What should I know about RTS?

What should I know about RTS? Quite a bit as it happens. From the perspective of Maria, there are two broad categories: physical issues and mental issues. 

Physically, Maria is going to need a lifelong program of continual monitoring for well known symptoms associated with RTS. This list of potential symptoms is quite long. 

Now I know from personal experience that when you make lists of things then it can make things look much worse than they really are. If I were to draw up a list of all the ailments I might potentially get from then it'd be pretty long and bleak. Fortunately, in the case of RTS then it's a list of quite well defined symptoms, so all I need to do is to be vigilant in recognising the symptoms when they occur and to take make sure Maria gets regular checkups in all the risk areas. 

When examining the list of symptoms, it's helpful to know what percentage of the RTS population actually develop any given symptom. Ideally, this should be compared to the risk associated with a "normal" population. It's also useful to know when the risk is greatest, so you can be better prepared to spot the first signs.

For example, a "talon cusp" is a potential symptom of RTS but it doesn't normally appear until the child's permanent teeth start at the age of six onwards, so don't expect to see one in the early years (as I did).

The two best sources of medical advice on RTS symptoms and their timeline are:
1. the RTS Medical Guidelines  by Wiley (2003)
2. the RTS Management Guidelines  by Hennekam 2010)

Keep these papers to hand; re-read them from time to time and ask all the doctors who treat your child if they've read both these papers. Maria's orthodontist implied that he knew all about RTS because he'd treated six RTS children over the past twenty years. He wanted to discharge Maria after seeing her at the age of 4 years and 9 months but I argued that this was contrary to the advice given in one of the two papers. It turned out he'd never heard of these papers, so I emailed him the details when I got home.

Knowledge is empowering and if you know more about RTS than your doctors (and you probably will) then you can help protect your child by making them aware of RTS-specific issues. For example, if Maria ever needed to go under a general anaesthetic then I know - thanks to these papers - that I need to warn the anaesthetist that because of Maria's RTS condition, she might have a collapsible windpipe and that special measures may be needed to bring her in and out of consciousness (details are given in one of these papers). Just imagine what could happen if you weren't there to forewarn them. 

Maria sucks

How about the mental issues of RTS? Well, that's a bit more tricky because at present nobody really knows how the mind and brain work normally, let alone abnormally. There's never been a shortage of theories or 'models' but nobody has proposed a holistic model of the brain that predictive and useful. Until that happens then I'm afraid the 'experts' are unlikely to commit themselves. You'll notice this by the distinct lack of advice you'll get on so many of the important issues. The only thing to do is talk to others who've tackled similar problems to see what solutions they've come up with. 

For example, I'm worried about how we're going to teach Maria to read. Well, there aren't any books on the market that cover reading for RTS children, so instead I've had to look at books like 'Teaching Reading to Children with Down Syndrome' by Patricia Logan Oelwein. You just have to use the best material you can get your hands on. One complication is that Down Syndrome is associated with short-term memory deficit whereas Rubinstein-Taybi Syndrome is associated with long-term memory problems, so I can't be sure the books approach will work for Maria. The Special School that Maria attends think they have a solution through their policy of continual reinforcement, meaning that if they keep reminding children then both long and short-term memory needs are covered. 

There's one final thing you should know about RTS. How will you and your partner cope with the news that your child has RTS? In case you think your doctor has the answer then let me tell you that this issue isn't even on their radar. Joan and I weren't offered any kind of counselling to address the issue; we were left to deal with the fallout by ourselves - and you already know from my earlier post what a hash we made of it during that first week. In short, the trauma I felt that week was akin to the bereavement of a close friend. Fortunately I'm pretty level-headed and so the following week I woke out of my zombie state and started work on how to deal with this situation. Notice I said 'I' and not 'we'. Emotionally, Joan lagged behind by several months, unwilling to come to terms with the diagnosis. Even now, after two years, she admits that she still hasn't accepted the diagnosis.  

