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autism (autistic spectrum disorder, ASD)

Communication disorder of childhood, distinct from schizophrenia (DSM-IV) characterized by morbidly self-centered, wishful thinking. Etiology: - idiopathic - genetic & environmental factors appear to contribute equally to risk for autism [44] - risk factors - younger siblings of children with autism with increased risk of autism [15] - more common among children of mothers with diabetes, hypertension, or obesity during pregnancy [19] - hypertension during pregnancy [80] - gestational diabetes in mother is a risk factor for autism in offspring (RR=1.3-1.4) [51,82] by 26 weeks [82] - pre-existing type 2 diabetes in mother (RR=1.2-1.4) [51,82] - diabetes mellitus type 1 in mother during pregnancy (RR=2.3) [82] - paternal age is a risk factor - grandfather age is a risk factor [28] - mother with a history of child abuse may be risk factor [28] - maternal use of antidepressants (SSRI & others) may be associated with increased risk of autism [29,72] - relative risk for SSRI (if any) is < 1.61 [34]; 2.17 [59] - 1st trimester antidepressant use not associated with increased risk for autism in offspring [69] - maternal use of valproate during pregnancy is associated with increased risk of autism [30] - prenatal exposure to air pollution is associated with increased risk for autism [31] - prenatal exposure to pesticide DDT may increase risk for autism [83] - paternal obesity (BMI >= 30) [42] - in utero exposure to pesticides [46] - increased autism risk observed in children born by C-section (RR=1.15-1.21) is likely due to genetic or other factors & is not caused by method of delivery [53] - epidural analgesia during delivery may increase risk for autism [91] - in utero exposure to beta-2-adrenergic receptor agonists may increase risk of autism (RR=1.3) [60] - high plasma folate (RR=2 for plasma folate > 59 nmol/L) [63] - high plasma vit B12 (RR=3 for plasma vit B12 > 600 pmol/L) [63] - plasma folate > 59 nmol/L & plasma vit B12 > 600 pmol/L (RR=17) [63] - maternal fever during the second trimester [71] - greater depth of prenatal ultrasound may be associated with increased autism risk for autism [77] - congenital heart disease mayt increase risk for autism [86] - preterm birth [92] - not risk factors - *exposure to thimerosal from vaccines not associated with autism [12] - *MMR vaccine not a risk factor [52] - *induced labor not a risk factor [43] - *mild infections, febrile episodes, or use of antibiotics during pregnancy are not risk factors [24] - *maternal influenza during pregnancy is not a risk factor [67] - *phototherapy for hyperbilirubinemia [65] - *1st trimester antidepressant use not associated with increased risk for autism in offspring [69] * children with autism their younger siblings are undervaccinated compared with unaffected children [78] Epidemiology: 1) prevalence of 0.05-1% [10]; 1.1% of children [20] a) 2.1% in Utah (highest); 0.48% in Alabama (lowest) b) prevalence higher in boys (1.85%) than in girls (0.4%) c) variation might be attributable to diagnostic practices, underrecognition of ASD symptoms in some racial/ethnic groups, socioeconomic disparities in access to services, & regional differences in clinical or school-based reporting practices [41,47] d) prevalence similar in white & black children [90] e) 1 in 40-60 children with autism [84]; 1 in 54 by age 8 [90] 2) associated with advanced paternal age [3] 3) 4 times as common in boys than girls 4) median age at diagnosis is 52 months [79]; 33 months [90] 5) mean annual precipitation positively correlates with autism prevalence [6] (California, Oregon, Washington) 6) 85% of children with autism have developmental concerns documented in the medical record by age 36 months, but only 42% receive a full evaluation [79] Pathology: - prenatal onset [39] - macrocephaly at birth [17] - brain volumes are enlarged in preschoolers & normalize during adolescence [40] - increased numbers of neurons in the prefrontal cortex a) dorsolateral prefrontal cortex (79% greater than normal) b) medial prefrontal cortex (29% greater than normal) [17] - RNA expression of 25 genes in autistic brain different from expression in normal controls [39] - imbalance in serotonin, dopamine, norepinephrine, GABA & neuropeptides suggested [4] - allergy & autism may share mechanism of immunologic dysfunction [81] Genetics: 1) X-linked forms associated with defects in neuroligin 3, neuroligin 4, MECP2 2) AUTS2 gene is interrupted by a translocation breakpoint in a pair of autistic twins 3) copy number variations in SHANK3, NLGN4, NRXN1 