The Neurobiology of Autism New Pieces of the Puzzle - Autyzm.pdf - Autyzm - flek

The Neurobiology of Autism:

New Pieces of the Puzzle

Maria T. Acosta, MD, and Phillip L. Pearl, MD

Address

Department of Neurology, Children's National Medical Center,

111 Michigan Avenue NW, Washington, DC 20010-2970, USA.

E-mail: macosta@cnmc.org

Current Neurology and Neuroscience Reports 2003, 3: 149–156

Current Science Inc. ISSN 1528–4042

ligence is average, cognitive profiles are frequently mark-

edly uneven. Significant deficits ( eg , in social cognition)

may coexist with islets of strength or even superiority ( eg ,

visuospatial skills). In addition to the triad of core deficits,

multiple other domains, including motor, sensory, and

perceptual ( eg , auditory, tactile), may be affected. The

developmental course varies, with regression in language

and social relatedness noted in perhaps one third of cases.

Epilepsy affects approximately one third of autistic chil-

dren as well, and subclinical epilepsy has been hypothe-

sized to play a role in clinical regression [1,2].

Prevalence is considered approximately four to five per

1000 people, but numbers differ according to criteria used

for diagnosis. Earlier identification and better availability

of services can increase the awareness of this entity [3].

The neurobiologic basis of autism is reviewed, with discus-

sion of evidence from genetic, magnetic resonance imaging,

neuropathology, and functional neuroimaging studies.

Although autism is a behaviorally valid syndrome, it is

remarkably heterogeneous and involves multiple develop-

mental domains as well as a wide range of cognitive, lan-

guage, and socioemotional functioning. Although multiple

etiologies are implicated, recent advances have identified

common themes in pathophysiology. Genetic factors play a

primary role, based on evidence from family studies, identi-

fication of putative genes using genome-wide linkage analy-

ses, and comorbidities with known genetic mutations. The

RELN gene, which codes for an extracellular protein guiding

neuronal migration, has been implicated in autism. Numer-

ous neuropathologic changes have been described, includ-

ing macroencephaly, acceleration and then deceleration in

brain growth, increased neuronal packing and decreased

cell size in the limbic system, and decreased Purkinje cell

number in the cerebellum. Abnormalities in organization of

the cortical minicolumn, representing the fundamental sub-

unit of vertical cortical organization, may underlie the

pathology of autism and result in altered thalamocortical

connections, cortical disinhibition, and dysfunction of the

arousal-modulating system of the brain. The role of

acquired factors is speculative, with insufficient evidence to

link the measles-mumps-rubella (MMR) vaccine with autism

or to change immunization practices.

Nosology: Autism as a Complex

Neurobiologic Disorder

Whether autism should be considered a single syndrome

with highly variable severity ( ie , the autistic spectrum) or

an aggregate of specific disorders that share common fea-

tures is unresolved. It is clear today that autism is a syn-

drome with multiple etiologies. Recently, enormous

advances in genetics, neuroimaging, and neurotransmitter

studies have advanced our knowledge of the pathophysiol-

ogy of autism, although much uncertainty remains.

There is an effort to develop a validated typology based

on behavioral criteria, based on the hypothesis that dys-

function of a particular brain region or neural network

may produce reasonably predictable behavioral deficits. In

autism, this dysfunction would potentially be a result of

genetic and environmental factors, expressed morphologi-

cally as alterations in early brain development.

Introduction

Autism is a behaviorally defined syndrome characterized

by atypical social interaction, disordered verbal and non-

verbal communication, restricted areas of interest, and lim-

ited imaginative play. Although autism has been well

validated as a syndrome, it is heterogeneous in its presenta-

tion. Severity varies widely; intelligence ranges from

severely deficient to superior, and language from absent to

grammatically complex but dysprosodic. Even when intel-

Advances in Genetics:

Genotype versus Phenotype

There is a body of evidence implicating genetic factors as

playing a primary role in the etiology of autism [4]. Multi-

ple twin and family studies demonstrate significant differ-

ences in monozygotic and dizygotic twin concordance

rates, suggesting an underlying genetic predisposition to

autism exceeding 90% [5]. In addition, the rate of autism

among a proband's siblings is 3% to 6%, or 50 to 100

times greater than the general population [6]. The signifi-

150

Pediatric Neurology

cant sibling risk versus the rapid fall-off in risk for distant

relatives is consistent with the involvement of multiple

susceptibility genes. The existing genetic models postulate

different numbers of interacting genes, ranging from less

than 10, with three loci providing the best fit [7], to more

than 15 genes, each with a minor effect [8].

