The neurological and diagnostic aspects of Angelman syndrome (AS) are reviewed by a geneticist at the University of Florida, Gainesville, FL. The prevalence of AS is 1/10,000 to 1/20,000. The syndrome presents in infancy with global developmental delay, microcephaly, seizures or an ataxic/hypotonic form of cerebral palsy. The facial features and general physical examination are generally normal, although a protruding tongue, strabismus, brisk deep tendon reflexes, and a happy demeanor may be present. Hypopigmentation in infants with AS due to deletion of the P pigment gene but may be overlooked. The diagnosis becomes more evident after 1 or 2 years of age, when speech does not develop, walking is impaired by severe ataxia, and seizures occur. The EEG findings can be diagnostic, with high voltage slow waves at 4-6 c/s throughout the record, 2-3 c/s slow activity in runs, especially anteriorly, and spikes or sharp waves posteriorly, provoked by eye-closure. The diagnosis is usually obvious clinically after 3 years of age and is sometimes first suggested by the parents. Behavior is often outgoing, hyperactive, hyperexcitable with excessive laughing, grabbing to engage siblings, putting objects in the mouth, and drooling. These characteristics without signs of degeneration and associated with microcephaly, seizures, and ataxia are classical. Maternally derived chromosome 15 was implicated in 1980, with microdeletion of 15qll.2-15ql3. Subsequently, the ubiquitin ligase gene, UBE3A, located at 15ql1.2, was identified as the AS gene, and 4 genetic mechanisms were involved, microdeletions being most common. The type of genetic mechanism was correlated with the severity of AS, patients with large chromosome deletions having a greater risk of seizures, microcephaly, and hypopigmentation of skin, eye and hair. The distinct behavioral syndrome and seizure patterns are related to the effects of UBE3A occurring during neuronal development. DNA methylation testing of blood is a sensitive and specific screening for 3 of the 4 genetic mechanisms. Chromosome 15 FISH analysis is necessary to distinguish which mechanism is involved. In 10-15% of cases genetic test confirmation is not possible. Genetic counseling should be offered to families of AS patients since UBE3A mutations carry a 50% recurrence risk, while common deletion cases have <1% recurrence risk. [1]

COMMENT. Clinical consensus criteria for the diagnosis of AS [2] include consistent (100%), frequent (in more than 80%), and associated (20-80%) symptoms and signs. The consistent findings include: developmental delay, speech impairment, ataxia or tremor, and unique behavioral abnormalities, with frequent laughing, happy demeanor, excitability, hand flapping, hyperactivity, and short attention span. Frequent findings include: delayed head growth with microcephaly by 2 years, seizures with onset <3 years, and characteristic abnormal EEG. Associated findings include: flat occiput, protruding tongue, feeding and swallowing disorders, drooling, strabismus, hypopigmented skin, hair and eyes, hyperactive relexes, flexed arm posture, sleep disorder, and fascination with water.

The prevalence of EEG abnormalities in AS is 80%, and 3 main patterns are present, independent of epileptic seizures: persistent rhythmic 4-6 Hz activity, anterior delta activity of 2-3 Hz with superimposed spikes and sharp waves, and posterior 3-4 Hz high amplitude waves with spikes and sharp waves, especially on eye closure. AS patients with a deletion of chromosome 15ql 1-13 have more prominent EEG abnormalities than those with other genetic disorders of chromosome 15 region. EEG abnormalities are helpful in the diagnosis of AS at an early age. [3]

The severity of developmental disturbance in AS is not invariably related to the severity of epilepsy, although repetitive nonconvulsive status epilepticus can sometimes result in transient or permanent mental and motor deterioration. [4]