GENETICS/BASIC DEFECTS Autism

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102 Autism is a pervasive developmental disorder, defined by impairments in social and communication function, and repetitive and stereotyped behavioral patterns. It occurs in approxi- mately 7–40 out of 10,000 persons.

GENETICS/BASIC DEFECTS

1. Secondary autism (nongenetic and genetic conditions associated with autism): accounts for a small minority of individuals with autism (<10%) in population-based studies a. Obstetric complications including uterine bleeding,

despite absence of demonstrable causal relationship in many studies

b. Intrauterine exposure to teratogenic drugs in a few affected children

i. Thalidomide ii. Valproate

c. Elevated cord blood levels of the following sub- stances:

i. Neuropeptides substance P ii. Vasoactive intestinal peptide

iii. Pituitary adenylate cyclase-activating polypeptide iv. Calcitonin gene-related peptide

v. Neurotrophin nerve growth factor d. Various epidemiologic data

i. Cerebral palsy (a static motor deficit of brain origin present from early life): present in 2.1–2.9% of individuals with autism and mental retardation

ii. Congenital rubella infection: present in 0.75% of cases

iii. Other pre- and postnatal infections (e.g., Hemophilus influenza and cytomegalovirus):

may cause autism when they significantly dam- age the immature brain

iv. No association between autism and inflammatory bowel disease or with a live MMR vaccination v. Epilepsy with the highest association with

autism: reported in up to one-third of individuals with an autistic spectrum disorder in adulthood vi. Behavioral symptoms of autism: frequent in

tuberous sclerosis complex and fragile X syndrome but account for only a minority of the total cases of autism

e. Genetic mutations associated with autism i. Chromosomal causes of autism

a) Angelman syndrome (more commonly associated with autism than Prader-Willi syndrome) can result from the loss or mutations of the maternally derived UBE3A or the ATP10C gene in 15q11-q13 region

b) Chromosomal duplication in the Prader- Willi/Angelman region of proximal 15q in

about 3% of individuals with autism: more commonly a supernumerary iso-dicentric 15q chromosome detectable by routine cytogenetic studies or less commonly an interstitial duplication of the region detected by FISH analysis of the SNRPN gene

c) Other chromosome abnormalities in 3–5%

of individuals with autism

d) A subtelomeric deletion detected by FISH telomere studies in 10% of unselected patients with autism

e) Down syndrome: Autism was found in at least 7% in one study in children with Down syndrome

ii. Single-gene causes of autism

a) Fragile X syndrome found in a few percent of children with autism: at least 50% of children with fragile X syndrome have autistic behaviors, including avoidance of eye contact, language delays, repetitive behaviors, sleep disturbances, tantrums, self-injurious behaviors, hyperactivity, impulsiveness, inattention, and sound sensitivities

b) Rett syndrome: children affected with both autism and Rett syndrome (almost universally female sex) have a period of normal development, followed by loss of language with stereotypic hand movements (hand-wringing behavior)

c) Tuberous sclerosis complex: Mentally retarded individuals with tuberous sclerosis complex frequently have autism (almost 50% in some studies)

d) Neurofibromatosis: much less frequently associated with autism than is tuberous sclerosis and fragile X syndrome

e) Duchenne muscular dystrophy: an unexpect- edly large proportion of boys with Duchenne muscular dystrophy have autistic spectrum f) Sotos syndrome

g) Joubert syndrome h) Williams syndrome

i) Hypomelanosis of Ito j) Cowden syndrome k) Moebius syndrome

iii. Metabolic cause associated with autism a) Mitochondrial disease or dysfunction b) Untreated phenylketonuria

2. Idiopathic autism (inherited autism of unknown cause) a. Family studies indicates genetics play the major

causative role in most individuals with “idiopathic”

autism (90–95%)

