The study investigates the neurological symptoms in mice lacking the Mecp2 gene, which is associated with Rett syndrome (RTT) in humans. Mice lacking Mecp2, either homozygous or heterozygous, exhibit severe neurological symptoms at around six weeks of age, including reduced movement, abnormal gait, limb clapping, irregular breathing, and weight loss. These symptoms are not due to compensation by Mecp1 in other tissues, as Mecp1 levels remain normal. The onset of symptoms in Mecp2+/− female mice overlaps with that in human RTT patients, suggesting that the stability of brain function, rather than brain development, is compromised by the absence of Mecp2. The results support the view that RTT is primarily a neurological disease and challenge the notion that RTT is caused by mutations that impair but do not inactivate Mecp2.The study investigates the neurological symptoms in mice lacking the Mecp2 gene, which is associated with Rett syndrome (RTT) in humans. Mice lacking Mecp2, either homozygous or heterozygous, exhibit severe neurological symptoms at around six weeks of age, including reduced movement, abnormal gait, limb clapping, irregular breathing, and weight loss. These symptoms are not due to compensation by Mecp1 in other tissues, as Mecp1 levels remain normal. The onset of symptoms in Mecp2+/− female mice overlaps with that in human RTT patients, suggesting that the stability of brain function, rather than brain development, is compromised by the absence of Mecp2. The results support the view that RTT is primarily a neurological disease and challenge the notion that RTT is caused by mutations that impair but do not inactivate Mecp2.