Angelman Syndrome

It is estimated that Angelman syndrome (AS) accounts for up to 6% of all children presenting with severe mental retardation and epilepsy. The main clinical features of AS may not be apparent early in life. Clinical findings present in all patients include developmental delay, which becomes apparent by 6–12 months of age, severely impaired expressive language, ataxic gait, tremulousness of limbs, and a typical behavioral profile, including a happy demeanor, hypermotoric behavior, and low attention span. Seizures, abnormal electroencephalography, microcephaly, and scoliosis are observed in >80% of patients.

Approximately 70% of patients show a deletion involving the maternally inherited chromosome 15q11-q13, encompassing a cluster of γ-aminobutyric acid receptor subunit genes, 3% show chromosome 15 paternal uniparental disomy (UPD), 1% harbor a mutation in the imprinting center (a transcriptional regulatory element), and 6% harbor intragenic mutations of the ubiquitin-protein ligase E3A (UBE3A) gene. Twenty percent of patients have no detectable genetic abnormality. Rare cases of familial recurrence of AS show either imprinting center (IC) or UBE3A mutations. Approximately 75% of cases are detected through the methylation test, which allows the detection of AS due to deletions, UPD and IC mutations. Mutation analysis of the UBE3A gene should be performed when the methylation test is negative.

Individuals with chromosome 15q11-q13 deletions have a more severe clinical picture and are more prone to develop severe epilepsy. Epilepsy has typical features, including absence and myoclonic seizures, and insidious episodes of nonconvulsive or subtle myoclonic status which are easily overlooked as children appear apathetic or in a state of neurologic regression. Tremulousness, present in all patients even when seizures are well controlled or absent, is related to distal cortical myoclonus. Valproic acid (sodium valproate), benzodiazepines, and ethosuximide, in various combinations, are quite effective in treating the typical seizure types. Piracetam may help in reducing distal myoclonus. Carbamazepine and vigabatrin may seriously aggravate absence and myoclonic seizures and should be avoided.

Cognitive, language, and orthopedic problems must be addressed with vigorous rehabilitation programs, including early physical therapy, which may help to develop communicative skills and prevent severe scoliosis and subsequent immobility. Where these treatment strategies are applied, individuals with AS may reach an appreciable level of integration, self care, and have a normal life span.