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b. Epidemiologic studies

i. A prevalence of 5–10 cases of classic autism per 10,000 (3–6 per 1000 if the entire spectrum of autism is included)

ii. A male-to-female ratio of 3 : 1

a) The preponderance of males suggests an X- linked disorder

b) Linkage to the X chromosome suggested by recent genome-wide screens, although the data are inconsistent

c) Male-to-male transmission of autism in multiplex families (families with more than a single affected family member) ruled out X- linkage in these families

d) No significant associations of autism to Y chromosome based on Y haplotype analysis, although Y chromosome abnormalities have been documented

c. Classification of idiopathic autism i. Essential autism

a) Defined by the absence of physical abnormalities

b) Seen in about 70% of children with idiopathic autism

c) Associated with better outcome overall d) More likely a male

e) A higher sibling recurrence risk ii. Complex autism

a) Defined by the presence of dysmorphic features (microcephaly and/or a structural brain malformation)

b) Seen in about 30% of children with idiopathic autism

c) Associated with a poorer prognosis d) A lower male-to-female ratio e) A lower sibling recurrence risk

d. Evidence suggesting genetic basis of autism without a diagnosable cause

i. 25% rate of recurrence in siblings of affected individuals from family studies: much greater than the prevalence rate in the general population

ii. Greater than 60% rate of concordance for classic autism in monozygotic twins, compared with no concordance found between dizygotic twins e. The identity and the number of genes involved in

autistic disorders: remained unknown i. Multigenic

a) Similar autistic phenotypes may arise from different genes or gene combinations in different families (single-mutation genetic het- erogeneity)

b) Example: tuberous sclerosis caused by TSC1 on chromosome 9q in some families and TSC2 on 16p in others

ii. Polygenic

a) Several synergistically acting genes in an affected individual’s genome may be required to produce the full autistic phenotype

b) Lowering of a theoretical threshold by cer- tain sets of genes acting in concert to allow the development of autism, either by themselves or given the right set of environmental or immunologic modifiers

c) Other related developmental disorders in family members presumed to have inherited some of the susceptibility genes found in the affected family member or to have the same set of susceptibility genes without exposure to the same environmental “trigger factors”

for autism 3. Search for candidate genes

a. Cytogenetics: scrutinize the region involved in visible breakpoints, translocations, duplications, inversions, and deletions for the presence of genes that potentially may be involved in the pathogenesis of autistic spectrum disorders

b. Whole genome search: microsatellite markers screening in multiplex family uncovers specific chromosomal regions that affected individuals inherit more often than predicted by chance

CLINICAL FEATURES

1. Early signs of infants with autism a. Do not care to be held or cuddled b. Do not reach out to be picked up c. Often “colicky” and hard to console

d. Typically quieting more readily when left alone e. Avoid and fail to initiate eye contact

f. Stare into space g. Sleep disturbances

h. Usually do not come to medical attention until after the second year when language delays are evident 2. Natural history

a. Onset of autism: prior to age three b. Gradual onset of autism in most children

c. “Regressive” onset of autism in about 30% of children i. Initially begin to talk

ii. Then often precipitously lose language and become distant

iii. Refuse to make eye contact within a matter of days and no longer respond to his or her name iv. Repetitive movements may develop immediately

or by 3 or 4 years of age.

d. About 25% of children who fit diagnostic criteria for autism at age 2 or 3 years

i. Subsequently begin to talk and communicate ii. Blend to varying degrees into the regular school

population by 6 or 7 years

e. Remaining 75% of children with autism continue to have a life-long disability requiring intensive parental, school, and societal support

f. Fewer than 5% of children with autism completely recover.

3. Mental retardation by nonverbal IQ testing in 50–70% of children with autism

4. Seizures develops in about 25% of children with autism

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5. Idiopathic autism

a. About 30% of children have complex autism, defined by presence of the following features:

i. Dysmorphic features ii. Microcephaly

iii. Structural brain malformation

b. About 70% of children have essential autism, defined by absence of physical abnormalities