I was frustrated because I needed to talk to someone who knew all about RTS but nobody was  available. Professor Raoul Hennekam (the authority on RTS) had left Great Ormond Street Hospital in London and returned to the Netherlands, so there was no expert left to discuss Maria's prognosis. RTS is so rare that you're very lucky to find another case in your vicinity. Joan and I live in London and our Social Services told us there was one other family in the Borough with an RTS child. We had no way of contacting them. Fortunately we followed the advice of our geneticist and joined the national RTS UK group. We felt very much at home with people who knew all about RTS and were prepared to share their deeply felt experiences. Joan and I were a lot happier after that; we no longer felt alone.

Is there a cure for RTS?

'Wild-type' Maria

The best way to find out if there's a cure for RTS is to routinely do the following:

1. read the latest research literature and know what's on the horizon. 

2. keep abreast of clinical trials and see what drugs are being currently tested or what the outcome was.

3. find which pharmaceutical drugs are available and contact your doctor.

Alternatively, you can let others do the donkey work and just visit your geneticist annually to find out about the latest treatments. Don't be like some carers and stop visiting your geneticist. And keeping a watchful eye on the scene still seems like a good idea to me. Your support group should be doing this too so stay in touch.

In this post, I'm going to review the research that helped me answer my questions. Some research papers need an advanced knowledge of biology, chemistry and statistics. I'm rusty on all three counts but I'll get better. You don't have to understand every word; the abstract, introduction and discussion are usually sufficient, especially if you find the paper heavy going.  

A brief note on terminology: It's conventional to write human gene names in capital italics (e.g. CREBBP)  and human protein names in regular capitals (e.g. CREBBP). Similarly, animal gene names are in lowercase italics with a capital initial letter (e.g. Crebbp) and animal protein names are in regular lowercase with an capital initial letter (e.g. Crebbp). You'll also find that gene names can have synonyms; for example, CBP means CREBBP and  p300  means EP300. You've probably already realised that RTS is often written as RSTS.

Finally, you'll need a good genetics dictionary; I use the Talking Genetics Glossary or the Genetics Home Reference Glossary.

I'll start by looking at the most important RTS research literature and summarise what's happened over the past few decades in the fields of medicine, biology, psychology and education. The most prolific area is biology, followed by medicine. There are very few papers that address the psychology of RTS and none that I've found on the education of RTS children, so instead I've chosen some classic papers on the education of children with developmental delay:

Medicine

1963: Jack Rubinstein and Hooshang Taybi discovered a new syndrome because of some common characteristics, including short and broad thumbs and toes, "odd" facial features and mental retardation (yes, these were the days when "imbecile" (IQ of 26 - 50) and "moron" (IQ of 51-70) were medical terms).

2003: M Shevell and colleagues review the scientific and clinical literature to determine how to evaluate a child with global development delay. They explain that the term 'global development delay' is restricted to children under the age of 5, whereas 'mental retardation' is reserved for older children for whom IQ assessment is more reliable and valid. 

2003: Gregory O'Brien tells us that the intellectual disability in RTS ranges from mild to moderate and severe. The psychiatric disturbances in RTS are mainly mood disturbances. That RTS is a non-progressive syndrome, meaning that it doesn't get worse during the lifetime of the person. And finally, the life expectancy of RTS is normal (age 70), subject to occasional cardiac complications and brain tumours. 

2011: Cathy A Stevens and colleagues conducted the first survey of RTS adults, mostly living in the US. It covered medical issues, education, independence and behaviour. The most common medical problems were short stature, obesity, visual difficulties, keloids, eating problems, spine curvature and joint problems. Educationally, the adults had moderate mental retardation but most achieved some degree of independence in communication and self-care. Many participated in supported work activities. They found one-third of those surveyed had some decreased abilities over time. Behaviour problems were common and often worsened with age. Very few saw a geneticist as adults. The survey recommends that long-term involvement with geneticists and adult education primary care providers may help with many of the challenges facing adults with RTS and their families. On the topic of communication, 41% of RTS adults were found to be conversational; the remaining 56% weren't (they communicated using short phrases (33%), single words (3%), signing (12%), words and signs (5%) or speech-assisted devices (3%)). I notice that 3% of this population are unaccounted for.

