In Rett syndrome, brain cells go quiet rather than die
Rett syndrome strikes almost only girls, usually after a normal-seeming first six months, taking away speech and purposeful hand use. For years it looked like a brain slowly wasting away. Yet in mouse studies the neurons survive, and restoring the missing gene in adult animals partly reverses symptoms, reframing it as a developmental condition.
The cause is usually a mutation in MECP2, a gene near the tip of the X chromosome that helps switch other genes off by reading chemical tags on DNA. At least 95% of cases arise fresh in the child, almost always on the X chromosome inherited from the father, and under one percent run in families. Because girls carry a second, working X, they survive; boys with a comparable mutation typically die shortly after birth. Estimates put it at about 1 in 8,500 females. Lebanese-American physician Huda Zoghbi identified the responsible mutation in 1999.
Classic Rett unfolds in stages. Early signs between 6 and 18 months are subtle: less eye contact, fading interest in toys, slow head growth. Between ages 1 and 4 comes rapid regression, as spoken words and deliberate hand skills vanish and constant wringing, clapping or mouthing movements appear, stopping only in sleep. Breathing can swing between pauses and over-breathing. A long plateau often follows, sometimes with brighter attention and communication, though seizures and motor planning problems are common. A late stage brings stiffness, spinal curvature and often lost walking, while thinking and hand skills generally hold steady.
Several variants exist. The milder Zappella form lets children partly regain speech around age 5. The Hanefeld form begins with epilepsy before 5 months. A severe congenital type linked to FOXG1 is abnormal from birth and is often classed separately, and CDKL5 mutations produce another look-alike.
Research points to specific circuits. People with Rett have low brain noradrenaline, and in MECP2-deficient mice the locus coeruleus, the main noradrenaline source for the cortex, becomes hyperexcitable and immature rather than dying. A 2021 study from Scottish universities argued the syndrome is neurodevelopmental, not neurodegenerative, which encourages work on treatments. There is no cure; care targets symptoms, and trofinetide became the first drug approved by the US FDA for the condition. Many patients live into middle age.
Source: Rett syndrome
