Home > News & Opinion > Viewpoint > 2013 > Regression in Rett syndrome may inform autism

Regression in Rett syndrome may inform autism

Popularity tracker
Jeffrey Neul
18 June 2013

A. Kramer, Texas Children's Hospital

Delayed onset: Jeffrey Neul studies Rett syndrome, which is characterized by a loss of language and motor ability around 1 year of age.

There seem to be two broad patterns of disease progression in autism. Many individuals with the disorder show features within the first year of life, with gradually developing impairments in social and language development1, 2.

However, a significant minority displays another distinct course, marked by loss of previously acquired skills around age 1 or 2, notably in language and social interaction. The prevalence of this ‘regressive' form of autism is not known, ranging from 12 to 50 percent of people with autism. (A meta-analysis published this year found the prevalence of regression in autism to be 32.1 percent3.) Part of the reason for this wide range is differences in the way these studies define regression in autism.  

Regression is better understood in Rett syndrome — a neurodevelopmental disorder that resembles autism — in which regression is a defining feature4. The syndrome predominantly affects girls, who appear to have normal motor, cognitive and social development until 6 months of age. These girls may show some developmental delay, but then at 1 or 2 years of age they undergo a severe developmental regression and lose the ability to speak and use their hands. 

Intriguingly, regression in Rett syndrome occurs at the same time as in regressive autism, and includes many of the same features, suggesting a common biological process.

Regression progression:

A fundamental question is: What is the biological basis of regression in autism? Loss of skills is seen in only a handful of other disorders. In some situations, loss of previously acquired skills is the first indication of a progressive, relentless disease process, as in some forms of childhood neurodegeneration, such as Batten disease.

However, the overall course in these conditions is distinct from that seen in regressive autism. In most neurodegenerative disorders, skills are progressively and continuously lost. In contrast, regression in autism occurs over a defined time period. Skills may ultimately stabilize and, potentially, be partially or even fully restored. Some studies have indicated that the presence of regression in autism correlates with poor social, intellectual and language function later in life. However, other reports did not find this relationship.

A small number of other disorders, such as childhood disintegrative disorder (CDD), do show the time-delimited regression seen in some cases of autism. There are many similarities between CDD and autism, with the notable distinction that the onset of symptoms and regression in CDD is seen later (older than 3 years) than in autism.

Severe seizures can also lead to loss of skills, for example in a condition known as epileptic encephalopathy. Although there is some relationship between seizures and autism, the rate of seizures in regressive versus non-regressive autism is not different, suggesting that the underlying cause of loss of skills is distinct between epileptic encephalopathy and regressive autism.

In the case of Rett syndrome, girls undergoing regression may have diminished eye contact and become socially withdrawn, indifferent to their surroundings and irritable. They have difficulty walking or lose the ability entirely, and display relentless, repetitive hand movements.

After this regression, they enter a period of developmental stabilization. During this time, they no longer lose skills and may show some improvement in hand skills and language, although most affected girls remain markedly impaired in these domains.

In contrast, social skills, especially gaze, dramatically improve after the regression period, and most girls with the syndrome show intense eye contact and use their gaze to communicate. Even so, they continue to show abnormal social behavior throughout life5, and more mildly affected individuals show distinct features of autism6.

Rett relationship:

What can Rett syndrome tell us about regression in autism? In both disorders, loss of spoken language and social skills are the key features. Also, the vast majority (95 percent) of Rett syndrome cases are caused by mutations in a single gene, MeCP2, which encodes a protein that regulates the expression of other genes.

Researchers can identify people who have MeCP2 mutations at a young age and then characterize clinical, physiological and molecular changes that occur during regression. For example, researchers could look at molecular changes in gene expression or metabolites in the blood, or at neuronal activity with electroencephalography or functional magnetic resonance imaging, as children undergo regression.

Understanding the genetic basis for Rett syndrome provides other distinct advantages. First, we know the underlying etiology of the clinical condition in essentially all affected individuals. Second, we can use the genetic information to create animal models, which can help us understand the disease process and allow testing of potential therapeutics. 

