Genetic Causes of Developmental Disability

1. Genetic Causes of Developmental Disability Craig A. Erickson, MD Director, Fragile X Research and Treatment Center Director, Developmental Disabilities Research and Treatment in Psychiatry Medical Director, P3 Southwest Neurodevelopmental Disorders Inpatient Unit Associate Professor of Psychiatry Cincinnati Children’s Hospital Medical Center Craig.erickson@cchmc.org

2. Conflicts of Interest

3. Roadmap: Non Inclusive, Ever Growing • Angelman Syndrome • Prader Willi Syndrome • Down Syndrome • Tuberous Sclerosis • 22q11.2 Deletion Syndrome (AKA DiGeorge or Velocardiofacial Syndromes) • Phelan McDermid Syndrome • Smith Magenis Syndrome • Williams Syndrome • Fragile X Syndrome

4. Angelman Syndrome • History • Genetics • Prevalence • Clinical Features of AS • Sleep • Seizures • Behavior Challenges • Autism in Angelman?

5. History of AS • In 1965, Dr. Harry Angelman described three children with characteristic features now known as AS in a paper entitled “Puppet Children” • Dr. Angelman reports the name “Puppet Children” came to him after viewing a painting called “Boy with a Puppet” • The name of the disorder was changed to Angelman Syndrome in the 1980s

6. Genetics of AS • In the 1980s discovery of microdeletion on maternally inherited 15th chromosome leading to phenotype • Later determined that disruption of UBE3A gene on the maternal 15th chromosome by several means caused similar phenotype - Deletion (70%) Uniparental Disomy (2-3%) Imprinting Center Mutation (3-5%) UBE3A mutation (5-10%) Unknown cause (10-15%)

7. Genetics of AS

8. Genetics of AS • UBE3A encodes E6-AP protein, important in the ubiquitin-proteasome pathway • Pathway allows ubiquitin to be attached to other proteins, which allows them to be degraded • UBE3A is associated with neuronal synaptic functioning

9. Prevalence of AS • Occurs in approximately 1/15,000 individuals • The exact incidence of AS is unknown • Best available data from studies of school age children living in Sweden and Denmark • Diagnosis of AS children in medical clinics was collected over an 8 year period of about 45,000 births • Swedish study showed an AS prevalence of about 1/12,000 • Danish study showed a minimum AS prevalence of about 1/10,000

10. Clinical Features of AS • Developmental Delay • Speech Impairment • Movement or Balance Disorder • Unique behavioral features • Frequent laughter/smiling • Easily excitable • Hypermotoric behavior Photo from Maggie’s Family Website: http://www.sheldonhickey.com/angelman/maggie_medical.html

11. Clinical Features of AS • Other frequently associated features • Seizures • Abnormal EEG even without seizures • Abnormal sleep/wake cycles • Light hair and eyes • Fascination with water and crinkly items • Mouthing/chewing behaviors • Drooling • Constipation

12. Sleep in AS • Sleep problems are frequent in AS • 20-80% of individuals with sleep issues • Trouble settling • Frequent night wakening • Contributes to caregiver stress • Can be challenging to treat • Melatonin (more on this later) • Safe sleep spaces

13. Seizures in AS • Onset often prior to age 3 • Can be treatment refractory • Abnormal EEG • Medication management • Dietary management • Low glycemic index treatment Photo posted by Kiano’s mommy: http://www.angelmanforum.org/viewtopic.php?t=2373&sid=6a8255c64cfb2d4f30912dd272cf551f

14. Behavior Challenges in AS • Hyperactivity/Impulsivity/Inattention • Occurs in essentially all children with AS • Ceaseless activity, constant movement • Limited attention span in childhood • Improves with age • May respond to behavioral therapy • Medications may be used at times

15. Behavior Challenges in AS • Disruptive/Aggressive Behavior • May arise more commonly in adolescents with AS • Multiple causes • Impulsivity • Communication deficits • Treatment primarily behavioral • Medication management in severe case • Look for upcoming module addressing this topic on ASF website

16. Autism in AS? • AS sometimes described as a genetic form of autism • Overlapping features including hand-flapping, stereotypic behaviors, language delays • To date no consensus on prevalence in AS • Evidence that duplication of chromosome 15q11-13 is associated with autism • Likely that autism effects a small percentage of individuals with AS

17. Prader Willi Syndrome • Disruption, most commonly deletion, of the paternal copy of the same region of chromosome 15 involved in Angelman Syndrome • Spontaneous event/ non inherited • Associated with mild to moderate intellectual disability

18. Prader Willi Syndrome • Behavioral Features • Temper outbursts/stubbornness • Compulsive behavior- skin picking • Physical/Medical Features • Sleep Disturbances • Facial Features • Narrow forehead • Almond-shaped Eyes • Triangular Mouth • Fair skin/light-colored hair • Underdeveloped genitals • Delayed/incomplete puberty, infertile

