Presentation on theme: "Autistic Spectrum Disorders: Current Perspectives April 8, 2011"— Presentation transcript:
1Autistic Spectrum Disorders: Current Perspectives April 8, 2011 Kathryn A. McVicar, MDAssistant Professor Pediatrics and NeurologyUTHSC-MemphisPediatric Neuroscience InstituteLe Bonheur Children’s Medical Center
3Introduction Epidemiology History Clinical Presentation Epilepsy Sleep disturbanceStructural brain differencesGenetic work suggesting future treatmentsCurrent treatmentConclusions
4Epidemiology Prevalence Initially thought to be 1/1,000 Reevaluation/Change in definitionsDSM IVInternational Classification of Diseases (ICD-10)Current estimates 1/99 (CDC 2010)3-4:1 boys to girls
5History Kanner in US/Asperger in Austria 1943 Simultaneously described autism phenotypeKanner- “autistic disturbances of affective contact”11 children-Mental retardationAsperger-”autistic phsychosis”4 boys-No mental retardationBehaviorsSocial remotenessObsessivenessStereotypyEcholalia
6History DSM 1952, 1968 Concept of ‘refrigerator Mom’ Autism as psychosisConcept of ‘refrigerator Mom’Child left untreatedMother given psychotherapy to improve ‘bonding’ with childAbove a clue to genetic component
7HistoryDSM III 1980First use of term pervasive developmental disorders…”distortions in the development of multiple basic psychological functions that are involved in the development of social skills and language such as attention, perception, reality testing, and motor movements.”
8History Lorna Wing 1988 Concept of the “Autistic Continuum” No clear cut offsTerm “Autistic Spectrum” (Autistic Spectrum Disorders, ASD) came into use increasingly after this
17Clinical presentation Receptive languagePragmatics absent or diminishedLacks comprehension of communicative intent of othersExpressive languageSemantics absent or diminishedLacks use of language/gestures with intent to communicate
18Clinical presentation Motor apraxia‘Clumsy’‘Stiff’Abnormal playNo imaginationNo pretendingPrefers to play alone
20Regression Up to 1/3 with ASD will regress Mean age at regression 18-24 monthsShinnar et al, 2001McVicar et, 200541.4 monthsJones LA and Campbell JM, 2010
21Epilepsy Comorbid epilespy 5-38% Bimodal incidence of epilepsy Rossi PG et al. Brain Develop ;17:169-74Tuchman and Rapin. Lancet Neurol ;1:352-58Danielsson S et al. Epilepsia ;46:918-23Bimodal incidence of epilepsyInfancy to age 5Adolescence (>10 years)Volkmar and Nelson. J Am Acad Child Adolesc Psychiatry ;29:127-29
22Epilepsy Cumulative probability of epilepsy Autism alone 2% at 5 years8% at 10 yearsAutism with severe mental retardation (MR)7% at 1 year16% at 5 years27% at 10 yearsAutism with MR and cerebral palsy (CP)20% at 1 year35% at 5 years67% at 10 yearsTuchman and Rapin. Lancet Neurol ;1:352-58
23Epilepsy Epilepsy persists into adult life Remission in 16% Danielsson S et al. Epilepsia ;46:918-23
24Epilepsy 10 year follow up (n=30) 25% epileptic seizures 68% epileptiform EEG prior to seizure onset18% epileptiform EEG/NO SEIZURESEpileptic groupLower IQLower social maturity score↑ frequency of psychotropic medication txHara H. Brain Dev. 2007;29:
25Sleep Sleep difficulties in children with autism 56%-68% Clements J et al. J Child Psychol Psychiat :27:Hoshino Y et al. Folia Psychiatrica et Neurologica Japonica. 1984:38:45-51Wiggs L and Stores G. J Intell Dis Res ;40:518-28Up to 89% in high-functioning if ‘past’ includedRichdale AL and Prior MF. Eur Child Adoles Psychiat ;4:175-86
26Sleep Disturbances More variable sleep patterns Sleep onset Sleep maintenanceIrregular sleep-wake patternsHoshino Y et al. Folia Psychiatrica et Neurologica Japonica. 1984:38:45-51
27Sleep Disturbance and Intensity of ASD Symptoms Parent report of sleep problemsFewer hours of sleep predicted↑ autism scoresSocial skills deficitsStereotypic behavior predicated byFewer hours of sleepScreaming during nightPredicted communication problems↑ sensitivity to environmental stimuli in bedroomScreaming at nightSchreck KA et al. Research Dev Dis ;255:57-66
