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The Contribution of Genetic and Malformation Syndromes to Autism Spectrum Disorders. H. Eugene Hoyme, MD Professor and Chair Department of Pediatrics Sanford School of Medicine The University of South Dakota Chief Medical Officer Sanford Children’s Hospital. Learning Objectives.

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The Contribution of Genetic and Malformation Syndromes to Autism Spectrum Disorders


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the contribution of genetic and malformation syndromes to autism spectrum disorders

The Contribution of Genetic and Malformation Syndromes to Autism Spectrum Disorders

H. Eugene Hoyme, MD

Professor and Chair

Department of Pediatrics

Sanford School of Medicine

The University of South Dakota

Chief Medical Officer

Sanford Children’s Hospital

learning objectives
Learning Objectives
  • Discuss the nature and epidemiology of autism spectrum disorders (ASD).
  • Define the role of genetics in the etiology of ASD.
  • Characterize the medical evaluation of a child with a potential ASD prior to genetics evaluation.
  • Outline known genetic and malformation syndromes associated with ASD.
  • Delineate a clinical genetics diagnostic approach to children with apparently idiopathic ASD.
clinical characteristics
Clinical Characteristics
  • The major features of autism are:
    • Impairment of reciprocal social interactions
    • Impairment of verbal and nonverbal communications
    • Restricted educational activities
    • Abnormal interests
    • Stereotypic behaviors
clinical characteristics5
Clinical Characteristics
  • Approximately 25% of children who fit the diagnostic criteria for autism at 2 or 3 years of age later begin to talk and communicate.
    • By 6 or 7 years they may transition into the regular school population.
    • For this group, social impairments usually continue.
  • The remaining 75% have improvement with age but continue to require significant support from the parents and the school.
definition of asd
Definition of ASD
  • ASD is an umbrella term that encompasses several conditions that share in common primary abnormalities of socialization and communication.
definition of asd7
Definition of ASD
  • Five ASDs are described under pervasive developmental disorders (PDD) in the DSM-IV of the American Psychiatric Association.
    • (1) Autistic disorder—sometimes called “classic” autism
      • The most commonly identified type of ASD
    • (2) Asperger syndrome
    • (3) Pervasive developmental disorder—not otherwise specified (PDD-NOS)
    • (4) Childhood disintegrative disorder
    • (5) Rett syndrome
epidemiology of asd
Epidemiology of ASD
  • The reported prevalence of autism has increased over the past 10 years.
    • Estimates for autism are now on the order of 10–60 per 10,000 individuals, if all forms of ASD are considered.
      • The CDC has recently estimated the prevalence of ASD in the US as approximately 5.6 per 1000 children (~1/150).
epidemiology of asd9
Epidemiology of ASD
  • The rise in the reported prevalence of ASD may in part be due to:
    • Better knowledge of the disease variability
    • Broader diagnosis, with improved public awareness
    • A higher degree of professional awareness of the disorder
genetic contribution to asd
Genetic Contribution to ASD
  • The calculated heritability (the degree to which a disorder is inherited) of autism is ~90%.
  • ASD occurs four times as often in men as in women, with an even higher ratio in the milder forms.
genetic contribution to asd11
Genetic Contribution to ASD
  • Concordance in twins is high.
    • 70% concordance in MZ twins; 90% if a broader definition of ASD is used.
  • ASD shows a significant familial recurrence rate much higher than expected given the general population occurrence.
    • Recurrence risk is 4% if the first affected child is female and 7% if first child is male.
    • The recurrence risk increases even more after the birth of a second affected child, up to 50%.
    • These data are compatible with multifactorial inheritance.
pediatric evaluation of a child with asd prior to genetics evaluation
Pediatric Evaluation of a Child with ASD (Prior to Genetics Evaluation)
  • Assure accurate diagnosis of ASD
    • Should be made by a professional trained in the area of autism diagnoses using strict criteria/appropriate and objective tools.
  • Perform an audiogram
pediatric evaluation of a child with asd prior to genetics evaluation13
Pediatric Evaluation of a Child with ASD (Prior to Genetics Evaluation)
  • Perform an EEG if the history is suggestive of a seizure disorder
    • To rule out Landau-Kleffner syndrome associated with seizures and acquired aphasia.
  • Perform a high resolution karyotype and molecular testing to rule out the Fragile X syndrome
why is genetics evaluation important in children with asd
Why is Genetics Evaluation Important in Children with ASD?
  • Accurate diagnosis relieves parental anxiety and guilt.
    • Families just “want to know.”
  • Accurate diagnosis leads to a more precise understanding of prognosis and treatment planning.
  • Accurate diagnosis leads to an understanding of recurrence risks with future pregnancies.
genetic and malformation syndromes and asd
Genetic and Malformation Syndromes and ASD
  • Most children with ASD have a normal structural examination and demonstrate normal growth.
    • As with any child with a disability, however, the first step in genetics evaluation of a child with ASD is to determine whether the neurobehavioral features are apparently isolated, or whether they are part of a broader pattern of malformation, which includes major and/or minor structural anomalies.
genetics evaluation of the child with asd
Genetics Evaluation of the Child with ASD

