Angelman Syndrome

Question 1

What type of genetic disorder is Angelman?

Answer 1

Disorder of imprinting = Uniparental disomy, deletion of MATERNAL copy

65-70% microdeletion MATERNAL chromosome 15q11.2-q13
3-7% paternal uniparental disomy chromosome 15 (milder phenotype)
3% imprinting center defect within maternal 15q11.2-q13
5-11% UBE3A gene mutation
10-15% unknown mechanism

Question 2

What is the most sensitive single test for Angelman Syndrome?

Answer 2

DNA methylation

DNA sequence analysis required to identify UBE3A

Question 3

What is the recurrence risk for microdeletion and paternal uniparental disomy?

Answer 3

<1%

Question 4

What is the recurrence risk for maternally inherited imprinting center defect or UBE3A mutation?

Answer 4

50%

Question 5

What are the associated medical findings with Angelman Syndrome?

Answer 5

1. Non-specific psychomotor delay and/or seizures
2. Speech delay
3. GDD
4. Abnormal forward gait, arms held high, flexed at elbows
5. Truncal hypotonia, hypertonic limbs
6. Tremulous, jerky
7. Feeding/growth problems
8. Acquired microcephaly (<2SD below mean)

Question 6

What are the developmental outcomes of Angelman Syndrome?

Answer 6

1. Intellectual disability (usu. severe to profound, 24-30m average cognitive skills)
2. Receptive language is a relative strength
3. Typically non-verbal with good social skills as adults (good non-verbal social communication)
4. Persistent SPONTANEOUS social smiling (1-3m) and fits of laughter (can be as early as 10wks)
5. Truncal hypotonia (hypertonic in limbs)
6. Commando crawl - not on all fours
7. Hand flapping with excitement
8. LOVE water, open mirrors, music toys
9. Cartoons are scary
10. Hyperactive, inattentive
11. Oral exploration
12. Abnormal sleep cycles

Question 7

What is the DDx for seizures and GDD?

Answer 7

1. Metabolic
2. CNS embryologic developmental abnormality
3. Genetic epilepsy syndromes

Question 8

What is the DDx for Angelman Syndrome?

Answer 8

1. Rett syndrome
2. Autism
3. Ataxia CP
4. Mowat-Wilson syndrome
5. Alpha Thalassemia-Intellectual Disability Syndrome (X-linked)
6. Pitt-Hopkins Syndrome

Question 9

What are the recommendations for Angelman Syndrome?

Answer 9

1. Anticonvulsants - peds neurology
2. Peds ophthalmology
3. Early intervention
4. Adaptive equipment as needed
5. Structured environment
6. Family support for abnormal sleep-wake cycles and hyperactivity (very few children require stimulants or sleep aides)

Question 10

What are the major clinical manifestations of Angelman syndrome?

Answer 10

1. Developmental delay
2 Lack of speech
3. MR
4. Abnormal gait
5. Seizures
6. Acquired microcephaly
7. Hypopigmentation