Rett syndrome

What Rett syndrome is

Rett syndrome — first described by Andreas Rett in the 1960s — is an X-linked neurodevelopmental disorder that mainly affects girls. Development is typically normal at first; head growth then slows (often at 2–4 months), followed between about 6 and 18 months by a period of regression in which purposeful hand use and spoken language are lost.

The condition is usually described in four clinical stages. Over time, hand stereotypies, autistic features, intellectual disability, gait problems, movement disorder and breathing irregularities take shape, followed by relative stabilisation. In the teenage years, spasticity, dystonia and scoliosis can develop.

The genetic cause (MECP2)

About 95% of typical Rett syndrome is caused by a change in the MECP2 gene, which carries the instructions for a protein (MeCP2) that helps regulate many other genes in the brain. The variant usually arises new in the child (de novo).

MeCP2 is unusually dose-sensitive: too little protein causes Rett syndrome, but too much causes a different condition (MECP2 duplication syndrome). This balance is central to how the new gene therapies are designed — they must restore MeCP2 without overshooting.

Some children have an 'atypical' or Rett-spectrum picture linked to other genes — most importantly CDKL5 (an early-seizure variant) and FOXG1 (a congenital variant) — which are now recognised as distinct conditions that are diagnosed and managed in their own right.

How it presents

• Apparently normal early development, then a period of regression at around 6–18 months
• Loss of purposeful hand skills, replaced by characteristic hand stereotypies (wringing, washing, clapping, tapping or mouthing)
• Loss or absence of spoken language
• Deceleration of head growth
• Impaired (dyspraxic) or absent walking, and a movement disorder (ataxia, dystonia)
• Irregular breathing when awake, disrupted sleep, and later scoliosis

Epilepsy and associated features

Epilepsy affects roughly 60–80% of individuals, usually appearing in the second or third stage rather than at the very start; onset before the first year is unusual. Focal and bilateral tonic–clonic seizures are common. Broad-spectrum antiseizure medicines are generally used, chosen and adjusted by the treating neurologist.

Rett syndrome affects many systems, so care also attends to breathing, feeding and growth, gut and bone health (scoliosis), sleep and autonomic features such as cold hands and feet — best managed by a coordinated, multidisciplinary team.

Current management

Care is multidisciplinary and supportive — physiotherapy, occupational therapy, speech and language therapy with communication aids (AAC), orthopaedic care for scoliosis, nutrition support, and management of seizures, breathing and sleep.

Trofinetide (Daybue) — a synthetic analogue of a peptide derived from IGF-1 — became the first medicine approved specifically for Rett syndrome (FDA, 2023; also approved in Canada and Israel), and a newer powder formulation has since been approved in the US. It can produce modest improvements in core symptoms; the most common side effects are diarrhoea and vomiting. Its approval in the European Union remains uncertain after a negative regulatory trend vote in 2026. Trofinetide eases symptoms but is not a cure.

The genetic pipeline: MECP2 gene therapies

Because Rett is usually caused by one faulty MECP2 copy, the leading experimental strategy is gene therapy that delivers a working MECP2 gene to neurons in a single dose. The key challenge is dosage: too much MeCP2 is itself harmful, so each programme uses a built-in mechanism to keep protein levels in a safe range. These therapies are investigational and not yet approved.

• TSHA-102 (Taysha Gene Therapies) — a one-time AAV9 gene therapy delivering a shortened MECP2 'mini-gene' with miRARE technology that self-adjusts the amount of MeCP2 produced. Early Phase 1/2 data (REVEAL trials) showed gains in developmental milestones and skills; dosing across the REVEAL and ASPIRE studies is expected to complete in 2026.
• NGN-401 (Neurogene) — a one-time AAV9 gene therapy delivering the full-length MECP2 gene with EXACT technology to control protein production, given into the cerebral ventricles. It received FDA Breakthrough Therapy designation in 2026, and the registrational Embolden trial (children aged 4–10) is expected to complete dosing in 2026.
• Earlier-stage approaches include reactivating the healthy MECP2 copy on the silent X chromosome (X-reactivation), as well as antisense and read-through strategies — these remain preclinical or early-clinical.

How an educational review can help

Rett syndrome brings a great deal to take in — the meaning of a specific MECP2 result, how seizures, breathing, scoliosis and communication are best supported, and fast-moving news about trofinetide and gene-therapy trials. An educational review can explain the genetic and clinical findings in plain language, set out how the current plan fits established guidance, and help you prepare focused questions for your treating team.

It is an educational second opinion — not a diagnosis, treatment or prescription — and it does not replace the care of your child's own clinicians.