Because autism is a complex disorder, it is clear that the

design of genetic studies plays an important role. One

source of discrepancy may be the heterogeneity in autism,

both genetic and phenotypic. Among these considerations,

two types of genetic studies have been designed. One

focuses on individuals with well-defined subtypes and

groups of patients that are homogeneous and, therefore,

reduce the "noise" of pooling subjects. This should facili-

tate detection of the genetic "signal" [9].

The other type of study design looks for a wide range

of clinical and subclinical forms of the disorder in rela-

tives of affected patients. For example, an increased fre-

quency of speech disorders has been found [7]. Also, an

increased prevalence of a series of personality traits ( eg ,

impulsive, aloof, shy, and eccentric) [10] and specific pat-

terns of social behavior have been identified [11]. As the

measurement and detection of these differences become

more refined, the information may be useful in genetic

analyses. Monozygotic twin studies have shown a concor-

dance rate as high as 60% for the diagnosis of autism.

Milder forms of social and communicative abnormalities

were found in up to 95% of monozygotic twins [5]. The

rate of these abnormalities among relatives of probands is

remarkably increased compared with the general popula-

tion, and falls rapidly with a decrease in the degree of

familial relationship [12].

with alterations in autism [24]. However, data from differ-

ent groups have shown that changes in RELN expression

exhibit a broad phenotypic spectrum, including several

neuropsychiatric disorders [25,26], neuromuscular disor-

ders, and lissencephaly [27].

Approximately 10% to 15% of autistic individuals

demonstrate comorbility with known genetic conditions,

including tuberous sclerosis, neurofibromatosis, fragile X

syndrome, and chromosome abnormalities [28]. Cytoge-

netic screening for chromosomal abnormalities has dem-

onstrated chromosome 15 and X chromosome break-

points as the most frequently associated with autism [29].

Researchers have assumed that gene alterations arising

from such mutations, or the presence of duplicated or

missing genes, are directly responsible for the behavior

phenotype [9]. Special interest has developed in chromo-

some 15, as cytogenetic abnormalities in the Prader-

Willi/Angelman syndrome critical region (15q11-13)

have been described in several individuals with autism.

Markers across this region have been screened for evi-

dence of linkage association. Three of the gamma-ami-

nobutyric acid (GABA)-A receptor subunits are localized

in this critical region. Several studies found an association

with polymorphisms of a GABA-A receptor subtype,

GABRB3, and autism [30] or other genes nearby [31,32].

Other studies have not replicated these findings [33].

UBE3A , an Angelman syndrome gene, has been associ-

ated with autism [34,35]. Although it is premature to

consider these findings determinants in the etiology of

autism, they open additional opportunities for genetic

and neurotransmitter studies.

The higher incidence of autism in boys compared with

girls and the relatively high frequency of autistic character-

istics in patients with Fragile X syndrome have led to signif-

icant interest in the X chromosome. Family studies have

demonstrated the presence of an association between

known genes of major significance on the X chromosome

and autism [16,36]. Mutations in the X-linked gene

MECP2 have been identified in up to 80% of typical Rett

syndrome patients, with most of the mutations originating

de novo [37]. However mutations in MECP2 have been

observed in a variety of neurobehavioral problems, includ-

ing autistic syndrome, learning disabilities, and neonatal

encephalopathies [38,39•]. Table 1 shows a list of some of

the genes that have been associated with autism [39•]

Cytogenetic and molecular studies

Genome-wide linkage analyses of families with autism

have yielded positive signals for chromosomes 1, 2q, 7q, 9,

13, 15q, 16p, 17q, 19, 22, and X [13–16]. The best candi-

dates for regions containing an autism locus are chromo-

somes 2q and 7q [17,18]. An independent linkage study

identified a region in chromosome 7q31 as the locus

responsible for the speech-language disorder 1 (SPCH1)

