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Objectives: Some associations between antiepileptic drugs (AEDs) and fracture risk have been reported in the general population. This study investigated the relationships between fracture risk and commonly used AEDs in Rett syndrome, a genetic disorder associated with intellectual and physical disability., Study Design: Cases (n=233) were sourced from the population-based Australian Rett Syndrome Database and longitudinal data were used. The Cox proportional hazard model was used to analyse relationships between fracture and prescribed AEDs, mobility, epilepsy diagnosis and genotype., Results: After controlling for mobility, epilepsy diagnosis and genotype, use of valproate increased the risk of fracture threefold after at least 1 year (HR 3.56; 95% CI 1.85 to 6.82) and after 2 or more years (HR 3.02; 95% CI 1.90 to 4.80). There was a lesser increased risk (HR 1.99; 95% CI 0.99 to 4.02) with lamotrigine in the first year of use but not for subsequent years of use. Carbamazepine slightly decreased the risk (HR 0.60; 95% CI 0.35 to 1.02) after 2 or more years of use., Conclusions: The effect of valproate on bone health should be considered when managing epilepsy in Rett syndrome. Multiple mechanisms could be contributing to this effect.

The overlap between autism and Rett syndrome clinical features has led to many cases of Rett syndrome being initially diagnosed with infantile autism or as having some autistic features. Both conditions seriously disrupt social and language development and are often accompanied by repetitive, nonpurposeful stereotypic hand movements. The aims of this study were to compare the early and subsequent clinical courses of female subjects with Rett syndrome categorised by whether or not a diagnosis of autism had been proposed before Rett syndrome had been diagnosed and compare the spectrum of methyl-CpG binding protein 2 (MECP2) mutations identified among the two groups. This study made use of a total of 313 cases recorded in two databases: the Australian Rett Syndrome Database (ARSD) and the International Rett Syndrome Phenotype Database (InterRett). Cases with an initial diagnosis of autism had significantly milder Rett syndrome symptoms and were more likely to remain ambulant, to have some functional hand use and not to have developed a scoliosis. Females with the p.R306C or p.T158M mutations in the MECP2 gene were more likely to have an initial diagnosis of autism, and the specific Rett syndrome symptoms were noted at a later age. We recommend that females who are initially considered to have autism be carefully monitored for the evolution of the signs and symptoms of Rett syndrome.

Introduction: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X and p.T158M. The influence of X-chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing., Methods: Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele-specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated., Results: Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations., Conclusions: XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear.

Objectives: To investigate risk factors for seizure onset in Rett syndrome., Study Design: Information on presence and age at onset of seizures, perinatal and developmental history, and genetic status was abstracted on 275 cases in the Australian Rett Syndrome Database. Cox and Weibull regression were used to investigate and provide a model for predicting the effects of genetic and developmental factors on age at seizure onset., Results: Seizures were reported in 81% of 275 cases; the median age of onset was 48 months. Not having gained the ability to walk (P = .003) and developmental problems in the first 10 months of age (P = .04) were associated with an almost 2-fold increased risk of seizures. Cases without a detectable MECP2 mutation had a higher risk of seizure onset up to 4 years of age (P < .001) but a lower risk after 4 years (P = .08)., Conclusions: Seizure onset in Rett syndrome is associated with early developmental factors and with genotype. Information on these factors can be used to predict age at seizure onset after diagnosis.

Objective: To examine the prevalence, cumulative incidence, and survival in an Australian cohort with Rett syndrome (RTT)., Study Design: The Australian Rett Syndrome Database is a longitudinal data collection that included 276 verified female cases at the end of 2004. Survival was calculated using the Kaplan-Meier product limit method, and cumulative incidence was determined using the complement of the Kaplan-Meier method., Results: Most cases (88.4%) have had MECP2 mutation testing, with positive results in 73%. The prevalence of RTT was .88 per 10,000 females in 5- to 18-year-olds, and the cumulative incidence was 1.09 per 10,000 females by 12 years of age. The cumulative incidence by the age of 5 years increased from .39 per 10,000 in the 1980 to 1984 cohort to .76 per 10,000 in birth cohorts beyond 1984. Survival was 77.8% at 25 years, compared with 99.96% survival in the Australian female population. Pneumonia (10/25) was the most common cause of death., Conclusions: The availability of genetic testing has contributed to the changing pattern and timing of RTT diagnosis in Australia. Girls with RTT have worse survival compared with the general female population. When more data are available, it will be possible to evaluate the relationship between survival and specific MECP2 mutations.

We present a linkage analysis and a clinical update on a previously reported family with X-linked recessive panhypopituitarism, now in its fourth generation. Affected members exhibit variable degrees of hypopituitarism and mental retardation. The markers DXS737 and DXS1187 in the q25-q26 region of the X chromosome showed evidence for linkage with a peak LOD score (Zmax) of 4.12 at zero recombination fraction (theta(max) = 0). An apparent extra copy of the marker DXS102, observed in the region of the disease gene in affected males and heterozygous carrier females, suggests that a segment including this marker is duplicated. The gene causing this disorder appears to code for a dosage-sensitive protein central to development of the pituitary.

One hundred eighteen cases of nevoid basal cell carcinoma syndrome (NBCCS, Gorlin's syndrome or basal cell nevus syndrome) are presented in this study. In aiming to ascertain all the affected families in Australia, we have examined the largest series to date. Relative frequencies of associated complications are presented and compared with those of the recent English survey by Evans et al. [J Med Genet 30:460-464, 1993]. The frequencies of most manifestations are similar. However, one major difference is that the multiple basal cell carcinomas are manifest from an earlier age in the Australian population, which probably reflects greater exposure to ultraviolet radiation. Of the 64 families ascertained, 37 represented simplex cases, and, accordingly, the apparent new mutation rate is surprisingly high (14-81%) given the lack of impact of NBCCS on reproductive capabilities. There is some evidence to suggest that this may be attributable to anticipation.

Nevoid basal cell carcinoma syndrome (NBCCS; basal cell nevus syndrome or Gorlin syndrome) is a cancer-predisposition syndrome characterized by multiple basal cell carcinomas (BCCs) and diverse developmental defects. The gene for NBCCS has been mapped to 9q23.1-q31 in North American and European families. In addition, loss of heterozygosity (LOH) for genetic markers in this region has been detected in sporadic BCCs, indicating that the NBCCS gene is probably a tumor-suppressor gene. In this study we have determined that the NBCCS gene is also linked to this region in Australasian pedigrees and that there is no significant evidence of heterogeneity. We have defined the localization of the gene by multipoint and haplotype analysis of 15 families, using four microsatellite markers. LOH at these loci was detected in 50% of sporadic BCCs, a rate that is significantly higher than that in other skin lesions used as controls.

Objective: To determine the level of understanding of personal genetic risk in people born with a one in two risk of having autosomal dominant polycystic kidney disease (ADPKD)., Design: Consenting individuals, contacted through affected family members, were asked standard questions about their knowledge of their own genetic risk. These questions were incorporated into a study investigating the use of DNA diagnostic techniques in ADPKD which was an opportunity to interview a substantial number of Australians at risk of inheriting this condition., Setting: Interviews were conducted in the individuals' homes, or at the Royal Melbourne Hospital Renal Clinic or the Royal Children's Hospital Genetics Clinic., Patients: Three hundred and eighty-seven individuals aged 15 years or more, born with a one in two risk but who had remained undiagnosed up until the time of study were identified within 46 families. Sixty-six were excluded from the study either because they resided too far away or they declined involvement. The remaining 321 were assessed clinically, 304 of whom were also interviewed about their understanding of their risk of having inherited this condition., Results: Thirty per cent knew their risk at birth was one in two. Nine per cent were unaware that ADPKD was an inherited condition. Forty-one per cent were aware that ADPKD was inherited but had no opinion about their personal risk. Three per cent thought that they had no chance of having the condition, 3% thought that they were definitely affected, 8% considered their risk lay from 1%-49% and 6% thought their risk lay from 51%-99%., Conclusion: Within this group of people with a high risk of having an inherited condition with preventable and treatable components, the majority has a poor understanding of their genetic risk.