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Craig A. Erickson, MD Director, Fragile X Research and Treatment Center Director, Developmental Disabilities Research and Treatment in Psychiatry – PowerPoint PPT presentation

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Title: Genetic%20Causes%20of%20Developmental%20Disability

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

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
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
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

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

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

Genetics of AS
  • In the 1980s discovery of microdeletion on
    maternally inherited 15th chromosome leading to
  • 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)

Genetics of AS
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

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
  • Swedish study showed an AS prevalence of about
  • Danish study showed a minimum AS prevalence of
    about 1/10,000

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//

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

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

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//

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

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

Autism in AS?
  • AS sometimes described as a genetic form of
  • 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

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

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

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

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

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
  • 1 in 691 babies in the USA is born with Down
  • More than 400,000 persons with Down Syndrome in
    the USA

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

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

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

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

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

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

22q11.2 Deletion Syndrome
  • Also known as DiGeorge or Velocardiofacial
  • 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

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

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

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

Phelan McDermid Syndrome
  • Physical/Medical Phenotype
  • Reduced sensitivity to pain
  • Possible reduced ability to sweat- prone to
  • 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

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

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

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

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

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

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

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

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

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
Full Mutation Fragile X Syndrome (FXS)
  • Males Approximately 1 in 4000
  • 50 likely remain undiagnosed
  • Females Approximately 1 in 6000-8000
  • Variable phenotype given random X inactivation

ACOG committee opinion. No. 338 Screening for
fragile X syndrome." Obstet Gynecol 107(6)
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
  • 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.
Full Mutation Common Physical Features/Medical
  • 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)

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
Full Mutation Behavioral Phenotype
  • Classic Gaze Aversion of Fragile X
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.
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
  • 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.
Genetic Testing
  • Everyone with developmental disability and/or
    autism needs the following
  • Chromosomal microarray testing
  • General chromosomes
  • Testing for Fragile X Syndrome
  • Whole Exome Sequencing
  • Discovering the many, many disorders not yet
  • Finding many rare syndromes and disorders where
    diagnosis was previously not feasible

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

Future Understanding of Developmental Disability
  • In large part may hinge on enhanced genetic
  • 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