces a            are not commonly found in multiple              alleles by focusing on the exons of
                    type of protein called a transcription          versions (also known as polymorphic             HOXA1. Using blood samples from
                    factor, which modulates the activity of         alleles, or allelic variants). The fact that    people with autism and from subjects in
                    other genes. What is more, Hoxa1 is             no one had ever discovered a variant of         a control group, we extracted the DNA
                    not active in any tissue after early em-        Hoxa1 in any mammalian species sug-             and looked for deviations from the nor-
                    bryogenesis. If a gene is active through-       gested that my colleagues and I might           mal sequence of nucleotides.
                    out life, as many are, altered function of      have trouble finding one in cases of                The good news is that we have identi-
                    that gene usually leads to problems that        autism. On the other hand, it seemed            fied two variant alleles of HOXA1. One
                    increase with age. A gene active only           likely that if a variant allele could be        has a minor deviation in the sequence of
                    during development is a better candi-           found, it might well be one of the trig-        one of the gene’s exons, meaning that
                    date to explain a congenital disability         gers for the development of the disorder.       the protein encoded by the variant gene
                    like autism, which seems to be stable af-                                                       is slightly different from the protein en-
                    ter childhood.                                              Zeroing in on HOXA1                 coded by the normal gene. We have stud-
                       Hoxa1 is what geneticists call a “high-                                                      ied this newly discovered allele in detail,
                    ly conserved” gene, meaning that the se-
                    quence of nucleotides that make up its
                    DNA has changed little over the course
                                                                    T        he human version of the gene,
                                                                             labeled as HOXA1, resides on
                                                                    chromosome 7 and is relatively small. It
                                                                                                                    measuring its prevalence among various
                                                                                                                    groups of people to determine if it plays
                                                                                                                    a role in causing autism. (The other
                    of evolution. We assume that this is a          contains just two protein-coding re-            variant allele is more difficult to investi-
                    characteristic of genes that are critical to    gions, or exons, along with regions that        gate because it involves a change in the
                    survival: they suffer mutations as other        regulate the level of protein production        physical structure of the gene’s DNA.)