28Sleep Behaviors and Quality of Sleep ASDBehavioral insomnia sleep-onset typeInsomnia due to PDDPicked up by questionnaire and actigraphySouders MC et al. Sleep behaviors and sleep quality in children with autism spectrum disorders. Sleep Dec 1;32(12):
29Sleep Treatment Melatonin (up to 6 mg) to treat insomnia Retrospective review of single pediatriciann=107 children2-18 year-oldsParental report of change with txMelatonin dose range mgAndersen IM et al. J Child Neurol ;23(5):482-5
30Sleep Treatment Results 25% no further sleep concerns 60% improved sleep, continued concerns13% sleep problems, major concern1% worse sleep with melatonin1% undetermined responseAndersen IM et al. J Child Neurol ;23(5):482-5
31Gastrointestinal symptoms in ASD GI symptoms52% of ASD7% TD age-matched healthy siblings (p<.001)ASD with irritability more likely with reflux eosphagitis43% with GERD vs 17% without GERDHorvath K and Perman JA, 2002
32Abdominal pain and discomfort in ASD Vocal BehaviorsThroat clearing, swallowing, tics, etc.Screaming, sobbing for unknown reason, sighing, whining, moaning, groaningDelayed echolalia-repeating what may have been asked of them in the pastChild saying “DOES YOUR TUMMY HURT?”Direct verbalizationsChild saying “tummy hurts”, etc with/without pointingTaken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4
33Abdominal pain and discomfort in ASD Motor BehaviorsGrimacing, gritting teeth, wincingConstant eating/drinking/swallowingMouthing behaviors/picaPressure to abdomenTaken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4
34Abdominal pain and discomfort in ASD Changes in overall stateSleep disturbanceIncreased irritabilityOppositional behaviorTaken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4
35Diagnostic considerations for GI symptoms in ASD Sleep disturbanceGERDSelf-injurious behavior, tantrums, aggression, oppositional behaviorConstipationGastritisIntestinal inflammationChronic diarrhea (≥3 loose stools daily for >2 weeks)MalabsorptionMaldigestionTaken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4
36Diagnostic considerations for GI symptoms in ASD Flatulence and/or bloatingConstipationLactose intoleranceEnteric infectionGiardiaCryptosporidiumTaken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4
38Structural brain differences Cortical connectivityImpaired ability to integrate informationFacial perception problemsImpaired social interactionImitation problems/Mirror neuronsContributes to learning delayContributes to disorders of communication and contact
39Cortical connectivity Corpus callosum smaller volumes:24 boys with autism (10.0 +/- 3.3 yr)26 control boys (11.0 +/- 2.5 yrs)3 Tesla MRILocalize regions of callosal thinning in autismVidal CN, Nicolson R, Thompson PM, et al. Mapping corpus callosum deficits in autism: an index of aberrant cortical connectivity. Biol Psychiatry Aug 1;60(3):218-25
40Cortical Connectivity Significant ↓Total callosal areaAnterior 1/3 of the CCSplenium and genu of the CCSuggest aberrant connections of cortical regionsVidal CN, Nicolson R, Thompson PM, et al. Mapping corpus callosum deficits in autism: an index of aberrant cortical connectivity. Biol Psychiatry Aug 1;60(3):218-25
42Cortical Connectivity DTI and volumetric measurements of the total CC and subregionsResults:Significant differencesvolume,fractional anisotropymean diffusivityradial diffusivityAlexander AL, Lee JE, Lainhart JE. Diffusion tensor imaging of the corpus callosum in Autism. Neuroimage Jan 1;34(1):61-73
43Cortical Connectivity Group differences driven by a subgroup of the autism groupsmall corpus callosum volumes↑ mean diffusivity↓ anisotropy↑ radial diffusivitySignificantly ↓ performance IQ measuresAlexander AL, Lee JE, Lainhart JE. Diffusion tensor imaging of the corpus callosum in Autism. Neuroimage Jan 1;34(1): Epub 2006 Oct 4.