19. Prader Willi Syndrome • Obesity • Childhood onset insatiable appetite • Chronic over eating • Many develop Type 2 Diabetes • Prevalence: 1 in about 10,000 worldwide • Practical Issues • Weight management- lock the fridge • Repetitive behavior • Some irritability

20. Down Syndrome • Occurs when an individual has a full or partial extra copy of chromosome 21 • Most common genetic form of developmental disability • 1 in 691 babies in the USA is born with Down Syndrome • More than 400,000 persons with Down Syndrome in the USA

21. Down Syndrome • Increased risk of Down Syndrome with increasing maternal age • Due to higher fertility rates in younger women 85% of children with Down Syndrome are born to women under age 35 years • Most common genetic form of developmental disability • 1 in 691 babies in the USA is born with Down Syndrome • More than 400,000 persons with Down Syndrome in the USA

22. Down Syndrome • Increased risk of the following medical conditions: • Congenital heart defects • Respiratory and hearing deficits • Alzheimer’s disease • Childhood leukemia • Hypothyroidism

23. Down Syndrome • Physical Features • Low Muscle Tone • Small Stature • Upward slant of the eyes • Single deep palmar crease

24. Down Syndrome • Generally mild to moderate cognitive delay • Increased risk for autism in Down Syndrome even when controlling for IQ • Seems counter intuitive given the highly social nature of many persons with Down Syndrome • Life expectancy has increased from 25 in 1983 to 60 years of age today • In mental health, we primarily treat associated anxiety, depression and agitation

25. Tuberous Sclerosis • Caused by mutations in the TSC1 or TSC2 genes • Code for the proteins hamartin and tuberin respectively • Proteins help regulate cellular growth • Act as tumor suppressors • Inheritance: • 2/3 cases spontaneous mutations • 1/3 cases inherited from parent: autosomal dominant inheritance

26. Tuberous Sclerosis • Prevalence: 1 in 6,000 people • Developmental Issues: borderline IQ to mild/moderate ID, risk for autism • Variable presentation • Medical Issues • Numerous benign tumors • Skin, brain kidney, other organs • Requires frequent monitoring • Facial angiofibromas

27. Tuberous Sclerosis • Frequent Seizures • Behavioral concerns: hyperactivity and aggression • Targeted treatment development • Sirolimus, mTor inhibitor • May reduce tumor growth • Can improve seizure outcome

28. 22q11.2 Deletion Syndrome • Also known as DiGeorge or Velocardiofacial Syndrome • Variable presentations with deletions in this chromosomal region • Many children have developmental delays, speech delay, and growth delays • Increased likelihood of ADHD and possible autism • Impacts 1 in 4,000 persons

29. 22q11.2 Deletion Syndrome • Autosomal dominant disorder • Most cases, though, from random events • 10% cases are inherited • In adult life, increased risks of depression, anxiety, bipolar disorder and schizophrenia

30. 22q11.2 Deletion Syndrome • Common medical features • Heart abnormalities • Cleft palate • Recurrent infections/immune system dysfunction • Low levels of calcium in blood (can cause seizures) • Autoimmune disorders such as Graves disease or rheumatoid arthritis • Breathing difficulties • Kidney abnormalities • Hearing Loss • GI problems and feeding challenges • Skeletal abnormalities/short stature

31. Phelan McDermid Syndrome • Due to chromosome 22q13.3 deletion • Disrupts the SHANK3 gene • Behavioral and Cognitive Phenotype: • High risk for autism • Moderate to profound intellectual disability • Delayed speech • Pica

32. Phelan McDermid Syndrome • Physical/Medical Phenotype • Reduced sensitivity to pain • Possible reduced ability to sweat- prone to overheating • Risk of cyclic vomiting • Risk of gastroesophageal reflux (GERD) • Long narrow head, prominent ears, pointed chin, ptosis, deep-set eyes • Large hands and feet • Some have rapid growth • Fusion of second and third toes • Small toenails

33. Phelan McDermid Syndrome • Exact prevalence unknown • Considering an increasingly well known genetic cause of autism spectrum disorder • Most cases are not inherited and occur spontaneously • Subject of targeted clinical drug trials • Utilizing Insulin Growth Factor 1 (IGF 1) treatment • High risk for autism • Moderate to profound intellectual disability • Delayed speech • Pica

34. Smith-Magenis Syndrome • Caused by a genetic deletion on chromosome 17 disrupting the RAI1 gene • Not inherited • Impacts 1 in 15,000 persons • Physical features • Prominent lower jar, deep-set eyes, flattened nasal bridge, downward turning mouth • Dental abnormalities and large tongue • Short Stature and scoliosis • Reduced sensitivity to pain and temperature • Hearing loss • Near sightedness

35. Smith-Magenis Syndrome • Behavioral, developmental and other features • Disturbed sleep pattern: day/night reversed • Often affectionate and engaging • Prone to tantrums, aggression, anxiety, self-injury, impulsivity, and inattention • Possible repetitive hugging and/or licking of fingers and flipping of pages • Mild to profound intellectual disability

