Rett syndrome

Posted on Autism

Autism – Uncovering the genetic mechanism behind Rett syndrome

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Images of brain organoids from control (top) and Rett syndrome (RTT) (left) patients, with astrocytes stained in cyan. You can see that the intensity of cyan color is higher in the RTT brain organoids CREDIT Kyushu University/Nakashima Lab

Medical researchers led by Kyushu University have revealed a possible underlying genetic pathway behind the neurological dysfunction of Rett syndrome. The team found that deficiencies in key genes involved in the pathology triggers neural stem cells to generate less neurons by producing more astrocytes–the brain’s maintenance cells.

The researchers hope that the molecular pathology they identified, as reported in the journal Cell Reports, can lead to potential therapeutic targets for Rett syndrome in the future.

Rett syndrome is a progressive neurodevelopmental disorder characterized by impairments in cognition and coordination–with varying severity–and occurs in roughly one in every 10,000 to 15,000 female births. However, it is difficult to initially identify because children appear to develop normally in the first 6-18 months.

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“Rett syndrome is caused by mutations in a single gene called methyl-CpG binding protein 2, or MeCP2. The gene was identified over two decades ago and much has been uncovered since, but exactly how the mutations cause the pathology remains elusive,” explains first author Hideyuki Nakashima of Kyushu University’s Faculty of Medical Sciences

In their past research, the team had identified that MeCP2 acts as a regulator for the processing of specific microRNAs to control the functions of neurons. So, they went back to investigate if that pathway was also involved in the differentiation of neural stem cells.

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Compared to messenger RNA, the final template transcribed from DNA that is used by a cell to synthesize proteins, microRNAs–or miRNAs–are much smaller and act to regulate messenger RNA to make sure the cell is making the correct amount of the desired protein.

“Through our investigation, we found several microRNAs associated with MeCP2, but only one affected the differentiation of neural stem cells: a microRNA called miR-199a,” says Nakashima. “In fact, when either MeCP2 or miR-199a are disrupted, we found that it increased the production of cells called astrocytes.”

Astrocytes are like the support cells of your brain. While neurons fire off the electrical signals, astrocytes are there to help maintain everything else. During development, astrocytes and neurons are generated from the same type of stem cells, known as neural stem cells, where their production is carefully controlled. However, dysfunction in MeCP2 or miR-199a causes these stem cells to produce more astrocytes than neurons.

“Further analysis showed that miR-199a targets the protein Smad1, a transcription factor critical for proper cellular development. Smad1 functions downstream of a pathway called BMP signaling, which is known to inhibit the production of neurons and facilitate the generation of astrocytes,” states Nakashima.

To investigate the process further, the team established a brain organoid culture–a 3D culture of neural stem cells that can mimic aspects of brain development–from iPS cells derived from patients with Rett syndrome. When they inhibited BMP, short for bone morphogenetic protein, the team was able to reduce abnormal neural stem cell differentiation.

“Our findings have given us valuable insight into the role of MeCP2, miR-199a, and BMP signaling in the pathology of Rett syndrome,” concludes Kinichi Nakashima, who headed the team. “Further investigation is needed, but we hope this can lead to clinical treatments for Rett syndrome symptoms.”

Posted on A to Z of Medical Conditions

Behavioral training could help babies with Rett syndrome, mouse study suggests

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Training babies’ brains and bodies might delay the onset of Rett syndrome, a devastating neurological disorder that affects about 1 in 10,000 girls worldwide.

In experiments with mice that replicate the genetic disorder, scientists discovered that intense behavioral training before symptoms develop staves off both memory loss and motor control decline. Compared to untrained mice, those trained early in life were up to five times better at performing tasks that tested their coordination or their ability to learn, Howard Hughes Medical Institute Investigator Huda Zoghbi and her colleagues report March 24, 2021, in the journal Nature.

Those data, from animals whose symptoms closely mimic the human disease, offers a clear rationale for genetically screening newborns for Rett syndrome, says Zoghbi, a physician and geneticist at Baylor College of Medicine who has been studying the disorder for more than 30 years.