Child with ASD

(Assume normal prior pediatric workup)

Careful Dysmorphology Examination

Normal structural examination

Non-Syndromic ASD

Multiple minor and/or major anomalies

(Syndromic ASD)

major vs minor anomalies
Major vs. Minor Anomalies
  • A major structural anomaly is of cosmetic and/or functional significance to the affected child.
  • Conversely, a minor structural anomaly is of no cosmetic and/or functional significance to the affected child.
mechanisms of structural maldevelopment
Mechanisms of Structural Maldevelopment
  • Malformation: A structural defect arising from an intrinsically abnormal developmental process.
  • Deformation: An abnormal structure resulting from nondisruptive mechanical forces applied to a once normally formed part.
  • Disruption: A structural defect arising from destruction of a once normally formed part .
teratogens and asd
Teratogens and ASD
  • A teratogen is a drug, chemical, infection or environmental agent which by exposing the embryo/fetus prenatally causes a functional or structural disability.
  • Teratogens associated with ASD:
    • Rubella
    • CMV
    • Alcohol
    • Thalidomide
    • Valproic Acid
genetic syndromes and asd
Genetic Syndromes and ASD

Schaefer GB, Mendelsohn NJ: Genetics evaluation for the etiologic diagnosis of

autism spectrum disorders. Genet Med 10(1):4–12, 2008.

fragile x syndrome
Fragile X Syndrome
  • Fragile X syndrome:An X-linked disorder due to mutations in the FMR1 gene.
    • FMR1 mutations are complex alterations involving non-classic gene-disrupting alterations (trinucleotide repeat expansions) and abnormal gene methylation.
  • Performance: Mild to profound MR in males: IQ’s 30-55; IQ’s <70 in 30-50% of females with full mutation.
    • Hand flapping or biting; poor eye contact; “cluttered” speech; autistic-like features
    • Attention problems and hyperactivity
  • Craniofacial:
    • Macrocephaly,
    • Prognathism,
    • Large ears with soft cartilage
    • Pale blue irides
    • Dental crowding
slide29

