As more people are identified with CDKL5 mutations, it is becoming apparent that Akt inhibitor mutations in this gene may cause a distinct clinical entity with some clinical features similar to RTT, but others very different. This argues that it may be beneficial to consider this as a distinct clinical entity rather than a variant of RTT. Congenital variant Some people with RTF-like features never have a period of normal development and may have microcephaly from birth.57,61 A major challenge in the diagnosis of people in this Inhibitors,research,lifescience,medical group with an atypical form of RTT

is establishing clear psychomotor regression as opposed to a lack of skill acquisition. Recent work has identified mutation in FOXG1 in some people with the congenital variant,62 and very few people with this variant have been found that have mutations in MECP2.63 Most people with FOXG1 mutations have a structural brain abnormality, partial agenesis of the corpus callosum,62 which is not found in typical RTT. Similar to people with Inhibitors,research,lifescience,medical CDKL5 mutations, as more individuals are identified with FOXG1 mutations it is becoming apparent that this represents a distinct clinical entity with unique features different from RTT.64 Other clinical conditions in girls with MECP2 mutations Girls with MECP2 mutations Girls with MECP2 mutations have been found with

clinical Inhibitors,research,lifescience,medical conditions distinct from RTT. Some are conditions that

have distinct similarities to RTT Inhibitors,research,lifescience,medical but are clinically distinct, such as Angelman syndrome.65-67 In other cases, the affected girls have clear neurodevelopmental problems of a less severe nature than RTT, such as learning disability and uncontrolled aggression,68 or electrical status Inhibitors,research,lifescience,medical epilepticus during sleep.69 Finally, although it has not been identified as a common cause of autism,70-74 some cases of autism have been found to have clearly pathogenic mutations in MECP2.75 Interestingly, there is evidence that non-coding mutations in the 3′UTR old of MECP2 may cause autism76,77 or other neurodevelopmental disorders such as attention deficit/hyperactivity disorder.77 Although animal work has determined that alteration to the 3′UTR can have clear detrimental effects on MECP2 function and behavior, the exact pathological basis of these 3′UTR mutations has not been established, and is an important area for further research. Although the number of cases of neurodevelopmental disorders other that RTT with clear pathogenic mutation in MECP2 is somewhat limited, this may reflect an observational bias both in terms of what clinical features cause physicians to perform testing and the exact molecular nature of genetic testing that is performed on a clinical basis, which primarily targets the coding region of MECP2.