Rett syndrome primarily affects girls, who are typically diagnosed around age three ¬- well after symptoms first appear. An earlier diagnosis could offer a window of opportunity for treatment, she says – potentially delaying disease progression in children, or even making them better able to benefit from future therapies. “We are losing precious time,” Zoghbi says. “If we could screen these girls and put them through training, maybe the time we gain prior to overt onset of symptoms will also create more opportunity for other treatments to work.”

A rapid decline

There are no effective treatments for Rett syndrome, and the unrelenting barrage of symptoms is grim. After developing normally for roughly the first one to two years of life, children progressively lose skills they’ve learned. By 18 months, kids may have trouble using their hands. By two years, their ability to balance deteriorates and language skills fade. When symptoms are full-blown, almost every part of the brain is affected. In severe cases, girls cannot talk, feed themselves, or even open their mouths. They can also experience seizures, teeth grinding, and difficulty breathing.

For parents watching their daughters regress, “it’s the most painful thing you can imagine,” Zoghbi says. Her journey with Rett syndrome began in 1983, after meeting two young patients who repetitively wrung their hands, a hallmark of the disorder. Zoghbi was convinced that Rett syndrome had a genetic root. In 1999, her team discovered that mutations in a gene on the X chromosome were to blame. A defective copy of the gene, called MECP2, disables about half the brain’s neurons, so that they function at only about 50-70% of their normal capacity, the team reported in 2011 and 2016.

Correcting MECP2 via gene therapy would be an ideal treatment, Zoghbi’s team writes, but delivering the right dose to the right neurons poses a challenge. Too much MECP2 can cause neurological problems, too. Scientists are currently pursuing a gene therapy candidate for Rett syndrome, though clinical trials have not yet begun.

Zoghbi’s team took an alternative approach. What if researchers could somehow prod those sluggish neurons into action? Using electrodes implanted in the brains of “Rett mice,” Zoghbi and her colleagues discovered that stimulating key neurons at the base of the brain activated hippocampal neurons and improved learning and memory, cranking neural activity back up to normal. The team reported the results of this deep brain stimulation in Nature in 2015. “That was really, really exciting,” Zoghbi says. “It gave us the idea that boosting the neurons’ activity could help them.”

Implanting electrodes into the brain isn’t ideal for children, though. For one thing, all brain regions are affected by Rett syndrome. So Zoghbi’s team tried to mimic the effects of deep brain stimulation with something non-invasive – intensive behavioral training.

“We thought it might work,” she says, “because both techniques are doing the same thing – stimulating neurons.”

Training time

The team trained Rett mice in two skills that wither in people with the disorder: coordination and learning ability. Instead of training only mice with symptoms, Zoghbi and colleagues tested an unconventional idea, too: They also trained mice before any symptoms had developed.

One type of training included a “rotarod” apparatus, a rolling log-like treadmill that requires mice to continuously walk to keep their balance. Twice a week, four times per day, researchers placed mice on the device for a five-minute session. Those trained early in life outperformed those trained later, and they stayed on the apparatus roughly five times longer than mice with no training.

The team saw something similar in a water maze test, where mice use pictures on the wall to learn where an underwater platform is hidden. Again, mice trained early performed better those trained after symptoms developed, the researchers found. “The results were really quite stunning,” Zoghbi says. “The difference is huge.” Training was task-specific: mice that received memory training did not make improvements in coordination, for example.

In lab experiments, the team traced improved performance to specific sets of neurons responsible for each training task. Under a microscope, those neurons actually looked different than those from late-trained mice, with more branches and connection points to other neurons. That difference suggests that intense early training physically changes the brain, in a way that counters the disease, Zoghbi says.

In fact, continued training of the animals even held off symptoms, her team discovered. These mice were symptom-free for up to four months longer than untrained mice. That’s a hefty chunk of time for the animals, which, like healthy mice, live about two years. Zoghbi thinks a clinical trial in humans is the next big step for this work. She imagines infant training could take many forms, including extra “tummy time” where babies lie on their stomachs to strengthen their core, or focused language training lessons to help the infants gain a few words.

