J. Hamabe

Angelman Syndrome in Three Siblings: Characteristic Epileptic Seizures and EEG Abnormalities

Summary: Neurologic findings in 3 siblings with Angelman syndrome (AS) with apparently normal karyotype but DNA deletion of 15q11‐q12 deriving from their mother are described. Increased auditory brainstem response (ABR) thresholds were noted in all 3. Interictal EEG findings included periodic 2‐ to 3‐Hz high‐voltage slow wave bursts bioccipitally and sporadic slow spike wave complexes mainly bifrontally. EEG findings suggestive of minor epileptic status were apparent in the elder brother and may be a characteristic feature in young AS patients. Seizures suggestive of generalized epilepsy have been reported in 90% of AS patients. AS is considered a good model of symptomatic generalized epilepsy associated with chromosomal DNA deletion of the (GABA), receptor β3‐subunit gene.

Exclusion mapping of the Cohen syndrome gene from the Prader-Willi syndrome locus

Karyotype and DNA analyses using DNA probes were carried out in a family with the Cohen syndrome. Two affected brothers had normal chromosomal constitutions. A major deletion or duplication of genomic DNA fragments hybridized with the DNA probes, pML34 at D15S9 locus and pTD3‐21 at D15S10 locus, assigned on 15q11‐q12 was not detected in the patients. In addition, a linkage of the syndrome to D15S9 and D15S10 loci was not observed in the family. These data suggest that a gene for the Cohen syndrome is excluded from the 15q11‐q12 region, on which a gene for the Prader‐Willi syndrome is assigned, and that the Cohen syndrome is distinctly different from the Prader‐Willi syndrome, although clinical manifestations of the Cohen and the Prader‐Willi syndromes are very similar.

A molecular deletion study with southern hybridization on typical Prader-Willi syndrome (PWS) patients with various chromosome abnormalities involving 15q11–12 and on an atypical PWS patient with apparently normal karyotype

SummaryWe previously proposed a phenotype-karyotype correlation in the Prader-Willi syndrome (PWS). In order to confirm this hypothesis, we analyzed the genomic DNA of 10 clinically typical PWS patients with various chromosome 15 abnormalities, consisting of four [del(15)(q11.1;q12)], one [del(15)(q11;q13)], one [−15,+der(15)(pter::?HSR::p11→q11.1::q12)], one [mos 45,X,del.(15)(q11.1;q12)/46,X,del(15)(q11.1;q12), +mar], two [t(15;15)(p11.2;q12)] and one [del(15)(q11.1;q12),+inv, dup(15)(q11.1;q11.1)], and that of one atypical PWS patient with an apparently normal karyotype. Densitometric analyses on autoradiographic bands of Southern hybridization using two DNA segments, pML34 and pTD3-21, as probes revealed that all 7 patients with an interstitial deletion of 15q11.2 or 15q11.2-12 band had only one copy for each of the probes. In the two patients with an unbalanced translocation 15q;15q, two copies of each sequence were retained in spite of a visible deletion of band 15q11. This suggests that both of the two sequences may localize in flank of a critical region for the PWS phenotype. The copy number for the two probes was two in the case of inv dup(15), indicating that the patient is not tetrasomic for the sequences corresponding to the two probes. Densitometric analysis of one clinically atypical patient revealed a copy number of two for the two probes. Our results may support both our previous hypothesis and a recently proposed conception that PWS is a contiguous gene syndrome. The results also show that the molecular-genetic analysis is useful for an early and unambiguous diagnosis of PWS. RFLP analyses performed on three patients with del(15q) supported the preferential paternal origin of de novo deleted chromosome 15 in PWS.

Possible Genomic Imprinting at the Angelman Syndrome Gene Locus

A family in which 3 children were affected with Angelman Syndrome (AS) was studied with molecular genetic techniques using 5 different genomic DNA probes each located at 15q11–ql2. Southern hybridization with one probe, pTD3-21 (D15S10), revealed one-copy density of the corresponding DNA in all of these children, their phenotypically normal mother and maternal grandfather, but two copies in the father and the maternal grandmother. The DI5S10 deletions were confirmed by segregation of RFLPs detected by 3 different restriction enzymes. Southern hybridization for other 4 loci (D15S9, D15S11, D15S12, D15S18) showed the presence of two copies of the sequences in all of these family members. These results were consistent with the genomic imprinting hypothesis for the occurrence of AS, in which the lack of a maternally derived D15S10 allele leads to AS. However, they may not support a model that AS is the alternative phenotype of PWS at the identical locus. This finding also suggests that the presumed AS gene is located near D15S10.