Distinct phenotypes distinguish the molecular classes of Angelman syndrome

Abstract

Background-Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy aVect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures. Methods-We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotypephenotype correlations. Results-In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely aVected, while UPD and ID patients are the least. DiVerences in body mass index, head circumference, and seizure activity are the most pronounced among the classes. Conclusions-Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15. (J Med Genet 2001;38:834-845)

Prader-Willi syndrome

“…86 Conversely, a loss of expression of the preferentially maternally expressed UBE3A gene in this region by several different possible mechanisms leads to AS. 90,91 Genes in the 15q11.2-q13 region. The 15q11.2-q13 region can be roughly divided into four distinct regions that are delineated by three common deletion breakpoints, 92 which lie within segmental duplications 93 (Figure 3): (1) a proximal nonimprinted region between the two common proximal breakpoints (BP1 and BP2) containing four biparentally expressed genes, NIPA1, NIPA2, CYF1P1, and GCP5.…”

“…No single gene mutation has been found in humans that will explain all the features of PWS, unlike the situation in AS where single gene mutations of UBE3A fulfill all the major clinical criteria for AS. 90,91 However, a "key" region to explain much of the PWS phenotype has been narrowed to the SNORD116 snoRNA gene cluster by several unique deletion and translocation families (reviewed by Buiting ref. 102).…”

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).…”

The expression and assessment of emotions and internal states in individuals with severe or profound intellectual disabilities

“…Angelman syndrome is a rare neurodevelopmental disorder first described in 1965 (Angelman, 1965) with a current prevalence estimate of 1 in 40,000 live births (Buckley, Dinno, & Weber, 1998;Clayton-Smith, 1993). It is caused by a disruption of the maternally inherited portion of chromosome 15q 11-13 (Clayton- Smith & Laan, 2003;Knoll, Nicholls, & Lalande, 1989) via four known genetic mechanisms (Jiang, Lev-Lehman, Bressler, Tsai, & Beadet, 1999;Lossie et al, 2001). The clinical presentation of Angelman syndrome has been described in detail within the literature.…”