[19]. The possible relationship between SPCH1 and autism

is supported by increased rates of language impairment in

relatives of autistic individuals [20,21]. Recently, the identi-

fication of the gene FOXP2 , which is responsible for

SPCH1 and encodes a putative transcription factor, pro-

vides light on the neurodevelopmental process that culmi-

nates in speech and language [22]. Additional associations

in chromosome 7 have been found with another candidate

gene for autism, RELN , which encodes for reelin, an extra-

cellular protein guiding neuronal migration during brain

development. Recent studies have found a significant asso-

ciation between autistic disorder and a GGC repeat located

at 5’ on the RELN gene [23]. Reelin plays a pivotal role in

the development of the cerebral cortex, cerebellum, hip-

pocampus, and brain stem, which are structures associated

Neuroimaging Studies:

Magnetic Resonance Imaging

Several neuroimaging studies have reported abnormalities

in specific brain regions, including cerebellum [40–44],

mesial temporal structures [45•,46], brain stem [47], basal

ganglia, and corpus callosum [48].

Increase in the overall size and weight of the brain in

individuals with autism compared with age-matched con-

trol subjects has been reported [49,50]. Brain size in chil-

The Neurobiology of Autism: New Pieces of the Puzzle • Acosta and Pearl

151

Table 1. Genes frequently associated with autism

Gene Location

MECP2 (methyl-CpG binding protein - 2) Xq28

5-HTT (serotonin transporter)

17q11.1-q12

grey and white matter volumes increased by 19% and 46%,

respectively, from 2 to 4 years of age compared with 9 to 12

years, but increased by only 1% and 14%, respectively, in

autistic children during this same age span [55••,56••].

Results from multiple studies, therefore, support the

conclusions that autism is associated with acceleration in

brain growth during early childhood, and that this increase

in brain volume does not persist throughout the lifespan

[54••]. Tissue enlargement, however, does not appear to be

a global phenomenon in the developing autistic brain.

Variations have been observed in areas including the cere-

bellum, limbic system, and corpus callosum [43,56••,57].

In a study of boys with autism aged 2 to 3 years, there was

less grey matter in the cerebellum, a smaller ratio of grey to

white matter, and smaller vermian lobules VI-VII than in

normal control subjects [52•]. There are 16 MRI studies

reporting significantly reduced size of the cerebellar hemi-

spheres or vermis in patients with autism, making the cere-

bellum the most widely replicated site of MRI abnormality

in the autism literature [43]. These neuroimaging findings

correlate with post-mortem examinations in which 95% of

autistic cases have loss of cerebellar Purkinje neurons.

A developmental defect has been hypothesized in the

limbic system, given its mediation of memory, social, and

affective functions. A developmental MRI study of

patients ranging from ages 29 months to 42 years showed

a smaller cross-sectional area of the dentate gyrus [41].

Posterior regions of the corpus callosum were also

reduced in size in autism in a study of patients ranging

from 3 to 42 years of age [58].

In conclusion, recent MRI observations suggest abnor-

mal regulation of brain growth in autism, characterized by

early overgrowth followed by abnormally slow growth in

some regions, but premature arrest of growth in others.

This evidence raises a growth dysregulation hypothesis of

autism in which there is pathologic dysregulation in the

timing and amount of growth as well as cessation of

growth. Pathologic growth regulation during this critical

period of life could lead to widespread and pervasive con-

sequences for the functional differentiation of systems

mediating many neurobehavioral domains. Evidence con-

sistent with this prediction of aberrant functional organi-

zation in autism comes from recent functional MRI (fMRI)

studies of mature patients performing tasks involving

movement [59,60], face perception [59,60], processing

emotions [61], and visual attention [58].

This abnormal pattern of brain growth in autism

may also include a lack of normal acceleration in

growth that occurs in typically developing adolescents.

This period of maturation is associated with the emer-

gence of a second phase of higher-order abilities, par-

ticularly frontal lobe functions [62]. This means that

even though the brain size is "normalized" in adoles-

cents with autism, this normalization may be the result

of both early acceleration and later deceleration in

brain growth.

