Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects

Abstract

Angelman syndrome (AS) can result from either a 15q11 -q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11 -q13 region. There were no major phenotypic differences between the two main classes (BP1 -BP3; BP2 -BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1 -BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2 -BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1 -BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2 -BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del  22.2% UPD) and hypotonia (73.3% del  28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.

Clinical and genetic aspects of Angelman syndrome

“…However, some clinical differences correlate with genotype. [43][44][45][46] The 5-7 Mb deletion class results in the most severe phenotype with microcephaly, seizures, motor difficulties (e.g., ataxia, muscular hypotonia, feeding difficulties), and language impairment. Those with the large deletion are more likely to exhibit clinical hypopigmentation (discussed above).…”

Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex ligation-dependent probe amplification in a patient with Angelman syndrome

“…The sensitivity of this test to detect deletion/duplication was also verified by comparing the Relative Peak Areas between ten males (mean RPA = 0.565; SE ± 0.022) and ten females (mean RPA = 1.112; SE ± 0.028) using a X-linked NLGN3 gene as control. Mb, but have similar propensity to seizures and microcephaly (Varela et al, 2004).…”

Anaesthesia for an adult with Angelman syndrome

“…Deletion defects give rise to a more severe phenotype with earlier onset, refractory epilepsy, more profound motor and neurodevelopmental delay, and poorer speech and language than those with uniparental disomy, imprinting or lone UBE3A mutation Angelman syndrome. The greater severity may be due to the associated loss of genes encoding GABA A subunits [16][17][18][19][20], which is not a feature of non-deletion Angelman syndrome. It is not known if this poses any additional hazards for anaesthesia.…”