Unexpected familial recurrence in Angelman syndrome

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. Am. J. Med. Genet. 70:253–260, 1997. © 1997 Wiley-Liss, Inc.     

Cytogenetic and molecular analysis in Angelman syndrome

We report on cytogenetic and molecular analysis of 29 Angelman syndrome (AS) individuals ascertained in 1990 through the first National Angelman Syndrome Conference. High resolution GTG- and GBG-banded chromosomes were studied. Standard molecular analysis with six 15q11q13 DNA sequences was used to analyze copy number and parental origin of 15q11q13. Concordance between molecular and cytogenetic data was excellent. The combind data showed that 23 of the 27 probands (85%) on whom we had definitive results have deletions of the chromosome 15q11q13 region. Two classes of deletion were detected molecularly: most patients were deleted for the 5 more proximal probes, but in 2 cases the deletion extended distally to include in sixth probe. In the 13 cases where the parental origin of the deleted chromosome 15 could be established, it was maternal. There were no cases of uniparental disomy. Cytological observations of the relative sizes of the heterochromatic regions of the short arm of chromosome 15 suggested that chromosomes with large heterochromatic blocks may be more prone to de novo deletion. © 1993 Wiley-Liss, Inc.     

人体各部位皮肤黑素细胞的分布及超微结构观察

对３６个不同部位正常皮肤表皮中黑素细胞的数量、形态及其超微结构进行了观察分析。结果表明：黑素细胞数量存在较大的个体差异，且部位不同，其分布数量也显著不同，即面颈部及上肢等暴露部位皮肤中黑素细胞数量显著高于躯干及十肢等暴露较少部位皮肤中的含量，部位不同，其黑素细胞的形态结构也略有差异。     

Autism in Angelman syndrome: implications for autism research

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, ataxia, and a happy/sociable disposition. Maternally, but not paternally, derived defects, such as duplications, within the AS critical region result in autistic symptomatology, suggesting that the UBE3A gene might be implicated in the causation of autism. This study examined the prevalence of autism in AS in 19 children representing three known molecular classes of AS. Children were studied over the course of 1 year. Forty-two percent of this population, eight of 19 children, met criteria for autism according to the Autism Diagnostic Observation Schedule (ADOS). Parents of children who were diagnosed with autism according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria as well as the ADOS - Generic, Module 1 (ADOS-G) were administered the Autism Diagnostic Interview - Revised (ADI-R). Data from the ADI-R were convergent with data from the ADOS-G in all cases. Children with comorbid autism and AS scored lower on measures of language, adaptive behavior, and cognition, and demonstrated a slower rate of improvement over the course of the study. Furthermore, they demonstrated deficits in communication and socialization that mirror those observed in children with idiopathic autism. The study highlights the phenotypic overlap between autism and AS and increases the probability that dysregulation of UBE3A may play a role in the causation of autism.     

Pigmented squamous cell carcinoma with dendritic melanocyte colonization in the external auditory canal

A case of pigmented squamous cell carcinoma (SCC) with dendritic melanocyte colonization in the external auditory canal is reported and the previous cases are reviewed. A 65-year-old Japanese female was referred with a 7-year history of otitis. The patient also had a darkly pigmented 9 x 8 mm nodule in the external auditory canal. Microscopically, the tumor was SCC, but in some areas melanin pigments were found in the cytoplasm of the tumor cells. The tumor was thus diagnosed as pigmented SCC. As well as the tumor cells, dendritic-shaped cells colonized the tumor parenchyma and were immunohistochemically defined as melanocytes. The authors believe this is the first case of pigmented SCC with dendritic melanocyte colonization in the external auditory canal.     

FISH analysis in Prader-Willi and Angelman syndrome patients

We report on a combined high resolution cytogenetic and fluorescent in situ hybridization study (FISH) on 15 Prader-Willi syndrome (PWS) and 14 Angelman syndrome (AS) patients. High resolution banding showed a microdeletion in the 15q11-q13 region in 7 out of 15 PWS patients, and FISH analysis of the D15S11 and SNRPN cosmids demonstrated absence of the critical region in three additional cases. Likewise 8 out of 14 AS patients were found to be deleted with FISH, using the GABRB3 specific cosmid, whereas only 4 of them had a cytogenetically detectable deletion. © 1995 Wiley-Liss, Inc.     

Clinical profile of Angelman syndrome at different ages

We describe 47 patients with Angelman syndrome (AS) from Belgium and the Netherlands, including the anamnestic data, the clinical and the behavioral attributes at different ages. The clinical picture of AS is most distinct between the ages of 2–16 years. Most patients of this age group show at least 8 of the major characteristics (bursts of laughter, happy disposition, hyperactive behaviour, microcephaly, brachycephaly, macrostomia, tongue protrusion, mandibular prognathism, widely spaced teeth, stiff and puppetlike movements, typical stature, wide based gait) beside the mental retardation and (almost) absence of speech, which is a universal trait. The diagnosis in infants is based on only a limited number of clinical characteristics or on anamnestic data. However, if these occur in combination, they are indicative of AS. In older patients, the diagnosis may be hampered in part because of the changing behavioral characteristics and the decreasing frequency of fits. Other manifestations, such as scoliosis, may become more pronounced with age. © 1995 Wiley-Liss, Inc.     

Deletion involving D15S113 in a mother and son without Angelman syndrome: Refinement of the Angelman syndrome critical deletion region

Deletions of 15q11-q13 typically result in Angelman syndrome when inherited from the mother and Prader-Willi syndrome when inherited from the father. The critical deletion region for Angelman syndrome has recently been restricted by a report of an Angelman syndrome patient with a deletion spanning less than 200 kb around the D15S113 locus. We report here on a mother and son with a deletion of chromosome 15 that includes the D15S113 locus. The son has mild to moderate mental retardation and minor anomalies, while the mother has a borderline intellectual deficit and slightly downslanting palpebral fissures. Neither patient has the seizures, excessive laughter and hand clapping, ataxia or the facial anomalies which are characteristic of Angelman syndrome. The proximal boundary of the deletion in our patients lies between the D15S10 and the D15S113 loci. Our patients do not have Angelman syndrome, despite the deletion of the D15S113 marker. This suggests that the Angelman syndrome critical deletion region is now defined as the overlap between the deletion found in the previously reported Angelman syndrome patient and the region that is intact in our patients. © 1995 Wiley-Liss, Inc.     

Sister chromatid exchange in families with Angelman or Prader-Willi syndrome

Using estimation of numbers of sister chromatid exchanges arising in 15q 11 q 13 as a measure, comparisons of the stability of the Prader-Willi syndrome critical region have been made. The groups studied included probands with Prader-Willi or Angelman syndromes either with or without a cytogenetically visible deletion in 15q11q13, their parents, specifically those parents who had passed on the homologue which had become deleted, and a control group. No significant differences were found between any of the four groups, indicating that there was no increase in the instability of the PWSCR region as measured by sister chromatid exchange.     

黑素小体发生及转运机制与白化病

黑素小体是合成和贮存黑色素的场所。黑素小体的发生、转运及黑色素的合成是一个复杂而精密的过程,包括黑素小体膜蛋白转运和正确定位、腔内pH值的调控、黑色素合成酶类发挥正常催化活性以及成熟的黑素小体沿微管微丝运输等环节。白化病各型致病基因所表达的异常蛋白TYR、P、TRP1、HPS1～3、CHS、MYO5A、Rab27a、MLPH,通过作用于上述一个或多个环节,影响黑素小体的发生、转运和黑色素合成,从而导致相应的临床表型。     

Two Prader-Willi/Angelman syndrome loci present in an isodicentric marker chromosome

We found an abnormal 47,XX,+mar karyotype in a patient with developmental delay, hypotonia, microcephaly, failure to thrive, and cognitive delay. When metaphases were hybridized with Prader-Willi and Angelman loci-specific probes by the FISH technique, two sites were noted at opposite positions on the marker chromosome. The alphoid satellite DNA probe documented the isodicentric nature while retention of the p arms on both sides of the marker chromosome was demonstrated by beta satellite probe. The patient does not exhibit manifestations of either syndrome despite the presence of these loci in tetrasomic dose. The present investigation suggests that other marker chromosomes be reevaluated, as their clinical manifestations are quite variable. © 1994 Wiley-Liss, Inc.     

Molecular and clinical study of 61 Angelman syndrome patients

We analyzed 61 Angelman syndrome (AS) patients by cytogenetic and molecular techniques. On the basis of molecular findings, the patients were classified into the following 4 groups: familial cases without deletion, familial cases with submicroscopic deletion, sporadic cases with deletion, and sporadic cases without deletion. Among 53 sporadic cases, 37 (70%) had molecular deletion which commonly extended from D15S9 to D15S12, although not all deletions were identical. Of 8 familial cases, 3 sibs from one family had a molecular deletion involving only 2 loci, D15S10 and GABRB3, which define the critical region for AS phenotypes. The parental origin of deletion, both in sporadic and familial cases, was exclusively maternal and consistent with a genomic imprinting hypothesis. Among sporadic and familial cases without deletion, no uniparental disomy was found and most of them were shown to inherit chromosomes 15 from both parents (biparental inheritance). A discrepancy between cytogenetic and molecular deletion was observed in 14 (26%) of 53 patients in whom cytogenetic analysis could be performed. Ten (43%) of 23 patients with a normal karyotype showed a molecular deletion, and 4 (13%) of 30 patients with cytogenetic deletion, del(15) (q11q13), showed no molecular deletion. Most clinical manifestations, including neurological signs and facial characteristics, were not distinct in each group except for hypopigmentation of skin or hair. Familial cases with submicroscopic deletion were not associated with hypopigmentation. These findings suggested that a gene for hypopigmentation is located is located outside the critical region of AS and is not imprinted. © 1994 Wiley-Liss, Inc.     

Manifestations in institutionalised adults with Angelman syndrome due to deletion

Undiagnosed institutionalised patients were reviewed in an attempt to identify those with Angelman syndrome (AS). The aim was to test these patients for deletion of chromosome 15(q11–13) and to describe the adult phenotype. The selection criteria included severe intellectual disability, ataxic or hypermotoric limb movements, lack of speech, a “happy” demeanour, epilepsy, and facial appearance consistent with the diagnosis. Patients were examined, medical records perused, and patients' doctors contacted as required. Genetic tests performed included routine cytogenetics, DNA methylation analysis (with probe PW71B), and fluorescence in situ hybridisation (with probes D15S10, GABRβ3, or SNRPN). A deletion in the AS region was detected in 11 patients (9 males and 2 females) of 22 tested. The mean age at last review (March 1996) was 31.5 years (range 24 to 36 years). Clinical assessment documented findings of large mouth and jaw with deep set eyes, and microcephaly in nine patients (two having a large head size for height). No patient was hypopigmented; 1/11 patients was fair. Outbursts of laughter occurred in all patients but infrequently in 7/11 (64%) and a constant happy demeanour was present in 5/11 (46%). All had epilepsy, with improvement in 5/11 (46%), no change in 4 (36%), and deterioration in 2 (18%). The EEG was abnormal in 10/10 patients. Ocular abnormalities were reported in 3/8 patients (37.5%) and 4/11 (36%) had developed kyphosis. Two had never walked. All nine who walked were ataxic with an awkward, clumsy, heavy, and/or lilting gait. No patient had a single word of speech but one patient could use sign language for two needs (food and drink). Our data support the concept that AS resulting from deletion is a severe neurological syndrome in adulthood. The diagnosis in adults may not be straightforward as some manifestations change with age. Kyphosis and keratoconus are two problems of older patients. Am. J. Med. Genet. 70:415–420, 1997. © 1997 Wiley-Liss, Inc.     

