Paternal UPD15: Further genetic and clinical studies in four Angelman syndrome patients

Abstract

Among 25 patients diagnosed with Angelman syndrome, we detected 21 with deletion and 4 with paternal uniparental disomy (UPD), 2 isodisomies originating by postzygotic error, and 1 MII nondisjunction event. The diagnosis was obtained by molecular techniques, including methylation pattern analysis of exon 1 of SNRPN and microsatellite analysis of loci within and outside the 15q11-q13 region. Most manifestations present in deletion patients are those previously reported. Comparing the clinical data from our and published UPD patients with those with deletions we observed the following: the age of diagnosis is higher in UPD group (average 7 3/12 years), microcephaly is more frequent among deletion patients, UPD children start walking earlier (average age 2 9/12 years), whereas in deletion patients the average is 4 (1/2) years, epilepsy started later in UPD patients (average 5 10/12 years) than in deletion patients (average 1 11/12 years), weight above the 75th centile is reported mainly in UPD patients, complete absence of speech is more common in the deleted (88.9%) than in the UPD patients because half of the children are able to say few words. Thus, besides the abnormalities already described, the UPD patients have somewhat better verbal development, a weight above the 75th centile, and OFC in the upper normal range.

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

“…In AS, most paternal UPD15 seem to be postzygotic events. 24,18 In the present study, in addition to the differences described previously, 13 deletion patients presented a higher incidence of swallowing disorders (73.9 Â 22.2%) and hypotonia (73.3 Â 28.57%) than UPD patients. Other features associated with the clinical diagnosis of AS, such as brachycephaly, occipital groove, macrostomia, wide-spaced teeth, outbursts of laughter, hyperactivity, sleep disturbance and frequent drooling, presented a higher incidence among deletion patients, suggesting that these patients have a more severe and more typical phenotype, although these differences did not reach statistical significance (Table 2).…”

“…Comparison of behavioral and clinical findings between AS deletion patients and paternal UPD patients Our previous report on 21 AS deletion patients and four paternal UPD patients 13 stated that UPD patients use to be diagnosed later than deletion patients, mainly because the phenotypic and behavioral traits are more subtle in UPD children. Microcephaly and complete absence of speech were more frequent among deletion patients; UPD patients usually walked earlier and had seizures later than deletion patients.…”

“…In all, 21 of the patients with a deletion and four with UPD were previously reported in Fridman et al, 13 and…”

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).…”

Diagnosis of patients with Prader-Willi and Angelman Syndromes: the importance of an overall investigation

“…PWS patients show neonatal hypotonia, with poor sucking and failure to thrive, hyperphagia with onset at 1-6 years of age, severe obesity, mild mental retardation, hypogonadism and characteristic facies and behavior (Prader et al, 1956;Holm et al, 1993;, Fridman et al, 2000a. AS patients present delayed psychomotor development, severe mental retardation, absence of speech, typical happy disposition with outbursts of laughter, ataxia, seizures, microcephaly, macrostomia, and prognathism (Angelman, 1965;Williams et al, 1995, Fridman et al, 2000b, Lossie et al, 2001. The prevalence of these syndromes has been reported to be 1/15-20,000 for PWS and 1/20,000 for AS (Clayton-Smith, 1993).…”