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Angelman Syndrome

Identified: 1965 by English physician HarryAngelman.Originally named the Happy PuppetSyndrome.First reports in North America were in the1980s.Incidence: 1:15,000-30,000

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Physical Characteristics in100% of cases confirmed

Developmental delaySpeech impairment,none or minimal use of

words.Movement or balancedisorder: manifested asgait ataxia, or tremulouslimb movements orboth.

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Clinical Characteristics

Any combination of:Frequent laughterFrequent smiling

Apparent happydemeanorEasily excitableHypermotoric behavior

Short attention span

Seizures (this is actually80 90%).

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Clinical Characteristics,seen in 20 - 80%

Flat occiputProtruding TonguePrognathiaWide mouth with widelyspaced teeth.Feeding problems duringinfancyExcessive Appetite

Frequent droolingHypopigmented skin withlight hair and eye color

StrabismusAttraction or fascinationwith waterHyperactive lower limbdeep tendon reflexesUplifted, flexed armposition especially duringambulation

Increased sensitivity to heatSleep disturbance

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Angelman Syndrome

Generally notrecognized until lateinfancy due to absence

of speech development,and developmentaldelay.

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Deletion 15 q11-13

Seen in 65 75% of AS cases.Recurrence risk is less than 1%.

Tested for with high resolution chromosomeanalysis which can detect up to 70%.Follow up testing with FISH (fluorescent in-

situ hybridization) is needed due to the fairlyhigh false positive and false negative results of the high resolution chromosome study.

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Paternal Uniparental Disomy

Seen in 3 5% of cases.Less than 1% recurrence rate.

The patient has 2 paternal copies of chromosome 15.This represents a loss of the genetic

information from the maternal chromosome15.

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IC (imprinting Center) mutation

7 9% of Angelman cases.The IC activates the maternal 15 q11-13chromosomal material.In absence of the IC, the 15 q11-13 material isnot activated, and Angelman syndrome results.Spontaneous mutations are associated with

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UBE3A Mutations

Seen in 6 20% of cases.If the mutation is spontaneous the recurrencerisk is

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UBE3A Mutation

UBE3A encodes for the protein E6-AP.E6-AP is an enzyme necessary for normalprotein turnover in the cell.In the normal child, only the maternal copy of the UBE3A gene is expressed in the brain.

The paternal copy is silent.In mice the gene is active in the hippocampus,and cerebellum.

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UBE3A Mutation

Therefore:No UBE3A gene segment

No E6-AP

Absence of breakdown of certain proteins within the brain.

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Testing

To test for Angelman Syndrome:Call your local geneticist.

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Seizures

Seen in >80% of individuals with AS.Myoclonic seizures are the most common typewitnessed.Generally the seizures are intractable.

Ketogenic Diet is the most effective treatment.

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Aging

Increased tendency for fallingWorsening ataxia

Coincides with the theory that the patient isunable to adequately able to break downcertain proteins in the brain, specifically thecerebellum and hippocampus.

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Rett Syndrome

First described by Dr.Andreas Rett in ViennaAustria.

Worldwide recognitionfollowed a paper by Dr.Bengt Hagberg, andcolleagues in 1983.

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Rett Syndrome

Commonly seen in girlsDescribed in boys, but is usually lethal,causing miscarriage, stillbirth, or early death.

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Rett Syndrome

Occurs in 1:10,000-23,000 live femalebirths.

75% have a geneticmutation (MECP2) onthe X chromosome(Xq28).Affects people of allethnic backgrounds.

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Developmental Characteristics

Usually show normal or near normaldevelopment until 6 18 months of age.

Sit independentlyFinger feed at the expected time.Most do not crawl, but tend to bottom scoot, orcombat crawl.

Many walk at the expected time.

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Associated manifestations

Seizures:Non-existant to severe andintractable.Tend to diminish with age.

Atypical Breathing pattern:Episodes of hyperventilation.Aerophagia.

Stereotypic handmovements

Hand wringingHand clappingHand mouthing

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Associated Clinical Features

Autistic Features:Rapid regressionIrritabilityLoss of social skillsDiminished eye contact

Most of these features tend to decrease somewith age.

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Genes

There are approximately 37,000 genes in eachcells nucleus. Each cell type expresses a subset of the geneticmaterial within the nucleus.The subset of genetic material expressed maybe expressed only at specific times in

development.Each cell needs to turn off about 25,000 itsgenes.

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MECP2 Gene

The MECP2 gene is transcribed and translatedto MeCP2 protein.The MeCP2 protein has 2 functional domains.The 1 st domain binds the MeCP2 protein to theregion of a segment of DNA (at the beginningof genes).The 2 nd domain recruits other proteins toinhibit transcription.

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Father XY + mother XX

Son (XY) healthy Daughter ( XX) with

Rett Syndrome

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Father XY + Mother X X

Son XY (usually

embryonic lethal)

Daughter X X Rett

Syndrome

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Recurrence Risk

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Long term outcome

Patients tend to improve after adolesence, butnever return to normal.Death is common in early adulthood due toautonomic dysfunction leading to suddencardiac death.

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Tuberous Sclerosis

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Background

First described by Dr. Von Recklinghausen in 1862.Dr. Bourneville in 1880 is usually credited with theinitial description of the disease.

Vogt (1908) emphasized the association of adenomasebaceum and cerebral scleroses.Triad:

Adenoma SebaceumMental retardationSeizures

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Epidemiology

Frequency: 1:5,800 30,000.No racial, ethnic, or sexual predilection.

Morbidity and Mortality:Highly variable depending on the severity withwhich an individual is affected.

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Adenoma Sebaceum

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Ungual or Periungual fibromas

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Hypomelanotic macules > 3

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Retinal Harmartomas

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Shagreen Patch

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Cortical tubers

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Subependymal Nodules

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Subependymal Giant CellAstrocytoma

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Renal Angiomyolipoma

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Lymphangioleiomyomatosis

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Minor Features

Multiple randomlydistributed dentalenamel pits.

Harmartomatous rectalpolypsBone cystsCerebral white matterradial migration lines

Gingival fibromasNon-renal harmartomasRetinal achromatic

patchConfetti Skin lesionsMultiple renal cysts

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Diagnostic Studies

EEGUseful in evaluation of seizure fociMay be repeated if clinically warranted.

ECGBaseline should be done to assess for arrhythmiasWolf-Parkinson-White is the most common type of arrhythmia seen in TS.Repeat ECG every 2 3 years until after puberty.

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Diagnostic Studies

EchocardiographyShould be performed in neonatal period if recognized clinically.

Can be performed in older children to confirm adiagnosis.Repeat echocardiography is not necessary.

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Diagnostic Studies

Renal ultrasoundShould be performed as a baselineRepeat imaging every 5 years before pubertyRepeat imaging every 2 3 years in adults(especially over 30 years)

CT scan of the chest with contrast:This should be done in women at least once inwomen around the age of 20 30 years to assessfor lymphangioleiomyomatosis.

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Treatment

Generally treatment is symptomaticCognitive outcome is anywhere from normalto profoundly mentally retarded.Seizures can range from none, to easilycontrolled, to intractable.

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Questions?