Screening girls at birth could give doctors the heads-up they need to begin such training – and potentially buy these children some time before the disease begins to encroach. The MECP2 genetic test is widely available and covered by insurance, Zoghbi says.

The team’s findings warrant genetic screening of infant girls, agrees HHMI Investigator Nat Heintz, who was not involved in the research. Whether or not the work will translate to humans is still unknown, “but there are many reasons why it might,” he says. And the payoff could be considerable. Not only could early treatment delay symptoms, “it’s possible that training may have lasting benefits,” says Heintz, a neuroscientist at The Rockefeller University. “I think people are going to find this exciting.”

Even a delay of six months would be “absolutely worthwhile,” Zoghbi adds. “I’m hopeful that we have a path forward to make a difference in the lives of these individuals.”

Posted on Autism

Lab-grown human brain organoids mimic autism , help test treatments

Alysson Muotri, PhD, is professor and director of the Stem Cell Program at UC San Diego School of Medicine and member of the Sanford Consortium for Regenerative Medicine. UC San Diego Health Sciences

Most autism has a complex, multifactorial genetic component, making it difficult to find specific treatments. Rett syndrome is an exception. Babies born with this form of the disorder have mutations specifically in the MECP2 gene, causing a severe impairment in brain development that primarily affects females. Yet there is still no treatment — current therapies are aimed at alleviating symptoms, but don’t address the root cause.

Researchers at University of California San Diego School of Medicine and Sanford Consortium for Regenerative Medicine recently used stem cell-derived brain organoids — also called “mini-brains” — that lack the functional MECP2 gene to better study the disease.

In a study publishing December 8, 2020 in EMBO Molecular Medicine, the team identified two drug candidates that counteract the deficiencies caused by lack of the MECP2 gene. These compounds restored calcium levels, neurotransmitter production and electrical impulse activity, returning the Rett syndrome brain organoids to near-normal.

“The gene mutation that causes Rett syndrome was discovered decades ago, but progress on treating it has lagged, at least in part because mouse model studies haven’t translated to humans,” said senior author Alysson R. Muotri, PhD, professor of pediatrics and cellular and molecular medicine at UC San Diego School of Medicine. “This study was driven by the need for a model that better mimics the human brain.”

Brain organoids are 3D cellular models that represent aspects of the human brain in the laboratory. These organoids help researchers track human development, unravel the molecular events that lead to disease and test new treatments. At UC San Diego, brain organoids have been used to produce the first direct experimental proof that the Brazilian Zika virus can cause severe birth defects and to repurpose existing HIV drugs to treat another rare, inherited neurological disorder. Muotri and team also sent their brain organoids to the International Space Station to test microgravity’s effect on brain development — and maybe prospects for human life beyond Earth.

They aren’t perfect replicas, of course. Organoids lack connections to other organ systems, like blood vessels. Drugs tested on brain organoids are added directly — they don’t need to get across the blood-brain barrier, specialized blood vessels that keep the brain largely free of bacteria, viruses and toxins.

But researchers find organoids very useful for checking changes in physical structure or gene expression over time or as a result of a gene mutation, virus or drug. What’s more, Muotri’s team recently optimized the brain organoid-building process to match the electrical impulse pattern of premature babies, making them resemble real human brains more than ever.

In the latest study, the researchers applied this new protocol for functional brain organoids, using induced pluripotent stem cells (iPSCs) derived from patients with Rett syndrome. In short, they collected a skin sample, treated the cells in such a way that converted them to iPSCs, then in a way that coaxed them into becoming brain cells, preserving each patient’s unique genetic background. To verify their findings, the team also engineered brain organoids that artificially lack the MECP2 gene, and even mixed mutated and control cells to mimic the mosaic pattern typically seen in female patients.

Lack of the MECP2 gene changed many things about the organoids: shape, neuron subtypes present, gene expression patterns, neurotransmitter production and synapse formation. Calcium activity and electrical impulses were also decreased. These changes led to major defects in the emergence of cortical neural oscillatory waves, aka “brainwaves.”