GABRB3 (gamma-aminobutyric acid

receptor subunit beta 3)

15q11-q13

UBE3A/E6-AP (ubiquitin-protein ligase) 15q11-q13

HRAS1 (c-Harvey-ras-1)

11p15.5

HOXA-1 (Homebox A-1)

7p15.3

RAY1 or FAM4A1 (supressor of

tumorigenicity 7)

7q31.3

WNT2

7q31-33

RELN (reelin)

7q22

ALDH51A1 (succinic semialdehyde

dehydrogenase)

6p22

HLA genes

GluR6 (glutamate receptor 6)

6q21

ASL (adenylosuccinate lyase)

22q13.3-q13.2

Mitochondrial transfer RNA (Lys)

Mitochondrial

DNA

HTR2A

13q

Bcl-2

18q 21.3

FOXP2 (speech-language disorder 1)

7q31

dren with autism appears to be normal at birth [43,51].

This conclusion is based on measures of head circumfer-

ence with an index that has been shown to be highly pre-

dictive of computed tomography (CT)-based or magnetic

resonance imaging (MRI)-based brain volume [52•,53].

By 2 to 4 years of age, however, 90% of autistic patients

have brain volumes that are larger than average. More-

over, 37% of 2- to 4-year-old autistic toddlers meet crite-

ria for developmental macroencephaly [51].

Several volumetric studies using MRI techniques have

explored this issue. Total brain volume by MRI volumetric

techniques was recently measured in a group of 67 autistic

individuals from 8 to 46 years of age and 83 normal con-

trol patients matched by sex, age, IQ, ethnicity, and socio-

economic status [54••]. All autistic individuals were non-

mentally retarded. An increase in total brain volume in

subjects with autism between 8 and 12 years of age was

found. No increase in brain volume was found for autistic

individuals 12 years or older. Similar findings in autistic

children aged 2 to 4 years has been reported [52•]. In this

study, 90% of autistic boys aged 2 to 4 years had more cere-

bral (18%) and cerebellar (39%) white matter and more

cerebral cortical grey matter (12%) than normal patients,

whereas older autistic children and adolescents did not

have such enlargement of grey and white matter. Addition-

ally, increased cerebral size in young autistic children

showed an anterior to posterior gradient, with frontal

lobes being the most enlarged and occipital lobes showing

the least effect. After a period of accelerated growth, cross-

sectional MRI data show slowed growth velocity through-

out cerebral and cerebellar regions, in contrast with nor-

mal subjects. For example, in normal children, frontal lobe

5-HTR 7 (serotonin receptor 7)

10q21-q24

152

Pediatric Neurology

Elevated brain neurotrophins and neuropeptides

(brain-derived neurotrophic factor, neurotrophin 4/5,

vasoinhibitory peptide, and calcitonin gene-related pep-

tide) have been found in neonatal blood spots of individu-

als who later developed autism and mental retardation

[63••]. These and other growth factors play roles in neu-

ronal proliferation, migration, differentiation, growth, and

circuit organization. These elevations or others could be

the molecular basis for the early and accelerated brain

growth in autism. Neurotrophins typically stimulate the

growth of both neuronal and glial elements and endothe-

lium. The increased levels of neurotrophins suggest that

there is a premature over-expression of genes that leads to

the production of neurotropins and neuropeptides. Future

studies should examine possible relationships between

nerve growth factors and brain growth patterns.

m wide depending on the cortical

area. Each minicolumn contains a repetitive array of affer-

ent inputs, intrinsic microcircuitry, and efferent outputs

infusing the structure with a putative role as a physiologic

unit [70••].

In autism, more numerous, smaller [67••,68], and

less compact minicolumns have been described

[52•,55••,65]. This may imply defects in the prolifera-

tion of neuronal precursor cells or environmental-

induced changes affecting minicolumnar architecture.

Altered minicolumnar organization has also been

described in Down syndrome, where minicolumns are of

normal width, but the radial structures attain adult mini-

columnar size earlier than normal. This is consistent with

the accelerated aging observed in this condition.