44Facial Perception Hypoactive in autism 7 post-mortem autism brains Fusiform gyrus (FG)Cortical regions supporting face processing7 post-mortem autism brains10 controlsFG analyzedvan Kooten IA, Palmen SJ, Schmitz C. Neurons in the fusiform gyrus are fewer and smaller in autism. Brain Apr;131(Pt 4):987-99
45Significant ↓ Facial Perception Neuron densities layer III Association cortexTotal neuron numbers layers III, V and VISensory in from thalamusCortical in to thalamusMean perikaryal volumes of neurons layers V and VIvan Kooten IA, Palmen SJ, Schmitz C. Neurons in the fusiform gyrus are fewer and smaller in autism. Brain Apr;131(Pt 4):987-99
46Inability to imitate/Mirror neurons EEG activity during videos showing actions or still scenes14 right-handed children with autismMean age 5 years 3 months14 right-handed, age- and gender-matched typical childrenMean age 7 years 11 monthsMartineau J, Cochin S, Barthelemy C, et al. Impaired cortical activation in autistic children: is the mirror neuron system involved? Int J Psychophysiol Apr;68(1):35-40
47Inability to imitate/Mirror neurons Results:Typical children: Desynchronization of the EEG with observation of human actionsmotor cerebral cortexfrontal and temporal areasWith autism: No desynchronizationInversion of the pattern of hemispheric activation was found in autistic children↑ cortical activity RT hemisphere posteriorly, including the centro-parietal and temporo-occipital sitesMartineau J, Cochin S, Barthelemy C, et al. Impaired cortical activation in autistic children: is the mirror neuron system involved? Int J Psychophysiol Apr;68(1):35-40
50Clues from other diseases with an autism phenotype
51Fragile X Genetics FMR1 gene FMR1 (fragile X mental retardation 1)X chromosomeFMR1 CGG repeatLoss of RNA-binding proteinRole in mRNA transport and translational regulationAffects synaptic plasticityPeng et al. RNA and microRNAs in fragile X mental retardation Nature Cell Biology 6, (2004) doi: /ncb
52Fragile X Genetics FMR1 gene AMPA receptor trafficking →driving process for synaptic plasticityNormal system, process learning and memoryAbnormal system,problems with learning and memoryLTP disruption↓ mGluR5 signaling can reverse fragile X sxPotential treatment with mGluR5 antagonistsNakamoto et al. Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors. Proceedings of the National Academy of Sciences of the United States of America. August 2007.Fulfilling the Promise of Molecular Medicine In Autism. M.Bear*, MIT Presented IMFAR 2009.
53mGluR5 antagonists Safety and efficacy in humans Phase II trial of fenobam in adults with FXSN=12 adults (mean age 23.9 yrs)UC Davis MIND InstituteRUSH, University in ChicagoAll tolerated single dose without significant SE50% had ≥ 20% improvement in prepulse inhibition (p = 0.03)Majority scored at ceiling on continuous performance taskNot helpful in assessing medication benefitsR. Hagerman et al. Trial of fenobam, an mGluR5 antagonist, in adults with Fragile X Syndrome. JIDR; Vol 52 (10):814.
