Bibliographie

We report on two instances of familial recurrence of Angelman syndrome which, from pedigree analysis, appear incompatible with currently known mechanisms of inheritance of this disorder. In these two families, deletion-positive Angelman syndrome has recurred in cousins. Several established mechanisms for deletion-positive familial recurrence have been ruled out. In each family, molecular cytogenetic studies show typical chromosome 15 deletions, and DNA methylation analysis verifies the maternal origin of the deleted chromosomes in all four individuals. Since the mothers of the affected individuals in each family are not known to be related, these recurrences appear to be secondary to coincidental, de novo events. This conclusion is consistent with direct and indirect estimates of the population frequency of Angelman syndrome.

Angelman syndrome (AS) is characterized by severe mental retardation, absent speech, puppet-like movements, inappropriate laughter, epilepsy, and abnormal electroencephalogram. The majority of AS patients (approximately 65%) have a maternal deficiency within chromosomal region 15q11-q13, caused by maternal deletion or paternal uniparental disomy (UPD). Approximately 35% of AS patients exhibit neither detectable deletion nor UPD, but a subset of these patients have abnormal methylation at several loci in the 15q11-q13 region. We describe here three patients with Angelman syndrome belonging to an extended inbred family. High resolution chromosome analysis combined with DNA analysis using 14 marker loci from the 15ql1-q13 region failed to detect a deletion in any of the three patients. Paternal UPD of chromosome 15 was detected in one case, while the other two patients have abnormal methylation at D15S9, D15S63, and SNRPN. Although the three patients are distantly related, the chromosome 15q11-q13 haplotypes are different, suggesting that independent mutations gave rise to AS in this family.

Familial Angelman syndrome (AS) can result from mutations in chromosome 15q11q13 that, when transmitted from father to child, result in no phenotypic abnormality but, when transmitted from mother to child, cause AS. These mutations therefore behave neither as dominant nor as recessive mutations but, rather, show an imprinted mode of inheritance. We have analyzed two sibling pairs with AS and a larger family with four AS offspring of three sisters with several recently described microsatellite polymorphisms in the AS region. AS siblings inherited the same maternal alleles at the GABRB3 and GABRA5 loci, and the unaffected siblings of AS individuals inherited the other maternal alleles at these loci. In one of the AS sibling pairs, analysis of a recombination event indicates that the mutation responsible for AS is distal to locus D15S63. This result is consistent with a previously described imprinted submicroscopic deletion causing AS, a deletion that includes loci D15S10, D15S113, and GABRB3, all distal to D15S63. The analysis of the larger AS family provides the first clear demonstration of a new mutation in nondeletion AS. Analysis of linkage of AS to GABRB3 in these three families, on the assumption of imprinted inheritance (i.e., penetrance of an AS mutation is 1 if transmitted maternally and is 0 if transmitted paternally), indicates a maximum lod score of 3.52 at theta = 0.

Molecular and cytogenetic studies in Angelman syndrome have demonstrated that the condition is genetically heterogeneous with a recurrence risk in certain families which may be as high as 50%. In an attempt to identify such families, cytogenetic polymorphisms of chromosome 15 have been studied in both affected and unaffected siblings of Angelman syndrome patients. The results suggest that in those cases with a cytogenetically visible 15q11q13 deletion where the recurrence risk is low, normal siblings inherit either maternal chromosome 15 homologue with impunity. By contrast, in cases where the proband does not demonstrate a cytogenetic 15q11q13 deletion, unaffected siblings tend to inherit the alternative homologue to that found in their affected siblings. These findings may have importance for genetic counseling.

The Angelman syndrome or "happy puppet" syndrome is a disorder of severe mental retardation, seizure, paroxysms of laughter, absent speech, jerky movements and ataxic gait. We present two sibs, man and woman, with this disorder, fact that support the possible autosomal recessive inheritance as a cause of this pathology, which hereditary mechanism is still a controversial point. Besides, we can observe different expression, being the woman more severely affected than the man. To our knowledge, this is the first mexican family reported with this syndrome, and with a ten years follow up. Chromosomal studies, with high resolution technique, were normal, we did not find the 15 chromosomic deletion referred as a possible cause in some cases, that is why it is undeniable that genetic heterogeneity exists in this syndrome.

We report two sibs with Angelman syndrome or an apparently new syndrome. In addition to severe mental retardation and seizures, clinical examination showed an ataxic and stiff legged gait, truncal hypotonia with hypertonia of the limbs, dysmorphic facial features (brachycephaly, large mouth, pointed chin and a prominent jaws) and scoliosis. Brain CT scan and MRI revealed ventricular enlargement and squared frontal horns. Pregnancy and delivery were uneventful. Karyotypes were normal. No deletion of chromosome 15q11-13 region was shown by molecular genetic techniques. The parents who are normal are second cousins. The condition is therefore probably inherited as an autosomal recessive one.

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)A receptor beta 3-subunit gene.

Eleven patients with Angelman syndrome (AS) and their parents from 5 families have been studied with high resolution chromosome analysis and molecular probes from region 15q11-13 in an attempt to elucidate the mode of inheritance in familial AS. No deletions were detected. All families were informative with a combination of different short arm cytogenetic markers. All sets of sibs inherited the same maternal chromosome 15, but in 3 families sibs inherited different paternal 15s. Analysis of 6 polymorphic DNA markers supported the conclusion that AS sibs inherit the same maternal 15, but often different paternal 15s. These data make autosomal recessive inheritance at a 15q11-13 locus very unlikely and support the hypothesis that familial AS is due to maternal transmission of a mutation within 15q11-13.

We report on two sibs with Angelman "happy puppet" syndrome. Out of 48 families reported in the literature, this is only the fourth family with affected sibs. A review of the literature shows a low but not negligible recurrence risk. Different explanations for this are discussed.

We report seven cases of Angelman's syndrome from three families. Recurrence risks are not small, as previously suggested.

We report a girl aged 11 and her brother aged five, both with the typical features of Angelman syndrome, and three isolated cases. This report, together with a review of published reports and contact with previous authors, has revealed a total of 41 sibs of probands, although only nine of these are known to have been later born. The possible effect of voluntary restriction of family size after the birth of an affected child is discussed in relation to the possibility of autosomal recessive inheritance, but a recurrence risk of 5% is appropriate for use in the genetic clinic.