-
-
The genetics of autism.
Class of 2004, Albert Einstein College of
Medicine, Bronx, New York 10461, USA.
Autism is a complex, behaviorally defined,
static disorder of the immature brain that is of great concern to
the practicing pediatrician because of an astonishing 556% reported
increase in pediatric prevalence between 1991 and 1997, to a
prevalence higher than that of spina bifida, cancer, or Down
syndrome. This jump is probably attributable to heightened
awareness and changing diagnostic criteria rather than to new
environmental influences. Autism is not a disease but a syndrome
with multiple nongenetic and genetic causes. By autism (the
autistic spectrum disorders [ASDs]), we mean the wide spectrum of
developmental disorders characterized by impairments in 3
behavioral domains: 1) social interaction; 2) language,
communication, and imaginative play; and 3) range of interests and
activities. Autism corresponds in this article to pervasive
developmental disorder (PDD) of the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition and International
Classification of Diseases, Tenth Revision. Except for Rett
syndrome--attributable in most affected individuals to mutations of
the methyl-CpG-binding protein 2 (MeCP2) gene--the other PDD
subtypes (autistic disorder, Asperger disorder, disintegrative
disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked
to any particular genetic or nongenetic cause. Review of 2 major
textbooks on autism and of papers published between 1961 and 2003
yields convincing evidence for multiple interacting genetic factors
as the main causative determinants of autism. Epidemiologic studies
indicate that environmental factors such as toxic exposures,
teratogens, perinatal insults, and prenatal infections such as
rubella and cytomegalovirus account for few cases. These studies
fail to confirm that immunizations with the measles-mumps-rubella
vaccine are responsible for the surge in autism. Epilepsy, the
medical condition most highly associated with autism, has equally
complex genetic/nongenetic (but mostly unknown) causes. Autism is
frequent in tuberous sclerosis complex and fragile X syndrome, but
these 2 disorders account for but a small minority of cases.
Currently, diagnosable medical conditions, cytogenetic
abnormalities, and single-gene defects (eg, tuberous sclerosis
complex, fragile X syndrome, and other rare diseases) together
account for <10% of cases. There is convincing evidence that
"idiopathic" autism is a heritable disorder. Epidemiologic studies
report an ASD prevalence of approximately 3 to 6/1000, with a male
to female ratio of 3:1. This skewed ratio remains unexplained:
despite the contribution of a few well characterized X-linked
disorders, male-to-male transmission in a number of families rules
out X-linkage as the prevailing mode of inheritance. The recurrence
rate in siblings of affected children is approximately 2% to 8%,
much higher than the prevalence rate in the general population but
much lower than in single-gene diseases. Twin studies reported 60%
concordance for classic autism in monozygotic (MZ) twins versus 0
in dizygotic (DZ) twins, the higher MZ concordance attesting to
genetic inheritance as the predominant causative agent.
Reevaluation for a broader autistic phenotype that included
communication and social disorders increased concordance remarkably
from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This
suggests that interactions between multiple genes cause
"idiopathic" autism but that epigenetic factors and exposure to
environmental modifiers may contribute to variable expression of
autism-related traits. The identity and number of genes involved
remain unknown. The wide phenotypic variability of the ASDs likely
reflects the interaction of multiple genes within an individual's
genome and the existence of distinct genes and gene combinations
among those affected. There are 3 main approaches to identifying
genetic loci, chromosomal regions likely to contain relevant genes:
1) whole genome screens, searching for linkage of autism to shared
genetic markers in populations of multiplex families (families with
>1 affected family member; 2) cytogenetic studies that may guide
molecular studies by pointing to relevant inherited or de novo
chromosomal abnormalities in affected individuals and their
families; and 3) evaluation of candidate genes known to affect
brain development in these significantly linked regions or,
alternatively, linkage of candidate genes selected a priori because
of their presumptive contribution to the pathogenesis of autism.
Data from whole-genome screens in multiplex families suggest
interactions of at least 10 genes in the causation of autism. Thus
far, a putative speech and language region at 7q31-q33 seems most
strongly linked to autism, with linkages to multiple other loci
under investigation. Cytogenetic abnormalities at the 15q11-q13
locus are fairly frequent in people with autism, and a "chromosome
15 phenotype" was described in individuals with chromosome 15
duplications. Among other candidate genes are the FOXP2, RAY1/ST7,
IMMP2L, and RELN genes at 7q22-q33 and the GABA(A) receptor subunit
and UBE3A genes on chromosome 15q11-q13. Variant alleles of the
serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent
in individuals with autism than in nonautistic populations. In
addition, animal models and linkage data from genome screens
implicate the oxytocin receptor at 3p25-p26. Most pediatricians
will have 1 or more children with this disorder in their practices.
They must diagnose ASD expeditiously because early intervention
increases its effectiveness. Children with dysmorphic features,
congenital anomalies, mental retardation, or family members with
developmental disorders are those most likely to benefit from
extensive medical testing and genetic consultation. The yield of
testing is much less in high-functioning children with a normal
appearance and IQ and moderate social and language impairments.
Genetic counseling justifies testing, but until autism genes are
identified and their functions are understood, prenatal diagnosis
will exist only for the rare cases ascribable to single-gene
defects or overt chromosomal abnormalities. Parents who wish to
have more children must be told of their increased statistical
risk. It is crucial for pediatricians to try to involve families
with multiple affected members in formal research projects, as
family studies are key to unraveling the causes and pathogenesis of
autism. Parents need to understand that they and their affected
children are the only available sources for identifying and
studying the elusive genes responsible for autism. Future
clinically useful insights and potential medications depend on
identifying these genes and elucidating the influences of their
products on brain development and physiology.
|
|
Loading...
Our research:
2 h). IL-10 gene therapy both prevented and
reversed thermal hyperalgesia and mechanical allodynia, without
affecting basal responses to thermal or mechanical stimuli.
Extra-territorial, as well as territorial, pain changes were
reversed by this treatment. Intrathecal AD-h-IL10 injected over
lumbosacral spinal cord led to elevated lumbosacral cerebrospinal
fluid (CSF) levels of human IL-10, with far less human IL-10
observed in cervical CSF. In keeping with IL-10's known
anti-inflammatory actions, AD-h-IL10 lowered CSF levels of IL-1,
relative to control AD. These studies support that this gene
therapy approach provides an alternative to neuronally focused drug
and gene therapies for clinical pain control.