                    62       Scientific American February 2000                                                                        The Early Origins of Autism
                                                                      Copyright 2000 Scientific American, Inc.
                                                       spectrum of autism disorders. Further-        substances that women need to avoid
                                                       more, the allele that we have studied in      during early pregnancy. What is more,
   Bryson and Landry found that children with          detail is variably expressed— its pres-       by examining the development of these
other kinds of brain damage are perfectly              ence does not guarantee that autism will      genetically engineered mice, we could
normal in their ability to disengage from one          arise. Preliminary data indicate that the     learn more about the brain damage that
stimulus and focus on another. Children with           variant allele occurs in about 20 percent     underlies autism. If researchers can de-
autism, however, repeatedly fail to disengage          of the people who do not have autism          termine exactly what is wrong with the
from the first stimulus, even if they are highly        and in about 40 percent of those who          brains of people with autism, they may
intelligent.Researchers suspect that this abili-       do. The allele approximately doubles          be able to suggest drug therapies or oth-
ty is a low-level brain function because it typi-      the risk of developing the condition. But     er treatments that could ameliorate the
cally appears in infants—as early as three to          in about 60 percent of people with            effects of the damage.
four months after birth—and in children with           autism, the allele is not present, mean-         Devising a genetic test for autism—
low IQs. Animals also orient themselves to-            ing that other genetic factors must be        similar to the current tests for cystic fi-
ward new stimuli, so scientists could conceiv-         contributing to the disorder.                 brosis, sickle cell anemia and other dis-
ably use a similar test in animal studies to ver-         To pin down those factors, we must         eases— would be a much more difficult
ify whether genetic manipulations or toxico-           continue searching for other variants in      task. Because so many genes appear to
logic exposures have produced this symptom             HOXA1, because most genetic disor-            be involved in the disorder, one cannot
of autism.                              —P.M.R.        ders result from many different deviant       accurately predict the odds of having a
                                                       alleles of the same gene. Variations in       child with autism by simply testing for
   d                                                   other genes involved in early develop-        one or two variant alleles in the parents.
                                                       ment may also predispose their carriers       Tests might be developed, however, for
                                                       to autism. We have already discovered a       the siblings of people with autism, who
                                                       variant allele of HOXB1, a gene on            often fear that their own children will
                                                       chromosome 17 that is derived from the        inherit the disorder. Clinicians could
                                                       same ancestral source as HOXA1 and            look for a set of well-established genetic
                                                       has similar functions in the develop-         risk factors in both the family member
                                                       ment of the brain stem, but its effect in     with autism and the unaffected sibling.
                                                       autism appears to be minor. Other in-         If the person with autism has several
                                                       vestigators are scrutinizing candidate re-    high-risk alleles, whereas the sibling
                        CHILDREN                       gions on chromosome 15 and on anoth-          does not, the sibling would at least be
                        WITH AUTISM                    er part of chromosome 7. Although re-         reassured that his or her offspring
                                                       searchers are focusing on alleles that        would not be subject to the known risks
                                                       increase the risk of autism, other alleles    within his or her family.
                                                       may decrease the risk. These could help          Nothing will make the search for
                                                       explain the variable expression of the        autism’s causes simple. But every risk fac-
                                                       spectrum of autism-related disorders.         tor that we are able to identify takes
                                                          Even a minimal understanding of the        away some of the mystery. More impor-
       We found that the rate of the variant al-       genetic basis of autism would be of           tant, new data spawn new hypotheses.
       lele among people with autism was sig-          great value. For example, researchers         Just as the thalidomide results drew at-
       nificantly higher than the rate among            could transfer the alleles associated with    tention to the brain stem and to the
       their family members who do not have            autism from humans to mice, engineer-         HOXA1 gene, new data from develop-
       the disorder and the rate among unre-           ing them to be genetically susceptible to     mental genetics, behavioral studies, brain
       lated individuals without the disorder.         the disorder. By exposing these mice to       imaging and many other sources can be
       The differences were much greater than          substances suspected of increasing the        expected to produce more welcome
       would be expected by chance.                    risk of autism, we would be able to           shocks of recognition for investigators of
          The bad news is that, just as the fami-      study the interaction of environmental        autism. In time, their work may help al-
       ly studies had predicted, HOXA1 is              factors with genetic background and           leviate the terrible suffering caused by
       only one of many genes involved in the          perhaps compile an expanded list of           the disorder.                            SA




                           The Author                                                     Further Information
          PATRICIA M. RODIER is professor of obstetrics       Autism in Thalidomide Embryopathy: A Population Study. K. Strömland, V.
       and gynecology at the University of Rochester. She      Nordin, M. Miller, B. Åkerström and C. Gillberg in Developmental Medicine and
       has studied injuries to the developing nervous sys-     Child Neurology, Vol. 36, No. 4, pages 351–356; April 1994.
       tem since she was a postdoctoral fellow in embryol-    Embryological Origin for Autism: Developmental Anomalies of the Cra-
       ogy at the University of Virginia, but she began to     nial Nerve Motor Nuclei. P. M. Rodier, J. L. Ingram, B. Tisdale, S. Nelson and
       investigate autism only after hearing the results of    J. Romano in Journal of Comparative Neurology, Vol. 370, No. 2, pages 247–261;
       the thalidomide study. Rodier has assembled a           June 24, 1996.
       group of scientists from many disciplines at six in-   Thinking in Pictures: and Other Reports from My Life with Autism. Temple
       stitutions to study the genetic and environmental       Grandin. Vintage Books, 1996.
       causes of the disorder and says that working with      More information on autism is available at the Web page of the National Alliance
       experts from other fields is rejuvenating.               for Autism Research at www.naar.org



       The Early Origins of Autism                                                                  Scientific American February 2000         63
                                                        Copyright 2000 Scientific American, Inc.

				
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