Genetic%20Causes%20of%20Developmental%20Disability

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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 Childrens Hospital Medical Center
• Craig.erickson_at_cchmc.org

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Conflicts of Interest
Source Consultant (past or present) Stock or Equity Interest Speakers Bureau Research Support (past or present)
Alcobra X X
Neuren X
Confluence Pharmaceuticals X X
US Dept of Defense X
AACAP X
FRAXA Research Foundation X
Simons Research Foundation X
Autism Speaks X
Cincinnati Childrens Hospital Research Foundation X
John Merck Fund X
National Fragile X Foundation X
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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

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Angelman Syndrome

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

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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

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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)

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Genetics of AS
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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

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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

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Clinical Features of AS

• Developmental Delay
• Speech Impairment
• Movement or Balance Disorder
• Unique behavioral features
• Frequent laughter/smiling
• Easily excitable
• Hypermotoric behavior
• Photo from Maggies Family Website
• http//www.sheldonhickey.com/angelman/maggie_medic
  al.html

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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

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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

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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 Kianos mommy
• http//www.angelmanforum.org/viewtopic.php?t2373
  sid6a8255c64cfb2d4f30912dd272cf551f

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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

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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

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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

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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

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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

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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

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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

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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

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Down Syndrome

• Increased risk of the following medical
  conditions
• Congenital heart defects
• Respiratory and hearing deficits
• Alzheimers disease
• Childhood leukemia
• Hypothyroidism

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Down Syndrome

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

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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

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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

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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

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Tuberous Sclerosis

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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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
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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.
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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.
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Full Mutation Common Physical Features/Medical
Comorbidities

• Long face
• Prominent Ears
• High-arched palate
• Hyperextensible joints
• Heart murmur/mitral
• valve prolapse
• Strabismus

• Flat feet
• Chronic otitis media (38-63)
• Macroorchidism in males (83-92)
• Seizure Disorder (10-20)

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Full Mutation Behavioral Phenotype
Condition Males n976 Females n259
Attention Problems 84 67
Hyperactivity 66 30
Anxiety 70 56
Self-Injurious Behavior 41 10
Aggressiveness 38 14
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
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Full Mutation Behavioral Phenotype

• Classic Gaze Aversion of Fragile X

www.fragilex.org
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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.
30020, 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.
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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.
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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

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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

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Future Understanding of Developmental Disability

• In large part may hinge on enhanced genetic
  understanding
• Finding more and more likely rare phenomena that
  cause DD and often MI
• Key element is enhanced availability of state of
  the art genetic testing
• Enhanced genetic knowledge spurs on targeted
  treatment development
• Fragile X
• Phelan McDermid Syndrome
• Rett Syndrome
• Others

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Questions

• Craig.erickson_at_cchmc.org