I suspect that they will be also be looking for patients in the early "stabilization" period before heavy motor skill impairment and muscle atrophy occurs. Even if the trial is successful they will probably need to do trials in patients in other stages adjusting dosage, etc. There is a lot that we don't know about the trial and even if the drug is approved there will be some heavy duty P4 research to be done.
RTT is distinguished by its unique time course and phenotypic complexity. Affected individuals present with postnatal neurological regression, usually starting between 1.5 and 3 years of age (but sometimes as early as 6 months of age), with loss of acquired hand skills and spoken language and, in some cases, social withdrawal or extreme irritability that can resemble autism (Hagberg, 2002; Neul et al., 2010). After regression, there is a stabilization of skills, rather than a relentless progression, a feature that differentiates RTT from neurodegenerative conditions such as Batten disease or Huntington’s disease. During this pseudo-stationary or plateau stage, characteristic features of RTT such as repetitive hand movements (stereotypies), which can be present before or during regression, become more prominent. Later in life, many affected individuals enter a stage of motor decline in which ambulation can be lost, and Parkinsonian features such as rigidity and hypomimia become prominent (FitzGerald et al., 1990a; FitzGerald et al., 1990b). Mutations in other genes such as cyclin-dependent kinase like 5 (CDKL5) and forkhead box G1 (FOXG1) can cause phenotypes overlapping with those seen in RTT (Archer et al., 2006; Ariani et al., 2008); however, several features, such as congenital onset and infantile spasms in CDKL5-mutant patients, and congenital onset and hypoplasia of the corpus callosum in FOXG1-mutant patients, distinguish these disorders from typical RTT (Kortüm et al., 2011).
During the regression stage, some individuals with RTT develop autistic features that include social withdrawal, avoidance of eye contact and indifference to visual or auditory stimuli (Mount et al., 2002a; Mount et al., 2003). After regression, some of these autistic features decrease, and most affected individuals develop intense eye gaze that they use for communication (Coenraads, 2007; Kaufmann et al., 2012). Recent work has shown that features such as stereotypies and lack of language skills persist throughout the life of affected individuals, although hand stereotypies can change from rapid movements to midline hand clasping with age. Additional behavioral problems include anxiety in response to novel situations (Mount et al., 2002b), increased behavioral rigidity and increased pain tolerance (Downs et al., 2010). Individuals with RTT are considered to have severe intellectual disability; however, because affected individuals have severe impairments in their ability to communicate, it is difficult to make accurate assessments of their intellectual ability (Baptista et al., 2006; Neul et al., 2010).
Movement abnormalities are a major issue in RTT (FitzGerald et al., 1990a; FitzGerald et al., 1990b), with the most obvious being the repetitive hand stereotypies, which seem to interfere with volitional hand use. Gait is almost always disrupted, with evidence of ataxia and apraxia. Dystonia is common, seen first in the ankles and eventually progressing to many joints. Axial hypotonia is present early in the disease course but, as children become young adults, increased tone with features of rigidity becomes more prominent. Additional movement abnormalities include tremor, myoclonus, chorea, facial grimacing and severe teeth grinding. Most individuals with RTT have scoliosis, and some require surgical intervention (Percy et al., 2010).
Nutrition and gastrointestinal function are also major clinical issues in RTT, and there is marked growth failure in most affected individuals (Tarquinio et al., 2012). It has long been recognized that head growth is impaired, resulting in acquired microcephaly (Hagberg et al., 1983), and height and weight are usually markedly diminished (Schultz et al., 1993). However, a subset of individuals with RTT are overweight or obese (Renieri et al., 2009), a feature that is often associated with higher functioning and possibly improved oromotor skills (Motil et al., 1999). Many individuals with RTT have various gastrointestinal problems, including significant chewing and swallowing difficulties, gastroesophageal reflux, gastrointestinal dysmotility and severe constipation, which severely decrease the quality of life for patients and their families (Motil et al., 2012).
Dysregulation of breathing and autonomic homeostasis are very common in RTT. Respiratory abnormalities, which include periods of forceful breathing (hyperventilation), severe pauses in breathing (including breath holds) that can cause cyanosis and even loss of consciousness, and abnormal cardiorespiratory coupling, are more severe during wakefulness than during sleep (Elian and Rudolf, 1991; Julu et al., 2001; Julu and Witt Engerström, 2005; Marcus et al., 1994; Weese-Mayer et al., 2008; Weese-Mayer et al., 2006) and can be exaggerated during periods of excitement or stress. Autonomic abnormalities include periods of vasomotor disturbance (usually associated with cold hands and feet), abnormal sweating, decreased heart rate variability, evidence of sympathetic-parasympathetic imbalance and prolongation of corrected QT interval (an indication of abnormal cardiac electrical activity) in a subset of individuals (Guideri et al., 2004; McCauley et al., 2011; Sekul et al., 1994). One quarter of deaths in RTT are sudden and unexpected (Kerr et al., 1997), and might result from complications of cardiorespiratory dysfunction.
Brain electrical activity is not typical in individuals with RTT, as shown by the markedly disrupted pattern observed on electroencephalograms (EEGs) (Glaze et al., 1998) and the high probability of seizures (Glaze et al., 2010). Seizures, ranging from complex partial to generalized tonic-clonic, are most commonly seen after other symptoms appear (usually after age two) and correlate with the severity of the phenotype. In addition to true epileptic events, individuals with RTT also have non-epileptic paroxysmal events, and video EEG is needed to differentiate between them (Glaze et al., 1998).
