September 2026 Research Update

This month included an early clinical study suggesting fenfluramine (Fintepla), added on to existing epilepsy medicines, may reduce seizures in some children and teens with classic Rett syndrome who still have frequent seizures. Beyond seizures, families and clinicians also reported improvements in areas that affect day-to-day life, like sleep and breathing during the day, although the study did not include a comparison group. Because it was small and open-label, these results are best viewed as an encouraging signal that needs confirmation in larger, controlled studies. [1]

In the study, all participants who were analyzed had at least a 50% reduction in seizures by 3 and 6 months, and some became seizure-free for a period of time. The same group also reported better overall clinical status scores, fewer Rett-related behavior concerns on a caregiver questionnaire, and sleep scores that normalized by month 6. The study also measured brain responses to sound as an objective marker, with improvements reported in some children, but this was not consistent across everyone tested. [1]

Side effects were common, with sleepiness reported most often, and some children had diarrhea or motor restlessness. No one stopped fenfluramine because of side effects in this small group, but the study size was too limited to fully understand safety across the wider Rett population. [1]

For families dealing with drug-resistant epilepsy in Rett syndrome, this study adds early human evidence that fenfluramine might help reduce seizures for some patients, and it may also affect sleep and breathing symptoms. Right now, the main value is as research because there was no control group and only a small number of participants, so it cannot show how much change would have happened without the drug. What remains uncertain includes how well these results apply to people without drug-resistant epilepsy, to different ages, and to longer treatment periods, as well as how consistently breathing changes can be measured. [1]

One study this month added a practical piece to the picture of scoliosis care in severe neurodisability, including Rett syndrome: bone strength seemed to matter for how much the spine could be corrected during surgery. Across conditions, lower bone mineral density measured before surgery was linked with poorer curve correction after posterior spinal fusion. This does not say surgery should or should not be done, but it clarifies one measurable factor that may help explain why surgical correction varies between patients. [2]

The study compared non-ambulatory adolescents with neuromuscular scoliosis to healthy controls and found the scoliosis group had lower volumetric bone mineral density on CT scans. Within the scoliosis group, those with poorer correction had more negative bone density Z-scores than those with better correction. Rett syndrome was one of the included diagnoses, but the report did not provide Rett-specific correction outcomes separate from the overall analysis. [2]

For families considering or living with scoliosis surgery decisions, this study helps explain why results can differ: lower bone density may make spinal correction harder to achieve. This may matter now as background understanding in surgical planning and expectations, but the study does not test any approach to improving bone density or prove what would change outcomes. What remains uncertain is how much this relationship varies by diagnosis (including Rett syndrome specifically) and whether addressing low bone density would improve correction in future studies. [2]

Several studies this month tightened the picture of how MeCP2 changes body functions beyond the brain, by identifying more specific pathways that could contribute to symptoms. In mice, researchers found clearer evidence that peripheral sensors in the neck (the carotid bodies) can drive breathing instability, and that signaling changes there can be modified to stabilize breathing. Other work in a Rett mouse model linked slow gut movement to weaker acetylcholine-based signaling in the gut nervous system, and lab work showed that MeCP2 binds not only methylated DNA but also structured RNA in a way that Rett mutations can selectively weaken. These are not patient trials, but they help explain symptom pathways that may be testable targets later. [3] [4] [5]

For breathing, MeCP2-deficient mice showed episodic breathing with more unstable patterns, and giving 100% oxygen stabilized breathing by reducing peripheral chemoreceptor drive. When MeCP2 was knocked down only in the carotid body, similar breathing instability appeared, supporting the idea that this peripheral organ can contribute directly. The study also reported disrupted dopamine-related signals in the carotid body, and a dopamine D2/D3 agonist (pramipexole) improved breathing stability after low-oxygen stress in mice, while L-DOPA had little effect; higher doses of pramipexole caused excessive grooming in these mice. [3]

For gut function, Mecp2 knock-out mice had slower gastrointestinal transit, and gut tissue tests showed weaker cholinergic signaling, which is the acetylcholine-based messaging used by many gut nerves. The researchers measured lower acetylcholine levels and lower activity of the enzyme needed to make acetylcholine, alongside changes in receptor function, which together offer a biological explanation for slow gut motility in this model. This work is in mice, so it cannot tell how often the same mechanism is present in people with Rett syndrome, but it narrows down what to look for. [4]