6. Behavioral impairments

a. Impairments in social interaction: separates individuals with autism from individuals around them

i. Unable to “read” other people, ignoring them and often strenuously avoiding eye contact ii. Do not comfort others or seek comfort and do

not share interests with others

iii. Usually prefer to be by themselves, engaging in their own, often repetitive, activities at home iv. Fail to develop friendship with peers and siblings

v. Demonstrate a marked deficit in imitating other’s actions, which may impede the development of interpersonal synchrony, communication, symbolic play, and the learning of new behaviors

b. Impairments in communication

i. Fail to develop reciprocal communication either by speech, gestures, or facial expression in most children with autism

ii. Fail to use eye gaze to communicate and direct attention in young children

iii. Display stereotypic speech that may involve echolalia or unusual inflections and intonations when children with autism learn to talk

c. Repetitive and stereotypic behaviors i. Staring or rocking

ii. Toddlers may have motor “stereotypies”

a) Movements of fingers b) Twirling strings c) Flicking pages of books d) Licking

iii. Repetitive whole body movements a) Spinning

b) Running back and forth

iv. Complex repetitive movements may last for hours

v. Develop elaborate rituals in which the order of events, the exact words, and the arrangement of objects must be followed

d. Other symptoms

i. Hyper- and hyposensitivities to sensory stimula- tion of all types (e.g., visual, auditory, tactile, and pain)

ii. Odd behaviors around foods and their presenta- tion

iii. Abnormal sleep patterns

iv. Tantrums and/or self-injurious and aggressive behaviors brought on by a change in routine, an offending touch, or no apparent reason

v. Impaired motor development with toe walking early in life and general clumsiness

vi. Total disregard for danger, resulting in high risk of early death, most commonly from drowning 7. Diagnostic criteria for autistic disorder (American

Psychiatric Association, 1994)

a. Presence of a total of >6 of the following areas:

i. Qualitative impairment in social interaction, in at least two of the following areas:

a) Marked impairment in the use of multiple nonverbal behaviors, such as eye-to-eye gaze, facial expression, body postures, and gestures, to regulate social interaction b) Failure to develop peer relationships appro-

priate to developmental level

c) Lack of spontaneous seeking to share enjoy- ment, interests, or achievements with other people (e.g., by lack of showing, bringing, or pointing out objects of interest)

d) Lack of social or emotional reciprocity ii. Qualitative impairment in communication, in at

least one of the following areas:

a) Delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication, such as gesture or mime)

b) Marked impairment in the ability to initiate or sustain a conversation with others in individuals with adequate speech

c) Stereotyped and repetitive use of language, or idiosyncratic language

d) Lack of varied, spontaneous make-believe, or social imitative play appropriate to developmental level

iii. Restrictive repetitive and stereotypic patterns of behavior, interests, and activities, in at least one of the following areas:

a) Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus

b) Apparently inflexible adherence to specific nonfunctional routines or rituals

c) Stereotyped and repetitive motor manner- isms (e.g., hand or finger flapping or twist- ing, or complex whole-body movements) d) Persistent preoccupation with parts of objects b. Delays or abnormal functioning with onset prior to 3

years of age, in at least one of the following areas:

i. Social interaction

ii. Language as used in social communication iii. Symbolic or imaginative play

c. The disturbance is not better accounted for by Rett syndrome or childhood disintegrative disorder 8. Differential diagnosis with other pervasive developmental

disorders

a. Asperger disorder

i. A variant of autism typically occurring in high- functioning individuals without mental retardation, not considered as a separate disorder

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ii. Language develops better than classic autism iii. Problems with the semantic and pragmatic use of

language

iv. Many individuals are misdiagnosed early on and in adulthood as odd or eccentric

b. Rett syndrome

i. A specific genetic disorder of postnatal brain development, caused by a single-gene defect predominantly affecting girls

ii. Cause: de novo mutations or microdeletions of the methyl-CpG-binding protein 2 (MeCP2) gene on Xq28 in the majority of cases

c. Childhood disintegrative disorder

i. Behavioral, cognitive, and language regression between 2 and 10 years of age after entirely normal early development

ii. Experience in at least two of the following areas:

language, social skills, bowel or bladder control, and play or motor skills

iii. Cognitive skills usually impaired significantly d. Pervasive developmental disorder, not otherwise

specified

i. Onset after 3 years of age

ii. Individuals who have autistic features but do not fit any of the other subtypes

iii. Presence of a wide range of cognitive and behavioral problems

iv. In general, less severe social, communicative, and behavioral deficits

DIAGNOSTIC INVESTIGATIONS

1. Cytogenetic studies and molecular genetic analyses a. High-resolution or multi-FISH telomere chromosome

studies

i. Chromosomal abnormality involving the proximal long arm of chromosome 15 (15q11-q13) observed in more than 1% of autistic individuals.