The larger brain size in autistic children, coupled with

the observation that cortical minicolumns are smaller and

more numerous, results in a novel cytoarchitectural

arrangement of a relative and absolute increase in columns

per brain surface area, or processing units [67••,71]. This

configuration may originate during the genesis of neurons

and the minicolumn. As cortical surface area has increased

evolutionarily with essentially constant size of the minicol-

umn, the result is an increase in the number and complex-

ity of processing units. During this slow process

throughout evolution, selection pressures would have

occurred to benefit the organism, or at least not prove mal-

adaptive [70••]. In autism, a significant increase in pro-

cessing units may occur as an acute event, not subject to

normal selection pressures. If thalamic terminations

remain the same in autism and minicolumns are smaller,

then more minicolumns will be innervated per thalamic

afferent terminal than in the normal brain. The failure to

assimilate extra processing units may result in cortical

"noise" that then overtaxes the system [67••].

Among several conceptual classifications, autism has been

considered a disorder of the arousal-modulating system of the

brain. Accordingly, autistic individuals experience a chronic

state of over-arousal and subsequently exhibit abnormal

behaviors. The arousal theory is consistent with a reduction in

inhibitory interneuronal activity. The cortex contains inhibi-

tory cells that define minicolumnar organization. Lateral

inhibition caused by GABAergic neurons helps to ensure indi-

vidual minicolumn discreteness and, during development,

compels adjacent minicolumns into establishing connections

with functionally dissimilar sets of thalamic neurons. A lack

of this inhibition would grossly alter the connective patterns

between thalamic input and the cerebral cortex. The result

would affect the ability to discriminate between competing

types of sensory information [67••].

Neuropathologic Studies: Morphologic

Developmental Alterations

Neuroanatomic abnormalities have been observed in the

limbic system and cerebellum. Three major neuropatho-

logic findings have been described. They are as follows: 1)

curtailed development of neurons in the forebrain limbic

system (anterior cingulate gyrus, hippocampus, subicu-

lum, entorhinal cortex, and mammillary body); 2) congen-

ital decrease in the number of Purkinje cells in the

cerebellum; and 3) age-related differences in cell size and

neuronal number in the cerebellar nuclei and the inferior

olivary nucleus of the brainstem, suggesting an evolving

process and disturbance in the synaptic relationships of

these nuclei [64,65].

Although gross neuropathologic changes are not typi-

cal in autism, abnormalities observed at the cellular level

may underlie the basis of clinical manifestations. Increased

neuronal cell density and decreased nerve cell size have

been found bilaterally in the amygdala, entorhinal cortex,

mammillary body, anterior cingulate gyrus, medial septal

nucleus, and hippocampal complex [66]. These changes in

the limbic system may be related to the emotional and

mood manifestations of the clinical syndrome. Although

dysmorphic neurons are not usually found, a simplified

dendritic pattern in hippocampal regions CA4 and CA1

has been described [46].

The minicolumn hypothesis

Microscopic examination of brain tissue in autistic patients

provides evidence for altered central nervous system (CNS)

development. The processes of neuronal genesis and

migration are accomplished mainly before birth in mam-

mals. Both events must occur at the proper tempo and in a

coordinated fashion for the critical events of neuronal dif-

ferentiation and synaptogenesis to occur properly. Recent

observations regarding minicolumnar organization pro-

vide important evidence about developmental alterations

in autism [67••,68]. The minicolumn, the fundamental

anatomic and physiologic unit of the cerebral cortex, is the

smallest level of cortical vertical organization.

Early in development, post-mitotic neurons leave the

ventral wall and travel in a path ending with their radial

arrangement within the cortical plate [69]. In the adult

brain, minicolumns appears as thin radial structures, rang-

ing from 30- to 60-

The Neurobiology of Autism: New Pieces of the Puzzle • Acosta and Pearl

153

Other developmental alterations

Other studies have reported dysregulation of the proteins

reelin and Bcl-2, with reduction of these two proteins in

autistic cerebellar tissue compared with human control tis-

sue [24]. Reelin, a signaling protein that guides neuronal

migration in the developing fetus, as well as a cellular sig-

naling system subserving cognition in adult brain [26], is

the product of the RELN gene, a candidate gene for autism

[23,72•]. The Bcl-2 protein governs programmed cell

death, or apoptosis, in the developing and maturing

human brain. Reductions in these neuroregulatory pro-

teins may explain the neuronal migration and cell density

abnormalities observed in autism, and are intriguing in

light of the aforementioned putative peptide biomarkers

found in newborns [63••].

