Phenotypic differences in Angelman syndrome patients: Imprinting mutations show less frequently microcephaly and hypopigmentation than deletions

Bürger, Joachim; Kunze, Jürgen; Sperling, Karl; Reis, André

doi:10.1002/(sici)1096-8628(19961211)66:2<221::aid-ajmg19>3.3.co;2-1

Cited by 17 publications

(25 citation statements)

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“…Similar findings have been reported by Moncla et al 5 Our study confirms these aspects. 5,8,18 All patients described by us had a normal head circumference for their age and normal pigmentation. In addition, they had normal or larger birth sizes, and all but one lacked epilepsy.…”

Section: Discussionmentioning

confidence: 89%

“…PWS was diagnosed clinically when he was 3 years old. This patient's data were partly described by Bürger et al 8 …”

Section: Case Reportsmentioning

confidence: 86%

“…In a study describing the phenotypical differences in AS patients of different molecular classes, Bürger et al 8 pointed out that microcephaly and hypopigmentation are less frequently observed in patients with imprinting mutations than in patients with deletions. Similar findings have been reported by Moncla et al 5 Our study confirms these aspects.…”

Section: Discussionmentioning

confidence: 99%

“…Such an imprinting defect can result from an imprinting centre (IC) mutation or occur spontaneously. 6,7,8 Genotype-phenotype correlations in PWS and AS have revealed subtle clinical differences. 5 It appears as if microcephaly is less frequent in AS patients with an imprinting defect.…”

Section: Introductionmentioning

confidence: 99%

“…5 It appears as if microcephaly is less frequent in AS patients with 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.…”

Section: Introductionmentioning

confidence: 99%

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

Gillessen‐Kaesbach

Demuth

Thiele³

et al. 1999

Eur J Hum Genet

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The clinical features of Angelman syndrome (AS) comprise severe mental retardation, postnatal microcephaly, macrostomia and prognathia, absence of speech, ataxia, and a happy disposition. We report on seven patients who lack most of these features, but presented with obesity, muscular hypotonia and mild mental retardation. Based on the latter findings, the patients were initially suspected of having Prader-Willi syndrome. DNA methylation analysis of SNRPN and D15S63, however, revealed an AS pattern, ie the maternal band was faint or absent. Cytogenetic studies and microsatellite analysis demonstrated apparently normal chromosomes 15 of biparental inheritance. We conclude that these patients have an imprinting defect and a previously unrecognised form of AS. The mild phenotype may be explained by an incomplete imprinting defect or by cellular mosaicism.

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Section: Discussionmentioning

confidence: 89%

“…PWS was diagnosed clinically when he was 3 years old. This patient's data were partly described by Bürger et al 8 …”

Section: Case Reportsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Gillessen‐Kaesbach

Demuth

Thiele³

et al. 1999

Eur J Hum Genet

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Prader-Willi and Angelman syndromes: Sister imprinted disorders

Cassidy

Dykens

Williams³

2000

Am. J. Med. Genet.

262

152

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Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct complex disorders mapped to chromosome 15q11-q13. They both have characteristic neurologic, developmental, and behavioral phenotypes plus other structural and functional abnormalities. However, the cognitive and neurologic impairment is more severe in AS, including seizures and ataxia. The behavioral and endocrine disorders are more severe in PWS, including obsessive-compulsive symptoms and hypothalamic insufficiency. Both disorders can result from microdeletion, uniparental disomy, or an imprinting center defect in 15q11-q13, although the abnormality is on the paternally derived chromosome 15 for PWS and the maternally derived 15 for AS because of genomic imprinting. Although the same gene may control imprinting for both disorders, the gene(s) causing their phenotypes differ. AS results from underexpression of a single gene, UBE3A, which codes for E6-AP, a protein that functions to transfer small ubiquitin molecules to certain target proteins, to enable their degradation. The genes responsible for PWS are not determined, although several maternally imprinted genes in 15q11-q13 are known. The most likely candidate is SNRPN, which codes for a small nuclear ribonucleoprotein, a ribosome-associated protein that controls gene splicing and thus synthesis of critical proteins in the brain. Animal models exist for both disorders. The genetic relationship between PWS and AS makes them unique and potentially highly instructive disorders that contribute substantially to the population burden of cognitive impairment.

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Familial interstitial 570 kbp deletion of the UBE3A gene region causing Angelman syndrome but not Prader‐Willi syndrome

et al. 2002

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Angelman syndrome (AS) is a disorder of psychomotor development caused by loss of function of the imprinted UBE3A gene. Since the paternal UBE3A copy is regularly silent, only mutations inactivating the maternal copy cause AS. Among 1,272 patients suspected of AS, we found one with an isolated deletion of the UBE3A gene on the maternally inherited chromosome. Initial DNA methylation testing at the SNURF-SNRPN locus in the patient revealed a normal pattern. The deletion was only detected through allelic loss at microsatellite loci D15S1506, D15S122, and D15S210, and confirmed with fluorescence in situ hybridization (FISH) using bacterial artificial chromosome (BAC) probes derived from the loci. It extends approximately 570 kilobase pairs (kbp), encompassing the UBE3A locus, and is flanked by loci PAR/SN and D15S986. The deletion is familial, and haplotype studies suggest that a great grandfather of the index patient already carried this deletion, and that it causes AS when inherited through the female germline but not Prader-Willi syndrome (PWS) when paternally inherited. Our findings support the hypothesis that the functional loss of maternal UBE3A gene activity is sufficient to cause AS and that the deleted region does not contain genes or other structures that are involved in PWS. Finally, this case highlights that methylation tests can fail to detect some familial AS cases with a recurrence risk of 50%.

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Phenotypic differences in Angelman syndrome patients: Imprinting mutations show less frequently microcephaly and hypopigmentation than deletions

Cited by 17 publications

References 0 publications

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

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

Prader-Willi and Angelman syndromes: Sister imprinted disorders

Familial interstitial 570 kbp deletion of the UBE3A gene region causing Angelman syndrome but not Prader‐Willi syndrome

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