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Later this month, from the 17th to the 21st, about 30,000 neuroscientists will gather in Chicago for the annual meeting of the Society for Neuroscience. There will be about 40 presentations on Rett Syndrome. Most are basic science oriented but one with clinical relevance caught our attention.

We often hear of parents being concerned because their daughters are not urinating as normal on a particular day or two. Turns out this is not unusual in Rett. Dr. Jeff Neul, formerly of Baylor and now at UCSD, found that individuals with Rett often suffer from urological dysfunction including frequent urinary tract infections, kidney stones, and urine retention. He also found urological problems in the Rett mice.

Loss of MeCP2 causes urological dysfunction and contributes to death by kidney failure in mouse models of Rett Syndrome
C. S. Ward, T.W. Huang J. Herrera, R. C. Samaco, M. Pitcher, J. L. Neul

Rett Syndrome (RTT) is a neurodevelopment disorder characterized by loss of acquired skills during development, autonomic dysfunction, and an increased risk for premature lethality. Clinical experience identified a subset of individuals with RTT that present with urological dysfunction including individuals with frequent urinary tract infections, kidney stones, and urine retention requiring frequent catheterization for bladder voiding. To determine if urological dysfunction is a feature of RTT, we queried the Rett Syndrome Natural History Study, a repository of clinical data from over 1000 individuals with RTT and found multiple instances of urological dysfunction. We then evaluated urological function in a mouse model of RTT and found an abnormal pattern of micturition. Both male and female mice possessing Mecp2 mutations show a decrease in urine output per micturition event. Furthermore, we identified signs of kidney failure secondary to urethral obstruction. Although genetic strain background significantly affects both survival and penetrance of the urethral obstruction phenotype, survival and penetrance of urethral obstruction do not directly correlate. We have identified an additional phenotype caused by loss of MeCP2, urological dysfunction. Furthermore, we urge caution in the interpretation of survival data as an endpoint in preclinical studies, especially where causes of mortality are poorly characterized.


Fyi, micturition describes fainting shortly after or during urination. It is a type of Vasovagal response.

If you’ve ever wondered why a Rett diagnosis is based on clinical features and not a positive MECP2 test or if you have a child with a Rett diagnosis but no MECP2 mutation or the other way around then this is a video for you. What exactly does atypical Rett mean and should individuals with CDKL5 and FOXG1 mutations be considered Rett? All these topics are covered in the video below.

[video transcript]

This past week, more than 30,000 neuroscientists convened in New Orleans for the annual Society for Neuroscience meeting. Here are some of their interesting (unpublished) findings on Rett Syndrome.

Rett rats

Recent progress in genetic engineering has made it possible to model Rett Syndrome in rats – whose behavior is easier to study than mice. Researchers led by Richard Paylor from the Baylor College of Medicine in Houston, Texas, designed a set of behavioral tests to capture the animals’ social interest, anxiety, vocalizations and sensory and motor abilities. The team found that male rats whose Mecp2 (the gene that is missing or mutated in girls with Rett Syndrome) is disrupted were less active, showed impairments in a memory task, and behaved in a way that suggested they have disrupted connections between sensory and motor brain areas.

IGF-1 on trial

Researchers administered a full-length version of insulin-like growth factor 1 (IGF-1) — which is now under clinical investigation for treating Rett Syndrome — to mice lacking Mecp2. This particular form of IGF-1 boosted neuron-to-neuron signaling and the ability of neural connections to change in strength, compared with untreated mutant mice. According to a report by, however, treatment did not improve mutant mice’s performance on a task of motor coordination and learning.

In a separate study of mutant mice, led by Jeffrey Neul’s team at Baylor, scientists administered a slow-release form of IGF-1, or PEG-IGF1, finding that it only slightly lengthened lifespan but did not improve heart rate, body temperature, breathing, motor function, or behavior. And a higher dose of PEG-IGF1 cut the lifespan of mice, the group found.

Neul is planning a clinical trial in adult women with Rett with a shorter, tripeptide form of IGF-1, which in 2009 scientists found delayed the onset of several symptoms of the disorder in a mouse model.

Selective expression

In 2010, Huda Zoghbi and her colleagues at Baylor showed that neurons that dampen brain signals through their production of the inhibitory chemical GABA (gamma-aminobutyric acid) play an important role in the development of Rett.

For a preliminary study presented this week, Zoghbi’s group found that reactivating Mecp2 expression exclusively in GABA neurons well into adulthood (6 and 9 weeks) improved two symptoms of Rett — obesity and ataxia — in male mice missing Mecp2. Her group is also measuring cognitive and breathing symptoms after selectively reactivating the gene in GABA neurons.

Reprogrammed Rett cells

Alysson Muotri at the Scripps Research Institute in La Jolla and his collaborators took cells from human males with Rett and converted them into induced pluripotent stem (iPS) cells, which have the ability to form any other cell in the body.

The group found that several molecular signaling pathways differ between the iPS cells of healthy people and individuals with Rett as their cells begin to form neurons. These early changes may underlie neuronal features of Rett. The scientists are working to validate the biochemistry, but report that the new findings suggest that iPS cells derived from people with Rett may help identify new drug targets.

Progress on point mutations

Two years ago, researchers from the Barrow Neurological Institute in Phoenix, Arizona, described a new Mecp2 mouse — the A140V model —that reproduces a point mutation (meaning a single “letter” of the DNA code is replaced).

Male mice with the mutation survive, though they have X-linked mental retardation and show some brain abnormalities — such as less intricate neuronal branching and more tightly packed cells – compared with healthy mice. Unlike other mutants, however, the A140V has a normal lifespan and weight gain and no seizures or trouble breathing. The same group presented a detailed protocol to characterize the shape and size of brain cells of female mice that carry the mutation.