Hippocampal studies in autistic individuals have

shown that cells in this region are often smaller, packed

more densely, and have less dendritic branching than is

expected [73]. Proteomic studies have demonstrated

changes in protein in frontal cortex. Reduction or absence

gic afferents to the cortex influence neural stem cell pro-

liferation [84,85] and may contribute to an increased

number of cortical minicolumns. Further studies on the

role of serotonin in prenatal cortical development are

needed, as abnormal neurogenesis or migration may

underlie the macrocephaly associated with autism.

Whole blood serotonin levels are increased in patients,

and serotonin transporter inhibitors reduce rituals and

aggression in autism. Comparative studies of monoamine

levels in autistic children versus control patients suggest

abnormal maturation of the serotoninergic system during

child development [86].

Chugani et al . [87] demonstrated developmental

changes in serotonin synthesis capacity in children using

alpha[C-11]methyl-L-tryptophan and positron emission

tomography. For nonautistic children, serotonin synthe-

sis capacity was greater than 200% of adult values until

the age of 5 years, and then declined toward adult values.

In autistic children, serotonin synthesis capacity

increased gradually between the ages of 2 and 11 years to

values 1.5 times of adult normal values. These findings

suggest that humans undergo a period of high brain sero-

tonin-synthesis capacity during childhood, and that this

developmental process is disrupted in autistic children,

with some brain regions more severely impacted [77,87].

Changes in serotonin synthesis and receptor density with

age suggest that serotonin plays an important role in

brain development [88].

Functional Neuroimaging

and Neurotransmitter Studies:

Serotoninergic Dysfunction

Serotonin, like other monoamine transmitters, has been

shown to play a role in regulating brain development

[75••]. It influences the processes of neurogenesis, neu-

ronal differentiation, neuropil formation, axon myelina-

tion, and synaptogenesis. Removal of serotonin during

very early fetal development in rats causes a permanent

reduction in the number of neurons in adult brain hippoc-

ampus and cortex [75••]. At a later time in development,

serotonin plays a role in dendritic development, including

overall dendritic length, spine formation, and branching in

both hippocampus and cortex. Additionally, serotonin lev-

els can be affected by multiple and nonspecific post-natal

factors, including hypoxia, viral infections, malnutrition

[76], social enrichment, and stress. Drugs, including

cocaine, nicotine, and alcohol, can alter serotonin levels.

Increased evidence points to an imbalance in seroto-

nin levels as important for the etiology of autism

[75••,77–79]. Although several reports conclude that

dysgenesis of several brain systems occurs in autism

[52•,55••,65,66,67••,68], only recently has a link been

made between the role of serotonin in brain development

and autism [75••,77,80]. When assessing the effects of

serotonin on cortical growth, both an abundance and a

paucity may be deleterious. Depletion of serotonin

results in a significant delay in maturation of the soma-

tosensory cortex [81,82]. In contrast, excessive serotonin

during early development results in hyperinnervation and

expansion of cortical architecture [83]. Early serotoniner-

Other neurotransmitters

Other neurotransmitter alterations associated with autism

include glutamate and GABA. The glutamate receptor 6

( GluR6 ) gene is localized in 6q21 and has been implicated

in autism [89]. It is highly expressed in brain regions

involved in learning and memory, and in motor and moti-

vational aspects of behavior [17]. GABAergic interneurons

in mouse cortex originate from the ganglionic eminence of

the ventral telencephalon. Disturbances of interneuron

migration and integration have been implicated in a vari-

ety of developmental disorders, including cortical dyspla-

sia with epilepsy [90], schizophrenia [91], Tourette's

syndrome [92], and autism [67••,68].

Acquired Factors/Immunizations

A possible etiologic connection between viral infections

and autism has received recent attention. Despite a pro-

posed link between autism and several pathogens, includ-

ing rubella, cytomegalovirus, and herpes simplex [93,94], a

direct search for viral genome or protein in blood and cere-

brospinal fluid of patients with autism has not produced

consistent results [95]. Congenital rubella has been associ-

ated with autism, although less than 1% of patients with

autism have congenital rubella [96].

A speculative association between the measles-mumps-

rubella (MMR) vaccine and autism has been described as a

B-crystallin in autistic brains has been reported [74].

Crystallin belongs to a group of small heat shock proteins

and functions as a molecular chaperone.

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