C

C

slide30

C

C

fragile x syndrome31
Fragile X Syndrome
  • Macro-orchidism, usually not evident until after puberty.
  • Occasional features:
    • Nystagmus
    • Strabismus
    • Epilepsy
    • Connective tissue laxity
rett syndrome
Rett Syndrome
  • Rett Syndrome: An X-linked progressive neurologic disorder in girls, due to mutations in the MECP2 gene.
  • Clinical Characteristics:
    • Normal birth and apparently normal psychomotor development during the first 6-18 months.
    • Short period of developmental stagnation, followed by rapid regression in language and motor skills.
    • The hallmark of the disease is the loss of purposeful hand use and its replacement with repetitive stereotyped hand movements.
rett syndrome33
Rett Syndrome
  • Additional characteristics:
    • Screaming fits and inconsolable crying by 18-24 months
    • Autistic features
    • Panic-like attacks
    • Bruxism
    • Episodic apnea and/or hyperpnea
    • Gait ataxia and apraxia
    • Tremors
    • Acquired microcephaly.
  • After this period of rapid deterioration, the disease becomes relatively stable
    • Development of dystonia and foot/hand deformities over time
angelman syndrome
Angelman Syndrome
  • Angelman syndrome: An MR syndrome associated with loss of the maternally imprinted contribution in the 15q11.2-q13 (AS/PWS) region that can occur by one of at least five different known genetic mechanisms.
  • Clinical Characteristics:
    • Severe developmental delay/MR
    • Severe speech impairment
    • Gait ataxia/tremor of the limbs
    • Unique behavior
      • Inappropriately happy demeanor (frequent laughing, smiling, and excitability)
    • Microcephaly and seizures
    • Developmental delays first noted ~ 6 months of age
prader willi syndrome
Prader-Willi Syndrome
  • Prader-Willi Syndrome: An MR/DD syndrome associated with loss of the paternally derived contribution in the 15q11.2-q13 (AS/PWS) region that can occur by one of several mechanisms.
  • Clinical Characteristics:
    • Severe hypotonia and feeding difficulties in early infancy
    • Excessive eating and gradual development of morbid obesity in childhood
    • Characteristic facies
    • Hypogonadism/hypogenitalism
    • Distinctive behavioral phenotype
      • Temper tantrums
      • Stubbornness
      • Manipulative/obsessive compulsive behavior
tuberous sclerosis complex
Tuberous Sclerosis Complex
  • Tuberous Sclerosis: An extremely variable autosomal dominant neurocutaneous disorder associated with mutations in the TSC1 and TSC 2 genes.
  • Clinical Features:
    • Skin
      • Hypomelanotic macules
      • Facial angiofibromas
      • Shagreen patches
      • Fibrous facial plaques
      • Ungual fibromas
tuberous sclerosis complex43
Tuberous Sclerosis Complex
  • Clinical Features:
    • Brain
      • Cortical tubers, subependymal nodules, seizures, mental retardation/developmental delay, autism
    • Kidney
      • Angiomyolipomas, cysts
    • Heart
      • Rhabdomyomas, arrhythmias
    • Eyes, lungs and other tissues
macrocephaly in children with asd
Macrocephaly in Children with ASD
  • A head circumference greater than the 50th percentile has been reported in 83% of patients with ASD.
  • 24% of patients with ASD have a head circumference > the 98th percentile.
  • Bannayan-Ruvalcaba-Riley syndrome is a malformation syndrome associated with macrocephaly and mutations in the PTEN gene.
    • PTEN mutations have been documented in 3%of all patients with ASD and in 17% of children with autism and macrocephaly— defined as OFC>+2.5 SD.
bannayan ruvalcaba riley syndrome
Bannayan-Ruvalcaba-Riley syndrome
  • Clinical Characteristics:
    • Macrocephaly,
    • Hamartomatous intestinal polyposis
    • Lipomas
    • Pigmented macules of the glans penis
chromosome loci linked to asd
Chromosome Loci Linked to ASD
  • Most common
    • 15q11–13
    • 7q22–31
    • 22q11
    • 22q13
    • 2q37
  • Others
    • Xp
    • 18q
    • 17p
    • 17q
    • 16p
  • A variety of duplications and/or deletions have been described at these sites.
    • Often the abnormalities are too subtle to be seen with standard cytogenetic techniques.
array comparative genomic hybridization acgh
Array Comparative Genomic Hybridization (aCGH)
  • In array-based comparative genomic hybridization (CGH), the patient’s DNA and normal DNA are differentially labelled and cohybridized to arrays of DNA clones which span the entire genome.
  • A comparison of the hybridization signals is expected to yield a ratio of 1:1, indicating equal DNA copy numbers in both samples.
    • Ratios greater or less than this indicate possible DNA copy number changes in the patient sample.
array comparative genomic hybridization acgh54
Array Comparative Genomic Hybridization (aCGH)
  • Array-based CGH technology offers 45 kb to 1Mb resolution, depending on the density of the array.
  • The resolution of oligonucleotide arrays may be at the level of single genes for detection of deletions and duplications, and at the level of single bases for detection of mutations.
slide55

Array-based

CGH

Conventional

CGH

slide56

BY: Microarray CGH results: del (8)(q21.3q22.1)

  • Length of deleted region - approx. 4Mb
  • Does not overlap any large-scale rearrangement polymorphisms
array cgh in the evaluation of asd
Array CGH in the Evaluation of ASD
  • Several studies have shown the utility of aCGH in the evaluation of children with idiopathic ASD.
    • A recent study* demonstrated that 11.6% of 397 children with ASD had de novo submicroscopic chromosome deletions or duplications.

