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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 Children’s Hospital Medical Center
[email protected]
Conflicts of Interest
Source
Consultant
(past* or
present^)
Alcobra
X*
Stock or
Equity
Interest
Research Support
(past* or present^)
X^
Neuren
Confluence Pharmaceuticals
Speakers’
Bureau
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X^
X
US Dept of Defense
X^
AACAP
X^
FRAXA Research Foundation
X*
Simons Research Foundation
X^
Autism Speaks
X^
Cincinnati Children’s Hospital
Research Foundation
X^
John Merck Fund
X^
National Fragile X Foundation
X^
Roadmap: Non Inclusive, Ever Growing
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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
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History
Genetics
Prevalence
Clinical Features of AS
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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 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 (35%)
-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
functioning
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
Clinical Features of AS
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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
Clinical Features of AS
• Other frequently associated features
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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
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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
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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
Behavior Challenges in AS
• Hyperactivity/Impulsivity/Inattention
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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
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
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
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
disability
– 1 in 691 babies in the USA is born with Down
Syndrome
– 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
disability
– 1 in 691 babies in the USA is born with Down
Syndrome
– More than 400,000 persons with Down Syndrome
in the USA
Down Syndrome
• Increased risk of the following medical
conditions:
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Congenital heart defects
Respiratory and hearing deficits
Alzheimer’s disease
Childhood leukemia
Hypothyroidism
Down Syndrome
• Physical Features
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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
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
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
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
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
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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
Phelan McDermid Syndrome
• Due to chromosome 22q13.3 deletion
– Disrupts the SHANK3 gene
• Behavioral and Cognitive Phenotype:
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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
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
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
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Utilizing Insulin Growth Factor 1 (IGF 1) treatment
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
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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
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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
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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): 14831485.
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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 n=976 Females n=259
Attention
Problems
Hyperactivity
84%
67%
66%
30%
Anxiety
70%
56%
Self-Injurious
Behavior
Aggressiveness
41%
10%
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. 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.
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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
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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
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Fragile X
Phelan McDermid Syndrome
Rett Syndrome
Others
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Questions
• [email protected]