In an attempt to compensate for the missing MECP2 gene, the team treated the brain organoids with 14 drug candidates that are known to affect various brain cell functions. Nearly all of the molecular and cellular symptoms were resolved when the researchers treated the Rett syndrome brain organoids with the two best drug candidates, Nefiracetam and PHA 543613. For example, the number of active neurons in Rett syndrome organoids roughly doubled following treatment. Nefiracetam and PHA 543613 were previously tested in Phase I and II clinical trials for the treatment of other conditions, meaning they are already known to cross the blood-brain barrier and to be safe for human consumption.

According to Muotri, these lab-based results provide a compelling argument for advancing Nefiracetam and PHA 543613 into clinical trials for patients with MECP2-deficient neurodevelopmental disorders.

But in the end, the best treatment for Rett syndrome may not be one “super” drug, he said.

“There’s a tendency in the neuroscience field to look for highly specific drugs that hit exact targets, and to use a single drug for a complex disease,” said Muotri, who is also director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine. “But we don’t do that for many other complex disorders, where multi-pronged treatments are used. Likewise, here no one target fixed all the problems. We need to start thinking in terms of drug cocktails, as have been successful in treating HIV and cancers.

2 Comments Posted on Autism, Children's health

Rett Syndrome – Signs and Symptoms. Find out how it is similar to autism and can help us understand autism better




Image result for rett syndrome youtube




I first encountered Rett Syndrome a few months back when I was told it was “like” autism. As my son is autistic I take something of an interest in the subject. (In fact Rett Syndrome is not really like autism but they do share some signs and symptoms in common).

That being said I thought it might be useful to share some of my finding with my readers. Both of course to create awareness of Rett Syndrome but also to spark a discussion among parents of children with Rett Syndrome about the condition and how they deal with it.

Okay so what is Rett Syndrome? Well it is described as a neurodevelopmental disorder. Which means that it only starts showing symptoms after a few months rather than at birth. In fact almost all people with Rett Syndrome are almost always likely to be female. Around 1 in 12,000 people are diagnosed with Rett Syndrome which means that it is described as a rare condition. It is caused by a genetic mutation.




Typically Rett Syndrome develops in 4 stages.

a) The first is slow development and late making of developmental milestones. As well it can include:-

general floppiness
some difficulty feeding
abnormal hand movements (for example flapping)
little of interest in toys
poor co-ordination

This occurs between 6-18 months.

 

b) The next stage is referred to as regression (which can be seen as similar to some forms of autism). At this stage the child will lose many quite a few of their abilities. This can include:-

social withdrawal as sometimes found in autism
difficulty in walking
meltdowns and significant distress
hard to use hand as with a typically developing
breathing problems
sleeping problems
slow head growth/small head

This seems to occur between 1 and 4 years of age.

c) The third stage is referred to as the plateau.

problems with weight gain
teeth grinding (or bruxism)
difficulty holding things and using the hands generally
difficulty with moving generally

Girls can also develop epilepsy at this stage and/or have heart problems. That being said some of the earlier symptoms can improve. While this stage starts between 2 and 10 many girls will remain here rather than develop into stage four.

d) The fourth stage is is general issues with movement. Often this involves:-

spasticity such as stiffness of the limbs
scoliosis or bending/twisting of the spine
losing the ability to walk

This stage may last many years.

Though there is no cure for Rett Syndrome there are many ways of managing the condition. Occupational therapy and physiotherapy works well. A diet promotes growth and the typical therapies for scoliosis and epilepsy.

 

For more information and an excellent overview of Rett Syndrome can I suggest you have a look at Rett UK’s web site here.

Thanks very much for your interest

Posted on Autism

Pupil dilation and heart rate, analyzed by AI, may help spot autism early


Michela Fagiolini, PhD, and her colleagues demonstrate a machine-learning algorithm that can spot abnormalities in pupil dilation that are predictive of autism spectrum disorder (ASD) in mouse models. The same algorithm, using heart rate fluctuations instead of pupillary data, successfully identified girls with Rett syndrome. CREDIT Pietro Artoni/Boston Children’s Hospital

Autism and other neurodevelopmental disorders often aren’t diagnosed until a child is a few years of age, when behavioral interventions and speech/occupational therapy become less effective. But new research this week in PNAS suggests that two simple, quantifiable measures — spontaneous fluctuations in pupil dilation or heart rate– could enable much earlier diagnosis of Rett syndrome and possibly other disorders with autism-like features.