Animal models of Rett syndrome show many, if not all, of the clinical problems seen in people with this disorder. We have used these models to understand the function of the gene and the effect of its loss on the nervous system. 

We can also use animal models of Rett syndrome to understand molecular, cellular and circuit-level changes that occur during regression. 

However, demonstrating that regression occurs in the animal model has been a challenge. The major regression that occurs in Rett syndrome is loss of hand skills and loss of language, neither of which are present in the same way in rodents.

One approach is to look at other clinical features present both in people and in the animal model. My lab has focused one such feature: breathing abnormalities.

We recently determined that breathing in Rett syndrome mouse models is normal early in life, but becomes abnormal over time. Rett syndrome model mice breathe at a faster rate and hold their breaths more than controls, and have an abnormal breathing response to a low-oxygen environment7.

By focusing on the neural circuit controlling breathing and looking at changes that occur in its cells and connections, we hope to understand the molecular, cellular and circuit-level problems that lead to loss of correct breath control. 

Another way to expand our understanding of regression is to use animal models to explore molecular, cellular and circuit-level changes that occur both as the disorder progresses and in the face of regression. We hope that the insights we gain from this particular circuit will shed light on the circuit-level dysfunction underlying regression in Rett syndrome and potentially in autism.

One of the most exciting findings that has emerged in Rett syndrome is that the disease is reversible in mice8. Restoring MeCP2 function reverses the disease process, even in sick animals. This has provided great hope that researchers can develop similar treatments for both Rett syndrome and other neurodevelopmental disorders in people.

In fact, researchers have used these animal models to determine that treatments that modulate brain-derived neurotrophic factor can treat Rett syndrome in mice. Also, a tripeptide derived from insulin-like growth factor-1 has been shown to alter the course of the disease in animals9. This finding has lead to two clinical trials in Rett syndrome and one in Phelan-McDermid syndrome, an autism-related genetic syndrome.

Ultimately, detailed characterization of genetically defined disorders such as Rett syndrome, which have excellent animal models, is likely to provide insight into many of the biological processes involved in related neurodevelopmental disorders such as autism. This is especially true with regard to regression, as this is a feature shared by Rett syndrome and autism, but found in few other disorders.

Jeffrey Neul is associate professor of molecular and human genetics at the Baylor College of Medicine in Houston, Texas.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1. Ozonoff, S., Heung, K. and Thompson, M. (2011). Regression and other patterns of onset. In D. Amaral, D. Geschwind and G. Dawson (Eds.), Autism spectrum disorders (pp. 60-74). New York, NY: Oxford University Press.

2. Stefanatos G.A. Neuropsychol. Rev. 18, 305-319 (2008) PubMed

3. Barger B.D. et al. J. Autism Dev. Disord. 43, 817-828 (2013) PubMed

4. Neul J.L. et al. Ann. Neurol. 68, 944-950 (2010) PubMed

5. Kaufmann W.E. et al. J. Intellect. Disabil. Res. 56, 233-247 (2012) PubMed

6. Renieri A. et al. Brain Dev. 31, 208-216 (2009)  PubMed

7. Ward C.S. et al. J. Neurosci. 31, 10359-10370 (2011) PubMed

8. Guy J. et al. Science 315, 1143-1147 (2007) PubMed

9. Tropea D. et al. Proc. Natl. Acad. Sci. USA 106, 2029-2034 (2009) PubMed

Comments

Name: RA Jensen
18 June 2013 - 4:49PM

It is highly questionable if Rett Syndrome provides much insight into idiopathic autism. Rett Syndrome along with Childhood Disintegrative Disorder were deliberately removed from the recently published DSM-5 because of a perceived lack of association with the autism spectrum disorder category.

Moss and Howlin have presented good evidence that in the genetically determined syndromes autism symptoms are associated with intellectual disability and cautioned against over interpreting the superficial similarities between autism and the behavioral phenotypes seen in most genetically determined syndromes. The authors also found that many genetically determined syndromes like Rett Syndrome have their own unique pattern of superficial autism symptoms.