56Neurofibromatosis 1 Neurofibromin Functions as a tumor suppressorKweh F, Zheng M, Kurenova E, Wallace M, Golubovskaya V, Cance WG. Mol Carcinog May 28Neurofibromin deficiencyLoss of regulation of signaling and intersecting pathwaysActs onActin cytoskeleton reorganizationCell motility and adhesionLarizza et al. Developmental abnormalities and cancer predisposition in neurofibromatosis type 1. Curr Mol Med Jul;9(5):634-53
58NF 1 Future TreatmentNF1-Malignant Peripheral Nerve Sheath Tumor (MPNST) explant grown subcutaneously in NOD-SCID miceRapamycin in low dosesInhibited human NF1-MPNST mTOR pathway activationInhibited explant growth in vivoWithout systemic toxicitiesBehavioral changes similar to ASD, improvedBhola P et al. Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft. Int J Cancer Jul 24
59Rett disease Most common basis of autism in girls X-linked MECP 2 Deficit in synaptic maturation in the brainMeCP2 mutant miceSparse dendritic spines↓ PSD-95 in motor cortex pyramidal neurons↓ synaptic amplitude in the same neuronsProtracted cortical plasticity in vivoTropea et al. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. PNAS. Feb 2009; vol. 106 (6):
60Rett disease mouse model ↑ brain weightPartially restoresSpine densitySynaptic amplitude↑ PSD-95Stabilizes cortical plasticity to wild-type levelsIGF-1 a candidate for pharmacological treatment of Rett disease and other neurodevelopmental disordersTropea et al. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. PNAS. Feb 2009; vol. 106 (6):
61IGF-1 in Autism Insulin-like growth factor-I (IGF-I) Role in early brain development.IGF-I levels measured in the CSF of 11 children with autism4 girls7 boysMean age 3.8 yearsCompared levels in 11 control children6 girls5 boysmean age 3.8 yearsIGF-I in the CSF lower with autism (p=0.03)Vanhala et al. Low levels of insulin-like growth factor-1 in cerebrospinal fluid in children with autism. Dev Med & Child Neuro. 2001, 43;9:614-16
62Rare syndromes with ASD co-occurrence Syndrome ASD co-diagnosis Gene mutation Cell function ReferencesAngelman >50% UBE3A (maternal) Protein degradationDown syndrome >5%–15% Chromosome 21 MultipletriplicationFragile X >45%–70% FMR1 RNA traffickingNeuro- >4%A NF1/NF2 PI3K signaling activityfibromatosisMacrocephaly >75% PTEN PI3K signaling activityPotocki-Lupski >90% 17p duplications UnknownRett >50% MECP2 Transcriptional regulationSmith-Lemli- >50%–75% DHCR7 Cholesterol biosynthesis;Opitz Ras-mediated ERK signaling; PI3K signalingTuberous >40%–50% TSC1/TSC2 PI3K/mTOR signalingSclerosis22q13 deletion >90% PDD-NOS Microdeletions MultipleTimothy >75% CACNA1C Calcium signalingPat Levitt and Daniel B. Campbell. The genetic and neurobiologic compass points toward common signaling dysfunctionsin autism spectrum disorders. J Clin Invest Apr;119(4):747-54
63Protein functions with known genes associated with ASD Neuronal cell adhesion and/or synapse functionNeuronal activity regulationNeurodevelopmental genesSodium channelCalcium channelNeurotransmitter genesMitochondrialOtherAdapted from GeneReviews, Copyright, University of Washington, Seattle
64Phenotypic variables that may define discrete (ASD) subgroups Morphology and growthGeneralized dysmorphology 15–20%Macrocephaly 35%Microcephaly 5–15%Brain malformations 20%Medical/neurologicSeizures 25%EEG abn 50%Sleep disorder 65%Adapted from Miles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.
65Phenotypic variables that may define discrete (ASD) subgroups Savant skills 5%Clinical courseAge of onsetRegressive onset 30%Adolescent/adult catatonic regression 17%Adapted from Miles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.
66Phenotypic variables that may define discrete (ASD) subgroups Significant family history of related disordersASD 25%Alcoholism 30%ADHD 70%Affective disordersBipolar/major affective disorder 30%Adapted fromMiles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.
67Phenotypic variables that may define discrete (ASD) subgroups Functionally defined variablesIQResponse to therapyAdaptive behaviors (unclear)Outcome measures (poorly defined/unclear)Adapted fromMiles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.
69Treatment Behavioral therapy Medical treatment of symptoms Sleep ADHD AggressionAnxietyObsessive compulsive tendenciesEpilepsyConstipationGERD
70Behavioral therapyMainstay of therapyConsistently proven benefit
71Medication Therapies Start LOW and go SLOW Trial and error Caregiver participationChoicesPermission to STOPFrequent appointmentsWITH BEHAVIORAL THERAPY
72Conclusions ASD often present as speech and language delay Any loss of language or behavioral function needs to be evaluated promptlyASD caused by abnormal /different brains with abnormal/different brain functionTreatment is symptomatic
73Conclusions Behavioral therapy is the BEST intervention Definitive medical therapy based on nerve cell functioning may be close