Biology

1995: Fred Petrij and colleagues show that RTS is caused by mutations in the CREBBP gene. Remember that chromosomes come in pairs, half from the mother and half from the father; the same applies to genes. Petrij proposes that RTS is caused by the loss of function in one half of the CREBBP gene (a haplo-insufficiency mechanism). They note that although the EP300 gene is functionally similar to CREBBP, it is incapable of compensating for the CREBBP haplo-insufficiency.

1999: Yuichi Oike and colleagues genetically engineer mice with a insertional mutation in the Crebbp gene. They find the mice develop RTS symptoms: slow body and bone growth, underdeveloped jaw bones with a narrow palate, heart problems, skeletal defects and long-term memory deficit; short-term memory appears normal. The RTS symptoms are thought to be caused by the inhibiting effect of the truncated Crebbp gene (a dominant-negative mechanism). 

2004: Edward Korzus, Michael Rosenfeld and Mark Mayford remind us that the transcription coactivator CREBBP together with the transcription factor CREB work together to control gene expression. But CREBBP is also an histone acetyltransferase (HAT) and it can acetylate (switch on) histones in neurons. By engineering mice with a Crebbp gene that blocks HAT activity in adults, they managed to show that Crebbp is an active component in memory formation. They found that the new gene caused long-term memory deficit without affecting new information or short-term memory. This establishes that HAT activity is critical for forming long-term memory. The effect in the mice was reversed by administering a histone deacetylase (HDAC) inhibitor called Trichostatin A (TSA). 

Princess Maria of Sodor

2005: Jeroen Roelfsema, Raoul Hennekam and their colleagues show that mutations in the EP300 gene causes RTS in humans.

2005: Barbara Monti and colleagues show that repeated (sub-chronic) doses of Rolipram to rats enhances memory retention and slows down extinction of conditioned fear.

2008: K Rutten and colleagues administer repeated (sub-chronic) doses of Rolipram to rats and demonstrate that long-term memory is improved. 

2010: O Bartsch and colleagues studied two families with inherited RTS traits. Their findings confirm that the HAT domain is crucial to RTS and that variable expression and somatic mosaicism contribute to the observable differences in RTS.

2010: Guiquan Chen and colleagues show that in mice the Crebbp protein plays a crucial role in the formation of short-term memory as well as long-term memory, object-recognition memory, spatial learning and spatial memory.

2012: J P Lopez-Atalaya and colleagues show that RTS is caused in humans by a deficit in the acetylation of the H2A and H2B histones. Interestingly, the deficit is reversed by treatment of human cells with a histone deacetylase (HDAC) inhibitor called Trichostatin A (TSA) but unfortunately this has noxious side-effects on humans. Epigenetic drugs (epi-drugs) like Trichostatin A are currently being tested by the pharmaceutical industry for the treatment of cancer and brain disease. A spin-off of this research might provide a treatment for RTS. 

2015: Hee Jeong Yoo and colleagues describe a young Korean girl with RTS and ASD (Autism Spectrum Disorder) whose condition was studied using Whole Exome Sequencing (WES). They found not only a de novo (non-inherited) frameshift mutation in the CREBBP gene but also de novo missense mutations in the TNC gene on chromosome 9 and the IGFALS gene on chromosome 16. They suggest the TNC gene is responsible for the neurological characteristics of RTS and the IGFALS gene is responsible for growth retardation in RTS.

Psychology

2004: Elizabeth Kay-Raining Bird and colleagues studied children with Down Syndrome (DS) and  found they were capable of learning two languages without any detrimental effects, although individuals were variable in abilities.