Over 99% of Rett Syndrome cases are not inherited. Rett Syndrome primarily in almost every case is caused by a de novo MECP2 mutation that is not present in either parent. Environmental influences are associated with the production of reproductive errors (sperm or egg) in the genetically determined syndromes.



References

Moss J, Howlin P. (2009). Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population. J Intellect Disabl Res. Oct;53(10):852-73. Epub 2009 Aug 25.

http://www.ncbi.nlm.nih.gov/pubmed/19708861



Christodoulou J. MECP2-Related Disorders. Last Update: June 28, 2012.

http://www.ncbi.nlm.nih.gov/books/NBK1497/


Jensen RA. The origins of de novo gene mutations in the genetic syndromes with high autism spectrum disorder (ASD) risk. OA Autism 2013 Apr 01;1(1):8. (In press).

http://www.oapublishinglondon.com/images/article/pdf/1370118463.pdf

Name: Autism Mother
18 June 2013 - 9:36PM

How refreshing it would be if autism researchers studied typical autistic regression!!
Let'e get right to the source! Almost no research is done on the environmental factors surely contributing to the
sudden regression of skills, speech and social behavior.
Why not talk to parents of these children and study the factors they saw toddlers react poorly too- infections, pesticide exposure, vaccine reactions....do autoimmune immune diseases run in these families....Let's look at their medical history and do parent interviews
So tired of the long way around every problem in autism. It isn't just genetic. Retts is exceedingly rare and genetic in origin, regressive autism is not.

Name: ASDDad
19 June 2013 - 6:31AM

This article seems at odds to this previous conclusion by SFARI

"On 13 February, SFARI hosted a workshop to explore whether regression is unique to some children affected by autism. Basic science and clinical researchers from around the world met to share and discuss current research and ideas. The participants concluded that regression is not a distinct classification within the autism spectrum because the majority of children with the disorder show a decline in skills starting as early as 12 months of age, with some having more severe regression than others."

It is a reminder that in children with gastrointestinal disorders and Autism rates of regression were quoted in two studies around the 90% mark.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0024585

Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances

"Regression (loss of language and/or other skills following acquisition) is reported in 20% to 40% of individuals with autism, and some studies suggest higher rates of GI symptoms in ASD subjects with regression than those without regression [27]. Eighty-seven percent of AUT-GI subjects in our study had behavioral regression "

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526159/

Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A Case-Control Study

"Median AUT onset age was 13.5 (7.0) months (Table 2). Cases had a high rate of CPEA-defined behavioral regression (loss of language and/or other skills following acquisition), 88%, compared to published rates of 20–40% for the general ASD population"

Name: ASDDad
19 June 2013 - 6:40AM

In regards to MECP2 there is some very interesting research surrounding the

"In 2005, other researchers identified the other side of the coin--MECP2 duplication syndrome. Too much of that critical protein results in other neurological problems that occur mainly in infant boys, again affecting their cognition and neurological development. These boys, however, have another troubling problem. They tend to get devastating infections, often pneumonias, that are difficult, and sometimes, impossible, to contain."

""The far-reaching effects of MeCP2 continue to surprise us," said Zoghbi, director of the Neurological Institute and a professor of pediatrics, neurology, neuroscience and molecular and human genetics at BCM. "This study highlights the power of combining clinical research and basic research. The finding that patients with MECP2 duplications suffer recurrent infections inspired studies in the mouse model that illuminated an important role of MeCP2 in immune responses."

MECP2 duplication affects immune system as well as brain development

http://www.bcm.edu/news/item.cfm?newsID=6571

Name: Anonymous
19 June 2013 - 3:45PM

That means susceptibility but the problem is that something in the environment is causing postnatal regressions in idiopathic autism. The SFARI workshop was disappointing. We need fewer psychologists and psychiatrists studying this issue and more immunologists and toxicologists.

Name: Elaine Chemistruck
20 June 2013 - 2:07PM

My son has a diagnosis of CDD, which now longer exists under DSM-5. His regression didn't begin until age 9 and lasted until age 18. After that, he regained some of the communication and social skills that he had lost. He does have a seizure disorder. My family members who have observed him connect his regression to the onset of his seizures. He had no significant health problems before the onset of seizures. I will always wonder what might have precipitated this regression in him.