genes associated with autism [5] 4) copy number variations at chromosome 16p11.2 in 1% of autism patients [5] 5) susceptibility to autism a) associated with polymorphisms in: - EN2 - autism type 1A - MET - autism type 1B - MARK1 - autism & autism spectrum disorders - RELN - polymorphic GGC triplet repeat located in the 5'-UTR region of RELN gene - CEP41 - CACNA1C & CACNB2 [27] b) associated with defects in SLC9A9 (autism type 16) 6) other implicated genes: AVPR1A 7) genetic factors account for greatest risk [85] Physical examination: - because patients with autism have difficulty with physical contact, physical examination should be limited to essential maneuvers, performed slowly, & explained in detail before proceeding [11] Clinical manifestations: 1) onset prior to age 3 2) see diagnostic criteria 3) unaffected siblings may show some autistic features [13] 4) attention-deficit/hyperactivity disorder symptoms may mask underlying autism in young children [55] 5) manifestations somewhat at odds with diagnostic criteria [11] - persistent deficits in communication & social interaction associated with impaired function - inability to read body language - repetitive, inflexible non-functional behaviors Laboratory: - urine p-cresol elevated in children with severe autism [37] - higher maternal levels of HSV-2 Ab in serum linked to autism in male offspring [68] - oxytocin in serum/plasma may predict response to nasal oxytocin [73] * also see ARUP consult [89] Radiology: - magnetic resonance imaging (MRI) of brain may show differences in development in white-matter tracts at age 6-24 months compared with normal children [18] Diagnostic criteria: 1) qualitative impairment in reciprocal social interaction: a) marked lack of awareness of the existence of feelings of others - treats a person as if he or she was a piece of furniture - does not notice another person's distress - apparently has no concept of the need of others for privacy b) failure or abnormality in seeking comfort at times of distress - does not come for comfort even when ill, hurt or tired - seeks comfort in stereotyped way (e.g. may repeat some irrelevant word when hurt) c) failure of, impaired or otherwise abnormal imitation - does not wave goodbye - does not copy mother's domestic activities - mechanically imitates others' actions out of context d) absence of or abnormal social play - does not actively participate in simple games - prefers solitary play activities - involves other children in play only as mechanical aids e) gross impairment in ability to make peer friendships - no interest in making peer friendships - lack of understanding of essential principals of social interactions 2) qualitative impairment in verbal & non-verbal communication & in imaginative activity a) no mode of communication b) markedly abnormal nonverbal communication c) absence of imaginative activity - no playacting - lack of interest in imaginary events d) marked abnormalities in the form or content of speech - volume, pitch, stress, rate, rhythm, intonation e) marked abnormalities in the form or content of speech - - stereotyped & repetitive use of speech - echolalia - use of 'you' when 'I' is meant - frequent irrelevant remarks f) marked impairment in the ability to initiate or sustain a conversation 3) restricted repertoire of activities & interests - stereotyped body movements - persistent preoccupation with parts of objects - marked distress over changes in trivial aspects of the environment - unreasonable insistence on following routine in precise detail - markedly restricted range of interests & a preoccupation with one narrow interest 4) onset during infancy or childhood * At least 8 of 16 criteria, including: - 2 from qualitative impairment in reciprocal social interaction - 1 from impairment in communication - 1 from restricted repertoire of activities Complications: 1) seizures may develop (especially in adolescence) 2) sleep disorders 3) attention-deficit/hyperactivity disorder (ADHD) [87] 4) mental retardation 5) feeding problems, gastrointestinal symptoms [87] 6) associated rare disorders a) fragile X syndrome b) tuberous sclerosis c) Down syndrome d) Prader-Willi syndrome e) neurofibromatosis 1 f) untreated phenylketonuria (PKU) g) hypomelanosis of Ito h) disorders of purine metabolism i) Sotos syndrome j) Leopard syndrome k) Noonan syndrome l) Joubert syndrome m) congenital myotonic dystrophy n) Duchenne muscular dystrophy o) Leber's congenital optic atrophy (mitochondrial) 7) increased likelihood of food allergy (RR=2.3), asthma, skin allergy [81] Differential diagnosis: - obsessive compulsive