*Christian SL, Brune CW, Sudi J et al: Novel submicroscopic chromosome abnormalities detected in autism spectrum disorder. Biol Psychiatry 63(12):1111-1117, 2008

genetics evaluation of the apparently non syndromic child with asd
Genetics Evaluation of the Apparently Non-Syndromic Child with ASD
  • The medical literature suggests that the overall diagnostic yield of a genetics evaluation in a child with ASD is ~15% in children in whom recognizable genetic and malformation syndromes have been ruled out.
  • The diagnostic yield increases to 40% if all children with ASD, syndromic and non-syndromic, are included.
genetics evaluation of the apparently non syndromic child with asd60
Genetics Evaluation of the Apparently Non-Syndromic Child with ASD
  • A reasonable genetics diagnostic approach to a child with ASD would include the following:
  • Perform first:
    • Prometaphase chromosome analysis (5% yield)
    • Fragile X molecular testing (5% yield)
  • If the above are normal, then proceed with:
    • Array comparative genomic hybridization (aCGH) (10% yield)
    • MECP2 molecular testing in females(5% yield)
    • PTEN molecular testingin children who are macrocephalic (3% yield)
    • Other genetic analyses (10%, depending on the phenotype)
second tier genetic tests in asd
“Second Tier” Genetic Tests in ASD
  • Metabolic tests
    • Disorders of purine metabolism
      • Adenylosuccinate lyase (ADSL) deficiency
      • Phosphoribosylpyrophosphate (PRPP) synthetase superactivity
    • Disorders of pyrimidine metabolism
      • Dihydropyrimidinase (DPD) deficiency
      • Cytosolic 5 nucleotidase (NT) superactivity
    • Unknown sulfation defect
      • Urine S-sulfocysteine
    • Disorders of GABA metabolism
      • Succinic semialdehyde dehydrogenase (SSADH) deficiency
    • Disorders of creatine metabolism
      • Guanidinoacetate methyltransferse (GAMT) deficiency
      • X-linked creatine transporter defect
    • Conditions that infer susceptibility to autism phenotype
      • Monoamine oxidase A (MOA)
      • Glyoxylase A (GLYA)
conclusions
Conclusions
  • Establishing a diagnosis and identifying the underlying etiology of ASD:
    • Helps with relieving parental anxiety and guilt
    • Aids in providing a prognosis and treatment plan for the affected child
    • Assists in recognizing co-morbid conditions
    • Provides a recurrence risk for families
  • Pediatricians should screen all children with ASD prior to referral for genetics evaluation; however, all families of children with ASD of unknown etiology should be offered a referral for genetics evaluation.
conclusions63
Conclusions
  • Genetics evaluation of a child with ASD should be performed in a logical step-wise fashion, depending on the phenotype of the child.
  • Practical limitations to genetics evaluation of children with ASD:
    • Cost
    • Length of time required for a complete evaluation
    • Availability of clinical geneticists and genetic counselors
references
References
  • Schaefer GB, Mendelsohn NJ: Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet Med 10(1):4–12, 2008.
  • http://www.geneclinics.org/

(Accessed September 1, 2008)

  • Muhle R, Trentacoste SV, Rapin I: The genetics of autism. Pediatrics 113:e1472-e486, 2004.
  • Christian SL, Brune CW, Sudi J et al: Novel submicroscopic chromosome abnormalities detected in autism spectrum disorder. Biol Psychiatry 63(12):1111-1117, 2008.
references65
References
  • Rapin I, Tuchman RF: What’s new in autism? Curr Opin Neurology 21:143-149, 2008.
  • Twedell D: Autism: Part I. Deficits, prevalence, symptoms, and environmental factors. J Contin Educ Nurs 39(2):55-56, 2008.
  • Twedell D: Autism: Part II. Genetics, diagnosis and treatment. J Contin Educ Nurs 39(3):102-103, 2008.