2007: Elizabeth Kay-Raining Bird writes more extensively to include children with intellectual disabilities learning two or more languages. She gives some positive and encouraging advice. [So, if you're from an RTS family that needs to speak several languages then go for it. In my experience, having been brought up speaking Polish first then English, I see my knowledge of these two languages as a continuum; depending on who I'm talking to, I'll pick words from one or both languages].  

2009:  S Carvey and B May Bernhardt studied communication in a 4-year old RTS child. The child made 6 communicative acts per minute. Commenting was the most common type of act, followed by requesting and then expressing feelings and attitudes. Vocalisation (making noises) was the most common mode of communication, followed by emerging linguistic skills (signs, single word verbalisation). The recommended intervention is parent training together with speech & language therapy focussing on early lexical and phonological development. Communication could be helped by modelling and encouraging communication in situations where communication is little used (e.g. during mealtime or during play or reading a book). Puzzle-playing and book-reading might be structured to encourage more child initiations and  fewer adult questions.

2012: Jane Waite examines in her thesis the relationship between executive function development and repetitive behaviour in RTS. Incidentally, Waite also defines a relationship between the mental age (MA) of an RTS child and the chronological age (CA):   

MA = 0.27 * CA + 4.18. For example, this formula predicts that Maria, aged 63 months (CA) to date has an approximate mental age of 21 months (MA). To validate this figure I looked at Maria's SEN Annual Review just released by her special school. My problem is which figure in the Early Years Foundation Stage (EYFS) review should I take as representative of her mental age (MA)? Is it the "Communication and Language" figure of 16-26 months for "Speaking" or is it 30-50 months for both "Understanding" and "Listening and attention"? Maybe I should be looking elsewhere at the "Personal, Social and Emotional Development" figure of 22-36 months for "Making relationships" or perhaps 30-50 months for both "Self-confidence and self-awareness" and for "Managing feelings and behaviour"? Are we asking too much to believe that just one number can represent all dimensions of our daughter Maria?

Education

1999: Shari Brand Robertson and Susan Ellis Weismer studied late-talking but otherwise normal toddlers. At the time this paper was written, clinical management of late-talking toddlers was unclear. The paper describes two schools of thought on how to tackle language delay: the "early intervention" and the "wait-and-see" approaches. This study tested the "early intervention" approach on several linguistic and social skills. They found their intervention not only improved language skills but also social skills as well as parental perception, which implied lower parental stress. 

2002: Paul J Yoder and Steven F Warren studied children with intellectual disabilities who cannot yet speak (prelinguistic). They applied a technique called 'Responsivity education for the parents and Prelinguistic Milieu Teaching for the children' (RPMT or RE/PMT). Milieu Teaching (MT) targets verbal communicative acts whereas Prelinguistic Milieu Teaching (PMT) targets non-verbal communicative acts (e.g. gestures, vocalisations, eye-contact). Responsivity Education (RE) targets parents participation in responding to children's communication acts. The results showed that child-initiated comments increased for some children but not for others. The authors recommend linguistic goals for communicative children and prelinguistic goals for non-communicative children.

2006: Marc E Fey, Paul J Yoder, Steven F Warren and colleagues studied children with developmental delays using Responsivity Education/Prelinguistic Milieu Teaching (RE/PMT or RPMT). The effects of RE/PMT on children with Down Syndrome found statistically insignificant improvements in overall communication. The study found no differences in parental stress levels. [Although not directly related to RTS, the three papers in this section together with the papers in the previous section should provide useful insights for your child's Speech & Language Therapist/Pathologist. And don't forget that sign language is another language]. 

Language

2007: Elizabeth Kay-Raining Bird reviews the literature on typical monolingual and bilingual child development compared with bilingual language-impaired children with and without intellectual disabilities (ID) but focussing on Down Syndrome (DS). The research finds that typical children can learn two languages at the same time (simultaneous bilingualism), even at preschool, provided the learning is intensive; there may even be cognitive advantages in doing so. It is normal for both languages to be used in a single utterance. The research is less clear about the effects of learning one language after another (sequential bilingualism) but the author guesses that the results are likely to be similar to simultaneous bilingualism. The author then tries to apply this research to children with ID and DS and concludes that 'it seems appropriate to stop thinking in terms of restricting children with language and intellectual disabilities to a single language and to focus on learning how to best support them in all the languages they need to know. To this end, further research is critical'. I'm therefore optimistic that Maria will learn both English and BSL languages and will then have a choice of which to communicate with when she is older, whether it be English, BSL or Makaton in SSE mode.