disorder (OCD) - repetitive behaviors may be common to autism & OCD Management: 1) intervention at age 9 months for infants showing early behavioral signs of autism with techniques to increase caregiver awareness of their infant's individual social communication - guiding specific caregiver responses to build infant social engagement & interaction reduces autism symptom severity across early childhood & reduces odds of an autism diagnosis at age 3 years. [93] - early intervention beginning at age 2-4 years with therapy sessions involving the parents of autistic children can reduce the severity of autism symptoms at age 10 years [66] 2) agents useful for obsessive compulsive disorder (OCD) may be useful in autism [4] a) respiridone (1st drug approved for use in autism) - diminishes tantrums, aggression, mood swings, self injury b) mirtazapine may have provide anxiolytic benefit in elderly with autism [17] - drug of choice in elderly with autism [17] - may be useful for inappropriate sexual behavior - strong supporting evidence not found c) selective serotonin reuptake inhibitor (SSRI) - citalopram NOT useful [9] d) methyphenidate - can help inattention, hyperactivity - can worsen behavioral symptoms e) valproate - can diminish aggression, impulsivity f) sulforaphane derived from broccoli-sprout extract associated with parent-rated improvements in core social & behavioral features in young boys with moderate-to- severe autism, but not with global ratings of autism severity [48] 3) nasal oxytocin - may be of benefit in children [57] - improves caregiver-rated social responsiveness - does not improve caregiver-rated repetitive behavior - benefits in children with low plasma oxytocin levels [73] - of no benefit in adolescents [58] 4) prognosis - in a minority of cases, patients with autism may recover [25] 5) prevention - periconceptional folic acid reduces risk for autism in offspring (women) [26] - multivitamin use during pregnancy may be associated with reduced risk for autism in offspring [75] - multivitamin or folic acid supplements before or during pregnancy may reduce risk of autism in offspring [76] - sulforaphanes from broccoli may mitigate effects of environmental pollutants known to increase autism risks [48] - prevent & correct vitamin D deficiency [49] - breast feeding may reduce risk of autism in infants homozygous for a specific CD38 variant that increases risk for autism [56] 6) cognitive behavioral therapy (6 sessions) seems to reduce depression & stress in mothers of autistic children [32] 7) music therapy of no benefit in reducing symptoms [74] 8) behavioral strategies 1st line for sleep disorders [88] - melatonin 1-3 mg QHS may be used in conjunction [88] 9) screening - all toddlers (age range, 14 to 31 months) with use of screening questionnaires [14] - American Academy of Pediatrics recommends standardized screening of at-risk children at 18- & 24 months [62] - USPSTF concludes insufficient evidence to recommend for or against screening of children - < 3 years of age [54] - 18-30 months of age [61] Comparative biology: - a mouse model for autism is characterized by an - unusual microbiome - compromised gut mucosal barrier - absorption & high blood levels of gut bacterial metabolites - one of these is related to a metabolite (p-cresol) elevated in urine of autistic children [36,37] - treatment of the autistic mice with the probiotic Bacteroides fragilis reversed the abnormal microbiome, high blood levels of bacterial metabolites, & behavioral abnormalities [36] - in two rodent models of autism, the GABA switch from excitatory to inhibitory neurotransmitter does not occur with the oxytocin surge during delivery - chloride concentrations remain high & GABA remains an excitatory neurotransmitter after birth - prenatal adminitration of bumetanide 1 day prior to delivery eliminates autistic behavior in the rodent offspring [38] - in a mouse moderl of autism, normal social behavior was restored by early oxytocin treatment [50] Notes: - lifetime cost of supporting a child with autism is $1.4-$2.4 million [45] - most of the costs in childhood are related to special education - most of the costs in adulthood, they are due to residential accommodation, medical care, & loss of productivity [45]

Interactions

disease interactions

Related

intellectual disability; mental retardation Rett syndrome schizophrenia

Specific

Asperger syndrome macrocephaly/autism syndrome

General

pervasive developmental disorder; autism spectrum disorder (ASD)

Database Correlations

OMIM correlations

References

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