The study, led by Boston Children’s Hospital neuroscientist Michela Fagiolini, PhD, and postdoctoral fellow Pietro Artoni, PhD, unveils a machine-learning algorithm that can spot abnormalities in pupil dilation that are predictive of autism spectrum disorder (ASD) in mouse models. It further shows that the algorithm can accurately detect if a girl has Rett syndrome, a genetic disorder that impairs cognitive, sensory, motor, and autonomic function starting at 6 to 18 months of age, as well as autism-like behaviors.

Fagiolini and colleagues hope this system could provide an early warning signal not just for Rett syndrome but for ASD in general. In the future, they believe it could also be used to monitor patients’ responses to treatments; currently, a clinical trial is testing the drug ketamine for Rett syndrome, and a gene therapy trial is planned.

“We want to have some readout of what’s going on in the brain that is quantitative, objective, and sensitive to subtle changes,” says Fagiolini. “More broadly, we are lacking biomarkers that are reflective of brain activity, easy to quantify, and not biased. A machine could measure a biomarker and not be affected by subjective interpretations of how a patient is doing.”

Altered arousal in autism

Fagiolini and Artoni, in close collaboration with Takao Hensch, PhD, and Charles Nelson, PhD, at Boston Children’s, began with the idea that people on the autism spectrum have altered behavioral states. Prior evidence indicates that the brain’s cholinergic circuits, which are involved in arousal, are especially perturbed, and that altered arousal affects both spontaneous pupil dilation/constriction and heart rate.

Fagiolini’s team, supported by the IRCN at Boston Children’s F.M. Kirby Neurobiology Center, set out to measure pupil fluctuations in several mouse models of ASD, including mice with the mutations causing Rett syndrome or CDKL5 disorder, as well as BTBR mice. Spontaneous pupil dilation and constriction were altered even before the animals began showing ASD-like symptoms, the team found.

Moreover, in mice lacking MeCP2, the gene mutated in Rett syndrome, restoring a normal copy of the gene, in cholinergic brain circuits only, prevented the onset of pupillary abnormalities as well as behavioral symptoms.

Predicting Rett syndrome in girls

To systematically link the observed arousal changes to the cholinergic system, the team took advantage of an earlier discovery by Hensch: mice lacking the LYNX1 protein exhibit enhanced cholinergic signaling. Based on about 60 hours of observation of these mice, the investigators “trained” a deep learning algorithm to recognize abnormal pupillary patterns. The same algorithm accurately estimated cholinergic dysfunction in the BTBR, CDKL5, and MeCP2-deficient mice.

The team then brought this algorithm to 35 young girls with Rett syndrome and 40 typically developing controls. Instead of measuring the girls’ pupils (as patients may fidget), they used heart rate fluctuations as the measure of arousal. The algorithm nonetheless successfully identified the girls with Rett, with an accuracy of 80 percent in the first and second year of life.

“These two biomarkers fluctuate in a similar way because they are proxies of the activity of autonomic arousal,” says Artoni. “It is the so-called ‘fight or flight response.”

Autonomic arousal, a property of the brain that is strongly preserved across different species, is a robust indicator of an altered developmental trajectory, Fagiolini and Artoni found.

Biomarkers for babies?

In a previous study with Nelson, Fagiolini showed that visual evoked potentials, an EEG measure of visual processing in the brain, could also serve as a potential biomarker for Rett syndrome. She believes that together, such biomarkers could offer robust yet affordable screening tools for infants and toddlers, warning of impending neurodevelopmental problems and helping to follow the progression of their development or treatment.

“If we have biomarkers that are non-invasive and easily evaluated, even a newborn baby or non-verbal patient could be monitored across multiple timepoints,” Fagiolini says.