At the molecular level, lab experiments showed that the MeCP2 region classically known for binding methylated DNA works together with a nearby region to form a combined unit that binds both methylated DNA and structured RNA with high affinity. Rett-associated mutations in this region reduced RNA binding more than methylated DNA binding, suggesting some mutations may disrupt RNA-related functions while leaving some DNA recognition intact. The same study noted that a therapeutic "MiniGene" construct preserved methylated DNA binding but had weaker RNA binding and lost some cooperative DNA-binding behavior seen with full-length MeCP2, highlighting a potential tradeoff that would need testing in living cells and organisms. [5]

A separate mouse study looked at whether puberty timing differs in female Mecp2-heterozygous mice, since Rett regression often occurs in early childhood. Puberty onset and estrous cycling were similar to wild-type mice at the ages studied, arguing against a large, easily measured difference in endocrine maturation before symptoms. This does not rule out subtler hormone-related effects, but it suggests that other mechanisms may better explain regression timing. [6]

These studies mostly matter for longer-term research because they were done in mice or in laboratory systems, not in people with Rett syndrome. What they add now is a clearer map of where symptoms might be generated: breathing instability may be influenced by peripheral sensors (carotid bodies), constipation and slow gut movement may relate to acetylcholine signaling in the gut nervous system, and some Rett mutations may change how MeCP2 interacts with RNA as well as DNA. What remains uncertain is how directly these findings translate to human symptoms and whether targeting these pathways would be safe and effective in patients, which would require clinical studies. [3] [4] [5] [6]

This month’s case reports underscored how Rett-like symptoms can arise from different genetic causes, and how real-world circumstances can shape recognition and care. One report described classic Rett features despite negative MECP2 and CDKL5 testing, with trio whole-exome sequencing identifying a de novo GABBR2 variant, expanding the set of genes that can look like Rett syndrome. Other cases highlighted that severe early illness can prompt rapid genetic testing for a different diagnosis (FOXG1 syndrome), and that limited access to testing or communication barriers can complicate symptom recognition and management. These are single-person reports, so they cannot predict what will happen for others, but they can broaden awareness of possibilities. [7] [8] [9] [10]

In the Rett-like genetics case, a girl met clinical criteria for classic Rett syndrome, but common genetic tests were negative and a de novo GABBR2 change was found with trio sequencing. The authors proposed that disrupted GABA signaling could contribute to Rett-like biology in some individuals, which may help explain why a small subset of people with a Rett presentation do not have MECP2 variants identified on standard testing. This report does not establish how often GABBR2 causes Rett-like symptoms, but it documents that it can happen. [7]

In the neonatal genetics case, a critically ill newborn with low muscle tone and abnormal breathing effort had trio whole-exome sequencing (testing the baby and both parents) that identified a de novo FOXG1 frameshift variant, leading to a FOXG1 syndrome diagnosis. The infant died within 24 hours, and the report emphasized the role of rapid genetic diagnosis for families and care teams in acute settings. This case is about FOXG1 syndrome rather than Rett syndrome, but it matters because FOXG1 can be part of the broader group of disorders that may be considered when symptoms overlap early in life. [8]

Two additional reports described lived clinical challenges around Rett syndrome. One described a 26-month-old girl whose severe self-injurious behavior dominated early presentation in a resource-limited setting, with diagnosis made clinically because MECP2 testing was unavailable; after 6 months of multidisciplinary support, some behaviors improved but core difficulties persisted. Another report described a 35-year-old woman with Rett syndrome who had a large ovarian mature teratoma with torsion and a small bowel obstruction. She underwent surgery while also being treated for viral pneumonia that was present on admission and went home on hospital day 14. The authors noted that the occurrence of the tumor alongside Rett syndrome may have been coincidental. [9] [10]

For patients and caregivers, these case reports mainly add perspective rather than changing anything immediately. They help clarify that a Rett-like clinical picture can sometimes have a different genetic explanation, especially when MECP2 and other common tests are negative, and they show how access to testing and communication barriers can affect the path to diagnosis and care. What remains uncertain is how frequently the specific findings in these single cases occur in the broader Rett population, and which genetic differences meaningfully change prognosis or symptom patterns. [7] [8] [9] [10]