The diagnosis of Rett syndrome, described by Andreas Rett in 19651 as a neurodevelopmental disorder predominantly affecting females, is based on clearly defined clinical criteria, modified periodically with improved understanding of its core features. In 1985, Hagberg and colleagues developed consensus criteria exclusively for females2, modified in 1988 to include males3. Following identification of mutations in the gene, Methyl-CpG-binding-protein 2 (MECP2), in individuals with RTT4, an international consensus meeting further modified those criteria to affirm the importance of carefully applied diagnostic criteria5 and to clarify possible ambiguities in interpretation of these criteria. This included recognition that 1) abnormal deceleration in the rate of head growth was not always present, 2) early development could be delayed, and 3) apraxia of gait should include the possibility of failure to develop gait. Further, it was important to provide consensus criteria for variant forms of RTT6. More recently, RettSearch, an international group of clinicians, completed a systematic review of these criteria to provide further clarifications including those core features that are essential for considering the diagnosis of RTT or its variants and to refine definitions of other previous criteria not included in this core group (see accompanying paper, Neul et al.). This revision follows on refinements in molecular diagnosis including identification of previously unrecognized MECP2 mutations in exon 17, large deletions encompassing one or more exons8,9, and duplication of the MECP2 Xq28 region in males with severe neurodevelopmental disorders10-12, as well as confirmation of mutations in 95% of females with classic RTT13. Further, an increasing number of females and males, not meeting RTT criteria, have been identified with MECP2 mutations.
The RTT Rare Disease Clinical Research Center (RDCRC) natural history study began enrolling participants in 2006 with the goal of 1000 individuals with classic or variant RTT based on the 2002 criteria5. The present analysis was conducted on 819 participants enrolled as of February 28, 2010, to assess the recently modified clinical criteria. The results validate the revised diagnostic format and emphasize the importance of having clearly defined criteria based on clinical features including clear regression of previously acquired skills in both classic and variant RTT and the necessity of supportive criteria only for variant forms.