Clinical and biological progress over 50 years in Rett syndrome

In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families

The Changing Face of Survival in Rett Syndrome and MECP2-Related Disorders

Purpose Survival in Rett syndrome remains unclear. Although early estimates were grim, more recent data suggest that survival into adulthood is typical. We aimed to define survival in Rett syndrome more clearly and identify risk factors for early death. Methods Participants with clinical Rett Syndrome or methyl-CpG-binding protein 2 mutations without clinical RTT were recruited through the Rett Syndrome Natural History study from 2006 to 2015. Clinical details were collected, and survival was determined using the Kaplan-Meier estimator. Risk factors were assessed using Cox proportional hazards models. Results Among 1189 valid participants, 51 died (range 3.9-66.6 years) during the 9-year follow-up period. Those who died included 36 (3.9%) classic Rett syndrome females, 5 (5.9%) atypical severe Rett syndrome females, 1 (2.4%) non-Rett syndrome female, the single atypical severe male, 6 (30%) non-Rett syndrome males, and 2 (7.1%) methyl-CpG-binding protein 2 duplication syndrome males. All atypical mild Rett syndrome females, methyl-CpG-binding protein 2 duplication syndrome females, and the single classic Rett syndrome male remain alive. Most deaths were due to cardiorespiratory issues. Only one died from severe malnutrition, scoliosis, and extreme frailty. Survival for classic and atypical Rett syndrome was greater than 70% at 45 years. Overall severity and several modifiable risk factors, including ambulation, weight, and seizures, were associated with mortality in classic Rett syndrome. Conclusions Survival into the fifth decade is typical in Rett syndrome, and death due to extreme frailty has become rare. Although the leading cause of death remains cardiorespiratory compromise, many risk factors for early death are modifiable. Intense therapeutic interventions could further improve the prognosis for individuals with Rett syndrome

Growth Charts for Individuals with Mucopolysaccharidosis VI (Maroteaux–Lamy Syndrome)

Background: The skeletal phenotype of mucopolysaccharidosis VI (MPS VI) is characterized by short stature and growth failure. Objective: The purpose of this study was to construct reference growth curves for MPS VI patients with rapidly and slowly progressive disease. Methods: We pooled cross-sectional and longitudinal height for age data from galsulfase (Naglazyme(®), BioMarin Pharmaceutical Inc.), treatment naïve patients (n = 269) who participated in various MPS VI studies, including galsulfase clinical trials and their extension programs, the MPS VI clinical surveillance program (CSP), and the MPS VI survey and resurvey studies, to construct growth charts for the MPS VI population. There were 229 patients included in this study, of which data from 207 patients ≤25 years of age with 513 height measurements were used for constructing reference growth curves. Results: Height for age growth curves for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles were constructed for patients with rapidly and slowly progressing disease defined by the pre-enzyme replacement therapy (ERT) uGAG levels of > or ≤200 μg/mg creatinine. The mean (SD) pre-ERT uGAG levels were 481.0 (218.6) and 97.8 (56.3) μg/mg creatinine for the patients ≤25 years of age with rapidly (n = 131) and slowly (n = 76) progressing MPS VI disease, respectively. The median growth curves for patients with ≤ and >200 μg/mg creatinine were above and below the median (50th percentile) growth curve for the entire MPS VI population. Conclusion: MPS VI growth charts have been developed to assist in the clinical management of MPS VI patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this chapter (doi:10.1007/8904_2014_333) contains supplementary material, which is available to authorized users

Association of human height-related genetic variants with familial short stature in Han Chinese in Taiwan

[[abstract]]Human height can be described as a classical and inherited trait model. Genome-wide association studies (GWAS) have revealed susceptible loci and provided insights into the polygenic nature of human height. Familial short stature (FSS) represents a suitable trait for investigating short stature genetics because disease associations with short stature have been ruled out in this case. In addition, FSS is caused only by genetically inherited factors. In this study, we explored the correlations of FSS risk with the genetic loci associated with human height in previous GWAS, alone and cumulatively. We systematically evaluated 34 known human height single nucleotide polymorphisms (SNPs) in relation to FSS in the additive model (p < 0.00005). A cumulative effect was observed: the odds ratios gradually increased with increasing genetic risk score quartiles (p < 0.001; Cochran-Armitage trend test). Six affected genes—ZBTB38, ZNF638, LCORL, CABLES1, CDK10, and TSEN15—are located in the nucleus and have been implicated in embryonic, organismal, and tissue development. In conclusion, our study suggests that 13 human height GWAS-identified SNPs are associated with FSS risk both alone and cumulatively.[[notice]]補正完