Name: Steve White
21 June 2013 - 9:39PM

I am just a layman/parent but I think it's unlikely all the regression is due to the same cause. And I also very much doubt it's always caused by some postnatal environmental factor.
In MAR, maternal antibody related autism, there are findings that prenatal environmental factors, ie, antibodies from the mother, are the cause of regression which occurs much later. That's a weird finding but why can't it be so? We know regression is genetic in the case of Retts, so why does it have to be environmental in autism?

Name: Puzzled
3 July 2013 - 12:47PM

Interesting article, but even more so for the elephant in the room that is being ignored.

I find it curious, to put it mildly, that this article forgets to mention reversal of both physical and behavioural - autism - symptoms in mice model of Retts by bone marrow transplants + irradiation (for anyone interested video presentation by J Kipnis is available somewhere on this website)

This is a major finding and a game-changer, why leave it out? ESPECIALLY since the same immunological treatments completely reversed autism symptoms in a mice model of autism, where it was induced through maternal prenatal immune activation.

Retts might be monogenetic but the immune system is obviously involved in its pathology a major way. Same for idiopathic autism it seems.

The sooner the research community and funders such as SFARI pull their heads out of the sand and stop searching for those elusive autism genes (which may well all be false positives anyway http://scienceoveracuppa.com/2013/06/30/all-roads-once-led-to-rome-but-do-all-roads-lead-to-autism/) the sooner we’ll find real answers to autism.

Name: Ray
8 July 2013 - 5:18PM

Very well said. genetic researh is fine but when there is none why push it. There are many with classic idiopathic autism which regress to lose their abilities speech and social aspects...why this regression when there is no genetic findings either in the patient as well as family history. The immune system and gut should be more researched in depth.

I am a process specialist and very gifted in it. I have observed that within these individuals the ymptomes of autism is not always consistent: Nothing to do with a bad day/good day...as if there is a dynamic cycle of high and low into autism...high and low stimmings, alertness, self body awareness etc...hope researchers take this into consideration as I am certain it can be traced and documented.

Name: Steve White
4 July 2013 - 10:40PM

Iam hoping if any researchers are still reading they might have some insight.
I just went and reread some things possibly relevant to my own son's autism.
His autism is Maternal Antibody Related. His Mom has antibodies to a protein previously identified only by molecular weight, 39kDw.
Recently, they have identified the protein as Y box binding protein 1, or Y box 1.
Y box 1 protein apparently interacts with MECP2. MeCP2 is the protein which causes Rett syndrome if it is defective.
I am wondering if any researchers think the known interactions between Y box 1 and MeCP2, if defective or inadequate in some way, in the case of Rett, because the MeCP2 is defective, in the case of kids whose Mom's had antibodies to Y box 1, presumably because there was not enough Y box 1 left in the body to perform it's function, might cause autism with regression?

Here is a cut and past from a paper in PNAS, (sorry it's so long)::::

roc Natl Acad Sci U S A. 2005 Dec 6;102(49):17551-8. Epub 2005 Oct 26.
Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2.
Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, Kang D, Richman R, Johnson JM, Berget S, Zoghbi HY.
Source

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Erratum in

Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1656.

Abstract

Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by the loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 cause a variety of neurodevelopmental disorders including X-linked mental retardation, psychiatric disorders, and some cases of autism. Although MeCP2 was identified as a methylation-dependent transcriptional repressor, transcriptional profiling of RNAs from mice lacking MeCP2 did not reveal significant gene expression changes, suggesting that MeCP2 does not simply function as a global repressor. Changes in expression of a few genes have been observed, but these alterations do not explain the full spectrum of Rett-like phenotypes, raising the possibility that additional MeCP2 functions play a role in pathogenesis. In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor.

Add a Comment

You can add a comment by filling out the form below. Plain text formatting.

Question: What is 10 + 4 ?
Your answer: