Arabella Smith

Mortality in prader-willi syndrome

Persons with Prader-Willi syndrome have been known to have a high mortality rate. However, intellectual disability, which usually accompanies Prader-Willi syndrome, is also associated with a higher mortality rate than in the general population. In this study, the death rates in a longitudinal cohort of people with Prader-Willi syndrome are compared with those for an epidemiologically derived control sample of people with intellectual disability from other causes. We found that those with Prader-Willi syndrome had a higher mortality rate than did controls. After the protective effect of mild intellectual disability or average intellectual function was accounted for, the hazard ratio for Prader-Willi syndrome versus controls was 6.07. Obesity and its complications were factors contributing to the mortality identified in this study.

Behavior and emotional disturbance in Prader-Willi syndrome

To determine if persons with the Prader-Willi syndrome (PWS) have increased psychopathology when compared with matched controls, and whether there is a specific behavior phenotype in PWS, the behavior of 46 persons with PWS was compared with that of control individuals derived from a community sample (N = 454) of persons with mental retardation (MR). Behaviors were studied using the Developmental Behaviour Checklist, an instrument of established validity in the evaluation of behavioral disturbance in individuals with MR. PWS subjects were found to be more behaviorally disturbed than controls overall, and especially in antisocial behavior. In addition, some individual behaviors were more common in PWS subjects than controls. When these behaviors are considered together with findings from other studies using acceptably rigorous methods, a consensus behavior phenotype for PWS can be formulated. This will provide a valid foundation for studies of the mechanism of genetic pathogenesis of behavior in PWS.

A girl with the Prader-Willi syndrome and Robertsonian translocation 45,XX,t(14;15)(p11;q11) which was present in three normal family members.

SummaryA 21-year-old girl with classical Prader-Willi Syndrome was found to have a 14;15 Robertsonian translocation—45,XX,t(14;15)(p11;q11). This type of Robertsonian translocation was not found in any patient from 8 surveys covering 6144 patients with mental retardation. Chromosome 15 has been involved in translocations in patients with the Prader-Willi Syndrome with greater than expected frequency. This is the first report of a 14;15 translocation and the Prader-Willi Syndrome. The same balanced translocation was present in the patients mother and 2 normal siblings. Future genetic counselling for these 2 siblings will be difficult.

Longitudinal Course of Behavioural and Emotional Problems of Young Persons with Prader-Willi, Fragile X, Williams and Down Syndromes.

We present a comparison of levels of emotional and behavioural disturbance in children and adolescents with four genetically determined causes of intellectual disability (ID) and a control group of epidemiologically derived young people with ID as a consequence of a range of known and unknown causes. The behavioural and emotional disturbances were reassessed 4 years later providing one of the few follow-up studies of these genetic disorders. The study shows that genetic cause of ID has a strong influence on the severity of behaviour problems. Persons with Down syndrome have significantly less behaviour disturbance than controls, and young persons with Prader-Willi or Williams syndrome have significantly more disturbance than controls. These patterns persist over time, although there are non-specific trends for the level of disturbance to improve or worsen in particular syndromes.

Familial unbalanced translocation t(8;15)(p23.3;q11) with uniparental disomy in Angelman syndrome

A 29-year-old male with Angelman syndrome and an unbalanced reciprocal translocation, 45,XY,-8,-15,+der(8),t(8;15)(p23.3;q11)pat, was evaluated with DNA studies. These showed the underlying mechanism to be paternal uniparental disomy. This is the second case reported of Angelman syndrome that has resulted from a familial unbalanced reciprocal translocation.

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, GABRbeta3, 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.

Fluorescence in-situ hybridisation and molecular studies used in the characterisation of a Robertsonian translocation (13q15q) in Prader-Willi syndrome.

A patient with classical Prader‐Willi syndrome was found to have a Robertsonian translocation 45,XY,t(13q15q)mat. On CBG banding, the translocation chromosome had a large centromere with one primary constriction. Using fluorescence in situ hybridisation, positive signals were obtained with chromosome 13 and chromosome 15 centromere probes, proving that the translocation was dicentric. NOR banding was negative in this chromosome, suggesting that the breakpoints were at 13p11 and 15p11. DNA studies showed that, while there was no deletion involving 15(q11′13), maternal uniparental disomy for chromosome 15 was present. We compare our findings with the five other cases of familial Robertsonian translocation PWS that have been reported.

UBE3A“mutations” in two unrelated and phenotypically different Angelman syndrome patients

Abstract Angelman syndrome (AS) is a rare neurodevelopmental disorder. Recently, several mutations have been found in the E6-AP ubiquitin protein ligase gene (UBE3A) in a group of patients who are nondeleted and do not have uniparental disomy or imprinting defects. Most of the reported mutations cluster within exons 9 or 16 of the UBE3A gene, and nearly all are predicted to give rise to truncated E6-AP ligases. Here, we describe two AS patients with dissimilar phenotypes. At the molecular level, they are both nondeleted, do not display uniparental disomy, and have normal imprint patterns. One has the typical AS phenotype and carries the previously reported 1344delAG de novo mutation involving a functionally significant region of UBE3A. The other expresses an atypical phenotype in that she has less severe ataxia, no inappropriate laughing, or epilepsy, and her EEG was normal at an early age. A 14-bp deletion in the 3’ untranslated region of exon 16 (3’UTRdel14) adjacent to the poly(A) signal was identified. Further investigation revealed that the DNA change was a neutral polymorphism. Haplotype analysis indicated that both the AS patient and her normal sibling had inherited the same maternal UBE3A gene and its 5’ flanking region. Although the 14-bp change has no functional significance, it assists with counseling to determine future risks of recurrence in this family.

Linkage analysis using multiple DNA polymorphic markers in normal families and in families with fragile X syndrome

SummaryLinkage data, using the polymorphic markers 52A (DXS51), F9, 4D-8(DXS98), and St14(DXS52), are presented from 14 fragile X pedigrees and from 7 normal pedigrees derived from the collection of the Centre dÉtude du Polymorphisme Humaine. A multipoint linkage analysis indicates that the most probable order of these four loci in normal families is DXS51-F9-DXS98-DXS52. Recombination frequencies (n