Clinical features as drescribed above.
Angelman Syndrome
AS, Happy puppet syndrome
Clinical Features
The Angelman syndrome (AS) is characterized by severe motor and mental retardation with an absence of speech, and by ataxia, in particular gait ataxia. Microcephaly, along with characteristic EEG charges and epilepsy are frequent. The term "happy puppet syndrome" was coined for the condition because it is usually associated with happy nature and excessive laughter and smiling. Muscular hypotonia results in tongue protrusion and nursing problems. Sleep disturbances are frequently long lasting and distressing for the parents. Children with Angelman syndrome exhibit a particularly pointed chin, a large mouth with widely spaced teeth and pigmentation abnormalities of iris, skin and hair.
Genetic Information
Several distinct genetic defects may underlie the Angelman syndrome:
- Deletion of maternally contributed chromosomal regions 15q11 to 15q13
with 70 % the most frequent underlying genetic defect. - Paternal uniparental disomy 15:
Approximately 1 % of all children with Angelman syndrome carry 2 chromosomes 15 which are both inherited from the father. A maternal chromosome 15 is missing. - Imprinting defect:
In approximately 4 % of Angelman patients an imprinting defect is found. This means that the Angelman gene is switched off on the maternal chromosome.
These genetic defects result in abnormal methylation. Diagnosis can be made in our laboratory by a methylation-sensitive test. For elucidation of the underlying genetic defect additional analyses are required which involve the analysis of parental blood samples (haplotype analysis). - Mutation in the UBE3A gene:
Approximately 10-15% of the Angelman patients with normal methylation pattern carry a mutation in the UBE3A (ubiquitin protein ligase) gene.
In approximately 20% of the children with AS there is no abnormal methylation pattern and no mutation in the UBE3A gene detectable. In these cases the underlying genetic mechanism is unknown, to date. The recurrence risk of an Angelman syndrome, especially for siblings, mainly depends on the underlying genetic mechanism.
Prevalence
Approximately 1 : 10 000 to 1 : 20 000
Diagnostic
Indication
Method
Step 1: DNA methylation testing
Step 2: Abnormal methylation pattern:
FISH analysis for detection of a deletion
Karyotype analysis for detection of a translocation
If applicable, haplotype analysis of the child and his/her parents
Step 3: Normal methylation pattern and clinical features strongly suggestive of AS: UBE3A gene mutation screening in a cooperating laboratory
Sample Requirement
Step 1: 2 to 4 ml of EDTA blood
Step 2: Additionally 2 to 4 ml of EDTA blood of each of the parents
2-5 ml heparinized blood from the affected child
Step 3: Mutation analysis in the UBE3A gene:
2 to 4 ml of EDTA blood
Duration
Step 1/2: 1 to 2 weeks
Step 3: 3 months