Angelman syndrome resulting from UBE3A mutations in 14 patients from eightfamilies: clinical manifestations and genetic counselling

Angelman syndrome (AS) is a neurological disorder with a heterogeneous gene tic aetiology. It most frequently results from a de novo interstitial delet ion in the 15q11-q13 region, but in a few cases it is caused by paternal un iparental disomy (UPD) or an imprinting mutation. The remaining 20 to 30% o f AS patients exhibit biparental inheritance and a normal pattern of alleli c methylation in the 15q11-q13 region. In this latter group, mutations in t he UBE3A gene have recently been shown to be a cause of AS. Here we describ e the phenotypic expression in 14 AS cases involving eight UBE3A mutations. These comprise 11 familial cases from five families and three sporadic cas es. Subtle differences from the typical phenotype of AS were found. Consist ent manifestations were psychomotor delay, a happy disposition, a hyperexci table personality, EEG abnormalities, and mental retardation with severe sp eech impairment. The other main manifestations of AS, ataxia, epilepsy, and microcephaly, were either milder or absent in various combinations among t he patients. In addition, myoclonus of cortical origin was frequently obser ved with severe fits inducing myoclonic seizures. The majority of the patie nts were overweight. This study showed that ataxia, myoclonus, EEG abnormal ities, speech impairment, characteristic behavioural phenotype, and abnorma l head circumference are attributable to a deficiency in the maternally inh erited UBE3A allele. Furthermore, analysis of mutation transmission showed an unexpectedly high rate of somatic mosaicism in normal carriers. These da ta have important consequences for genetic counselling.