Objective Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials. Method RettSearch members, representing the majority of the international clinical RTT specialists, participated in an iterative process to come to a consensus on a revised and simplified clinical diagnostic criteria for RTT. Results The clinical criteria required for the diagnosis of classic and atypical RTT were clarified and simplified. Guidelines for the diagnosis and molecular evaluation of specific variant forms of RTT were developed. Interpretation These revised criteria provide clarity regarding the key features required for the diagnosis of RTT and reinforce the concept that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. We recommend that these criteria and guidelines be utilized in any proposed clinical research.

mutations in MECP2 seem to be the main cause for RTT and can be expected to be found in approximately 77% of patients that fulfil the criteria for RTT. Therefore analysis of MECP2 should be performed if RTT is suspected. Three mutation hotspots (T158M, R168X and R255X) were confirmed and a further one (R270X) newly identified. We recommend screening for these mutations before analysing the coding region.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that apparently is lethal in male embryos. RTT almost exclusively affects female offspring and, in 99.5% of all cases, is sporadic and due to de novo mutations in the MECP2 gene. Familial cases of RTT are rare and are due to X-chromosomal inheritance from a carrier mother. We analyzed the parental origin of MECP2 mutations in sporadic cases of RTT, by analysis of linkage between the mutation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and we found a high predominance of mutations of paternal origin in 26 of 27 cases (P<.001). The paternal origin was independent of type of mutation and was found for single-base exchanges as well as for deletions. Parents were not of especially advanced age. We conclude that de novo mutations in RTT occur almost exclusively on the paternally derived X chromosome and that this is most probably the cause for the high female:male ratio observed in patients with RTT. Affected males recently have been described in a few cases of familial inheritance. Identification of the parental origin may be useful to distinguish between the sporadic form of RTT and a potentially familial form. This distinction will allow geneticists to offer more-specific counseling and discriminate between higher (maternal origin) and lower (paternal origin) recurrence risk.

Rett syndrome (RTT) is an inborn neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 gene (MECP2). Besides mental retardation, most patients suffer from potentially life-threatening breathing arrhythmia. To study its pathophysiology, we performed comparative analyses of the breathing phenotype of Mecp2 −/y knockout (KO) and C57BL/6J wild-type mice using the perfused working heart-brainstem preparation (WHBP). We simultaneously recorded phrenic and efferent vagal nerve activities to analyse the motor pattern of respiration, discriminating between inspiration, postinspiration and late expiration. Our results revealed respiratory disturbances in KO preparations that were similar to those reported from in vivo measurements in KO mice and also to those seen in RTT patients. The main finding was a highly variable postinspiratory activity in KO mice that correlated closely with breathing arrhythmias leading to repetitive apnoeas even under undisturbed control conditions. Analysis of the pontine and peripheral sensory regulation of postinspiratory activity in KO preparations revealed: (i) prolonged apnoeas associated with enhanced postinspiratory activity after glutamate-induced activation of the pontine Kölliker-Fuse nucleus; and (ii) prolonged apnoeas and lack of reflex desensitization in response to repetitive vagal stimulations. We conclude that impaired network and sensory mediated synaptic control of postinspiration induces severe breathing dysfunctions in Mecp2 −/y KO preparations. As postinspiration is particularly important for the control of laryngeal adductors, the finding might explain the upper airway-related clinical problems of patients with RTT such as apnoeas, loss of speech and weak coordination of breathing and swallowing.