The Contribution of Genetic and Malformation Syndromes to Autism Spectrum Disorders

2. 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

3. 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.

4. 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

5. 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.

6. Definition of ASD • ASD is an umbrella term that encompasses several conditions that share in common primary abnormalities of socialization and communication.

7. 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

8. 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).

9. 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

10. 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.

11. 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.

12. 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

13. 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

14. 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.

15. 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.

16. 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)

17. Syndromic Autism Spectrum Disorders

18. 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.

19. 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 .

25. 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

26. 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.

27. 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

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31. Fragile X Syndrome • Macro-orchidism, usually not evident until after puberty. • Occasional features: • Nystagmus • Strabismus • Epilepsy • Connective tissue laxity

32. 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.

33. 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

35. 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

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37. 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

41. 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

42. Skin Manifestation of Tuberous Sclerosis

43. 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

45. 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.

46. Bannayan-Ruvalcaba-Riley syndrome • Clinical Characteristics: • Macrocephaly, • Hamartomatous intestinal polyposis • Lipomas • Pigmented macules of the glans penis

48. 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.