Angelman syndrome due to paternal uniparental disomy of chromosome 15: A milder phenotype?

Abstract

The Angelman syndrome (AS) is a neurological disorder characterized by severe mental retardation, absent speech, seizures, gait disturbances, and a typical age-dependent facial phenotype. Most cases are due to an interstitial deletion on the maternally inherited chromosome 15, in the critical region q11-q13. Rare cases also result from paternal uniparental disomy of chromosome 15. In a group of 14 patients with sporadic AS diagnosed in Switzerland, we found 2 unrelated females with paternal isodisomy for the entire chromosome 15. Their phenotypes were milder than usually seen in this syndrome: one girl did not show the typical AS facial changes; both patients had late-onset mild seizures; as they grew older, they had largely undisturbed gross motor functions, in particular no severe ataxia. Both girls were born to older fathers (45 and 43 years old, respectively). The apparent association of a relatively milder phenotype in AS with paternal uniparental disomy will have to be confirmed by detailed clinical descriptions of further patients.

A previously unrecognised phenotype characterised by obesity, muscular hypotonia, and ability to speak in patients with Angelman syndrome caused by an imprinting defect

“…Previous observations focused on a milder phenotype in AS patients with UPD. [9][10][11][12] These patients showed a milder degree of ataxia and mental retardation, normal stature and head circumference as well as obesity. Minassian et al 18 reported that AS patients with a typical interstitial deletion of 15q11-q13 have more severe epilepsy than patients with UPD, a UBE3A mutation or an imprinting defect.…”

“…8 Furthermore, there are some case reports about AS patients with uniparental disomy and a milder phenotype. [9][10][11][12] It should be noted, however, that genotype-phenotype studies can suffer from an ascertainment bias, because in general the patients are diagnosed according to standard diagnostic criteria. 2,3 Thus, patients with atypical or very mild phenotypes may usually not be included in such studies and most often are identified by chance only.…”

Clinical and genetic aspects of Angelman syndrome

“…44,103 In contrast to PWS, the paternal UPD observed in AS is most likely to be postzygotic in origin. 104 …”

The behavioural phenotype of Angelman syndrome

“…Cicchetti and Sroufe, (1976, cited in Reddy et al,) suggest that infants with Down syndrome may reportedly follow the same pattern as in typically developing infants, with physically intrusive events eliciting laughter earlier than distal events. In children with autism, humorous interactions are suggested by St James and Tager-Flusberg to potentially be unaffected with the more cognitively more complex forms of humour being affected (1994( , cited in Reddy et al, 2002. Further studies are required to establish the onset and topography of laughing in infants with Angelman syndrome, to establish if these children laugh more or less frequently, or laugh in different situations to other children with intellectual disabilities, which appears to be the case with children with Down syndrome.…”