Methodological note: video analysis of the early development of Rett syndrome--one method for many disciplines.

Rett syndrome is a profoundly disabling X-linked neurodevelopmental disorder that predominantly, but not exclusively, occurs in females. It is mainly caused by mutations in the gene MECP2 for methylCpG-binding protein 2 (Xq28 [1]); recently, CDKL5 and FOXG1 have also been described to correspond with the early-seizure onset variant and the congenital variant of Rett syndrome [2, 3]. MECP2 is primarily expressed in neurons, when they become functionally mature, and before synaptogenesis [4]. Hence, Rett syndrome should be understood as a genetic interference with normal brain development rather than the result of tissue loss or destruction. Mutations in the gene MECP2 can be found in 95–97% of girls with classic Rett, but only in 50–70% of its variants [5, 6]. There are, however, girls who show the clinical criteria for Rett but no MECP2 mutation, asymptomatic female carriers and boys with MECP2 mutations who exhibit severe post-natal encephalopathy and die early. Furthermore, individuals with a MECP2 mutation but different neurodevelopmental disorders like autism, Angelman syndrome or intellectual disabilities not otherwise specified have been described. Hence, MECP2 mutations are neither necessary nor sufficient for the diagnosis of Rett syndrome. Consequently, the diagnosis is clinical and is based on consensus clinical criteria that were recently re-defined [5]. The presence of a regression period that goes along with the following four main criteria constitutes the basis for the diagnosis of Rett syndrome [5]: (1) partial or complete loss of acquired purposeful hand skills; (2) partial or complete loss of acquired spoken language; (3) gait abnormalities; and (4) stereotypic hand movements (e.g. wringing, washing, mouthing). Furthermore, two exclusion criteria for typical Rett and 11 supportive criteria for atypical Rett were defined. Rett syndrome has been reported to typically manifest in a four-stage trajectory: an apparently inconspicuous early development is followed by a stagnation (pre-regression period, Stage I) and furthermore by the loss of certain abilities (regression period, Stage II). Regression of various functions such as communication, fine motor abilities and gross motor abilities sets in at individual points in time (8–18 months) [5, 7, 8]. At Stage III a certain improvement of behaviour may be noticed. Stage IV, the late deterioration stage, is characterized by severe cognitive and motor impairment. Focusing on the early development (i.e. before the onset of regression) a number of researchers, clinicians and parents have assumed that the early development of girls with Rett is not asymptomatic, as had been previously believed [9–15]. Admittedly, the subtlety of peculiarities and the intermittent character of typical and atypical age-specific behavioural patterns make it difficult to detect the disorder before the onset of profound regression [5, 11, 14, 15]. One methodological approach to get around this issue to a certain extent and yet assess the early behavioural characteristics comprehensively is the retrospective video analysis. This method is based on family videos recorded at a time when parents were not aware of the