Duplication is usually maternally derived, with one or two extra copies of the area roughly corresponding to the typical Angelman syndrome/Prader Willi syndrome deletion region:

a) Pseudodicentric 15 (inverted duplication 15) b) Atypical marker chromosomes

ii. Other chromosome abnormality: cytogenetic abnormalities have been found on virtually every chromosome in individuals with autism

b. Molecular genetic testing for fragile X syndrome: unlikely positive in the presence of high-functioning autism 2. Metabolic studies: positive in probably <5% of children

with autism

a. Inborn errors in amino acid, carbohydrate, purine, peptide, and mitochondrial metabolism

b. Toxicologic studies

3. Increased serum serotonin in about one-third of individuals with autistic disorder

4. Electrophysiologic studies: epileptiform EEG abnormalities in autistic children with a history of regression 5. Neuroimaging: absence of significant structural brain

abnormalities

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib

i. Secondary autism: The recurrence risk is based on information relevant to the primary diagnosis

a) Supernumerary iso-dicentric 15q chromosome: no increased recurrence risk since it is a de novo occurrence

b) Duplication of proximal 15q: an increased recurrence risk since it may result from seg- regation of a parental chromosome translocation or a maternally-derived interstitial 15q duplication

ii. Idiopathic autism

a) The empiric aggregate risk to sibs: 4%

b) An additional 4–6% risk for milder symptoms including language, social, and psychiatric disorders

c) For families with ≥2 children: the recurrence risk approaches 35%

iii. Essential autism

a) For male sibs: 7% of risk for autism and an additional 7% risk for milder autism spectrum symptoms

b) For female sibs: a 1% risk for autism and an unknown risk for a milder autism spectrum disorder

iv. Complex autism: the sib recurrence risk of a proband with complex autism

a) 1% for autism

b) An additional 2% for a milder autism spectrum disorder

b. Patient’s offspring: no available data 2. Prenatal diagnosis: not available 3. Management

a. General goals of treatment

i. Improve language and social skills

ii. Decrease stereotypic and disruptive behaviors iii. Support parents and families in their adjustment

and to educate their children iv. Foster independence

b. Early intervention programs: focused on developing the following areas:

i. Language

ii. Cognitive and imitation skills iii. Social responsiveness

iv. Appropriate behavior c. Behavior modification programs

i. Structure the environment

ii. Provide consistent responses to behaviors iii. Reward a desired behavior (positive reinforce-

ment)

iv. No reward for undesirable behavior (negative reinforcement)

v. Apply an adverse stimulus to deter an unwanted response (punishment)

vi. Reinforcing closer and closer approximations to the desired behavior (shaping)

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d. School-aged children with autism

i. Need a curriculum that is tailored to individual strengths and needs

ii. Effective education programs

a) Well-structured, systematic teaching routines b) Consistency and repetition

c) Concrete and functional learning objectives e. Adolescents and adults with autism

i. Need specific help in vocations and avocations in adult life

ii. Social skills groups iii. Recreational activities

iv. Individual psychotherapy

v. Vocational coaching and assistance

f. Medications: no medications are autism-specific i. Antidepressants: Selective serotonin reuptake

inhibitors with some success in treating preoccu- pations, ritualized behaviors, mood disorders, and anxiety

ii. Stimulant medications: little or no clinical improvement to decrease the activity levels and to improve the attention span of some children

iii. Antipsychotic medications: New atypical antipsychotic medications may be useful in treating aggressive and hyperactive behavior with fewer side effects

iv. Anticonvulsant medications: used to treat individuals with autism who suffer from seizures and may be effective in decreasing aggressive behavior and episodic behavioral outbursts, par- ticularly in children with seizure disorder

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Fig. 1. A girl (at 4 years and 10 years) with autism. Her chromosome study showed a balanced translocation between the short arm of chromosome 5 and the long arm of the chromosome 10 [t(5;10)(p13;q21)]

(karyotype shown). Her parents had normal chromosomes.