36. William Syndrome • Caused by deletion on chromosome 7 in the 26 to 28 region • Disruption of several genes in this region • Most cases are not inherited • Impacts 1 in 7,500 persons • Impacts 1 in 15,000 persons • Mild to moderate intellectual disability • Outgoing engaging personalities with an extreme interest in other people

37. William Syndrome • Other behavioral/cognitive features • Difficulties with visual spatial tasks • ADHD, anxiety and phobias are common • Facial Features • Broad Forehead • Short nose with broad tip • Full cheeks • Wide mouth with full lips

38. William Syndrome • Other medical features • Dental problems • Small, widely spaced and at times missing teeth • Aortic stenosis: narrowing of large blood vessal • High blood pressure • Joint problems and soft, loose skin • Increased calcium levels in blood • Coordination difficulties • Short stature

39. Fragile X Syndrome: History 1943: Originally reported by Martin and Bell as “mental deficiency showing sex-linkage” 1969: Discovery on X chromosome of “Fragile” site that fractured in folate-deficient medium 1991: Cloning and characterization of the fragile X mental retardation gene (FMR1) Gene sequencing indicated that a portion of the gene was dramatically expanded 2004: Metabotropic glutamate receptor theory of fragile X Theory has led to large wave of ongoing translational treatment development efforts

40. Triplet Repeats Cytosine, guanine, guanine (CGG) repeat expansion noted near promoter of FMR1 gene Net effect of expansion is gene methylation with little FMR1 RNA produced or protein (Fragile X Mental Retardation Protein (FMRP)) translated Gene is effectively silenced

41. Brown, WT. The Molecular Biology of the Fragile X Mutation. In Fragile X Syndrome, 3rd Edition. Hagerman RJ & Hagerman, PJ (eds.). Johns Hopkins University Press, Baltimore, 2002

42. Full Mutation Fragile X Syndrome (FXS): Epidemiology Males: Approximately 1 in 4000 50% likely remain undiagnosed Females: Approximately 1 in 6000-8000 Variable phenotype given random X inactivation patterns ACOG committee opinion. No. 338: Screening for fragile X syndrome." Obstet Gynecol 107(6): 1483-1485.

43. Full Mutation FXS: Epidemiology • Most common inherited cause of intellectual disability (ID) • 2-6% of persons with intellectual disability have FXS; ID universal among males • Most common known single gene cause of autistic disorder • 2-3% cases of autism associated with FXS • 2 in 3 males with FXS meet additional criteria for an autism spectrum disorder Hatton, D. D., J. Sideris, et al. (2006). "Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP." Am J Med Genet A 140A(17): 1804-1813.

44. Flat feet Chronic otitis media (38-63%) Macroorchidism in males (83-92%) Seizure Disorder (10-20%) Full Mutation: Common Physical Features/Medical Comorbidities • Long face • Prominent Ears • High-arched palate • Hyperextensible joints • Heart murmur/mitral valve prolapse • Strabismus

45. Full Mutation: Behavioral Phenotype Adapted from Bailey DB, Raspa M et al. Co-Occurring Conditions Associated with FMR1 Gene Variations: Findings from a National Parent Survey, presented at 11th International Fragile X Conference, July 23-27, 2008

46. Full Mutation: Behavioral Phenotype Classic Gaze Aversion of Fragile X www.fragilex.org

47. Fragile X: Indications for Testing • Persons with intellectual and developmental disabilities/delays and/or autistic behaviors • Features consistent with premutation carrier pathology (beyond scope of this talk) • Adult women with features of early menopause • Older adults with gait ataxia, intention tremor or both • 1 in 209 females is a FXS premutation carrier Hagerman RJ & Hagerman PJ, Testing for fragile X gene mutations throughout the life span. JAMA. 300:20, 2419-2421 Tassone, F., K. P. Iong, et al. (2012). "FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States." Genome Med 4(12): 100.

48. Fragile X Testing: The Future • Universal Newborn Screening • Need to have inexpensive testing: likely less than $1 per test • Now testing is available using the “blood spot card” • Still somewhat costly • Two large-scale newborn screening studies ongoing in United States • Push driven by prospect of disease modifying drugs and need for early genetic counseling Tassone, F., K. P. Iong, et al. (2012). "FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States." Genome Med 4(12): 100.

49. Genetic Testing • Everyone with developmental disability and/or autism needs the following • Chromosomal microarray testing • General chromosomes • Testing for Fragile X Syndrome • THE FUTURE: • Whole Exome Sequencing • Discovering the many, many disorders not yet discovered • Finding many rare syndromes and disorders where diagnosis was previously not feasible

50. Genetic Testing • Challenges • Insurance, in particular medicaid, coverage • What is “medically necessary”? • Is finding out your child has a disorder important to their “medical treatment” • An ongoing battle