Angelman and Prader-Willi syndrome: A magnetic resonance imaging study of differences in cerebral structure

Recent improvements in magnetic resonance imaging techniques now allow the developing brain to be visualized in sufficient detail to perform “in vivo neuropathology.” In this study we compared the cortical morphology in six children with Angelman and four with Prader-Willi syndrome. These two syndromes are of especial interest because, although they are both caused by deletions in the same region of chromosome 15, Angelman children are far more severely affected, and do not speak. We measured the length of the banks of the Sylvian fissure in a gapless series of thin sagittal images. Angelman children had a significantly larger proportion (75%) of anomalous fissures than the Prader-Willi children (12%). Anomalous cortical growth could result from mistimed expression and recognition of macromolecules involved in axonal guidance, target recognition, and pruning. We hypothesize that misrouting of long projection axons may be related to the Sylvian fissure anomalies and the language disorder in Angelman syndrome. © 1993 Wiley-Liss, Inc.     

Clinical research on Angelman syndrome in the United Kingdom: Observations on 82 affected individuals

Clinical information has been obtained on 82 Angelman syndrome (AS) families in the UK. Each patient was examined by the author and a detailed clinical history taken. The findings of this study are presented. © 1993 Wiley-Liss, Inc.     

Methylation PCR analysis of Prader-Willi syndrome,Angelman syndrome,and control subjects

We report on a relatively large survey of Prader-Willi syndrome, Angelman syndrome, and control subjects with the newly described methylation polymerase chain reaction (PCR) method to determine its usefulness for molecular diagnosis. Sixty-one Prader-Willi syndrome (PWS) individuals (26 men and 35 women), 9 Angelman syndrome (AS) patients (5 men and 4 women), and 58 other individuals were studied with methylation PCR following sodium bisulfite treatment of genomic DNA. In addition, multiple tissues, including fetal tissue, were studied from several individuals to determine the effects of various tissues on methylation PCR results. The expected methylation PCR result was observed in each case. This PCR-based assay evaluates the methylation status of the CpG island of the SNRPN gene and allows for rapid molecular diagnosis of PWS or AS with less labor than Southern hybridization for methylation analysis. The PCR results were identical to those achieved by Southern hybridization in those individuals studied. Am. J. Med. Genet. 80:263–265, 1998. © 1998 Wiley-Liss, Inc.     

Molecular and clinical overlap of Angelman and Prader-Willi syndrome phenotypes

The Prader-Willi (PWS) and Angelman syndromes (AS) share the same apparent cytogenetic and molecular lesions of 15q11-13 and yet exhibit distinct clinical phenotypes. The etiology of PWS or AS appears to depend on the parental origin of the aberrant chromosome 15. Substantial clinical overlap has not been reported between deletion-positive PWS and AS patients. In the present study, we report the clinical, cytogenetic, and molecular findings in three AS patients. The first patient is a mentally retarded woman with a visible deletion of 15q11-13 with typical craniofacial, behavioral, and neurologic changes of AS. This patient is hyperphagic, and she is moderately obese for her height. Her hands and feet are small. These manifestations are more characteristic of PWS and not of AS. The molecular studies showed deletions of maternal origin for five distal PWCR loci. The most proximal locus, D15S18, was not deleted. These findings are identical to those found in our third AS patient who does not have any PWS features. To the best of our knowledge, this is the first report of concurrence of hyperphagia with consequent obesity and the AS phenotype in a patient with a del 15(q11-13) of maternal origin. These clinical findings suggest that overlap in the symptoms of PWS and AS can occur. Our second AS patient presents with atypical molecular findings in that he cannot be classed into any of the three proposed sub-groups of AS patients and may be representative of a fourth sub-group of AS patients.     

Angelman syndrome in adulthood

We studied the clinical and EEG-findings in 28 adult patients (aged 20–53 years) with Angelman syndrome (AS). Twenty-three showed a maternal chromosome 15q11–13 deletion; in 5, the diagnosis was based on a combination of typical clinical findings. Compared to the clinical manifestations present in childhood, “coarsening” of facial traits (100%), thoracic scoliosis (71%), and being wheelchair-bound (39%) were found more frequently. Paroxysms of laughter were still observed in adulthood (79%), but less frequently than in childhood. Most adult patients could feed themselves, but needed help with many daily activities. The majority (82%) had epileptic seizures. Abnormal EEG-activity consisting of 2–3/s rhythmic triphasic waves of high amplitude with a maximum over the frontal regions, which has been identified in many AS children, was found in 67% of these adult patients. © 1996 Wiley-Liss, Inc.