Latest Research and Trials

Call that a 'grimace'?

The latest EU and US clinical trials can be found via the following links:
OrphaNet (EU)
Clinical Trials (US)
Clinical Trials (Worldwide)

The latest EU licensed pharmaceutical (orphan) drugs can be found here:
OrphaNet (EU)
OrphaNews  (EU)

I've been warned by a bioethicist that clinical trials are not always conducted as ethically as you might expect in the UK. I have a healthy scepticism of new research and I've promised myself to research the researchers and carefully read the waivers on their contracts before permitting Maria to participate in a clinical trial. If in doubt, I'd probably get some legal advice.

In reality this is a tough choice: I want to help RTS research but on the other hand I don't want Maria harmed by an experimental drug. By the same token I don't want these same risks taken by any other individuals either, so that leads to a bit of a stalemate. 

The only way around this is to be rational and understand a bit more about how the research field works. Although there are no specific RTS videos on this topic, there is an excellent summary of the whole field of research from the perspective of Rett Syndrome (RTT) given by Monica Coenraads of the Rett Syndrome Research Trust (RSRT). If you have a spare hour then this will bring you up to speed; so many of the issues in RTT parallel those found in RTS. The video is called 'Curing Rett Syndrome: How Do We Get There?'; just click on the title. 

Genetics, Epigenetics and RTS

When I think of genetics, I usually think of the process of creating proteins from genes; but that's not the whole story. The environment interacts with proteins and genes to determine what finally happens in our bodies. Studying environmental influences on genetics is called "epigenetics" and is the state-of-the-art in biological research today. Our biggest hope of eradicating cancer and RTS lies mainly with epigenetics. 

To create a protein from a gene, the gene needs to be expressed (switched on) to become active and later silenced (switched off). Expressing a gene occurs by a process called "acetylation" and silencing the gene occurs by the reverse process of "deacetylation". Now, acetylation is performed by a family of proteins called histone acetyltransferases (HAT); deacetylation is performed by another family of proteins called histone deacetylases (HDAC).  

To create a protein then we need to acetylate (switch on) the gene first. The acetylated parts of the "gene" are actually the H2A and H2B histones of the nucleosome. This allows gene expression to commence, resulting in the manufacture of the corresponding protein.

Two important members of the HAT family are the CREBBP and EP300 proteins,  manufactured from the correspondingly named genes. Any malfunction in these two genes will cause problems in the process of creating many of the body's proteins. And guess what? These are the very same genes associated with RTS. RTS is usually caused by a malfunction (due to mutation) of the CREBBP or EP300 genes. Approximately 63% of people with RTS have a mutation in one of these two genes. 

So there you are.  A fairly detailed explanation of what probably causes RTS in your child. How does that help? 

From a day-to-day perspective, not much. But it's worth keeping an eye open for new clinical trials or drugs that might help alleviate the symptoms of RTS. I've included some links in the panel on the right to important sites that will inform you of new developments; particularly OrphaNews and Clinical Trials (US).

What causes RTS?

Once you've looked-up the symptoms of RTS, it's natural to ask what causes it. About one birth in every 100,000 has RTS. The European Commission defines a "rare disease" as a 1 in 2000 event, making RTS very rare. Little wonder the professionals don't seem to know much about it.

RTS is a genetic condition. We all have 23 pairs of chromosomes in all the cells of our body (excepting sperm and egg cells); half of each pair comes from your mother and half from your father. 

Each chromosome is made of chromatin, which looks like a string of beads: the string represents DNA and the beads represent nucleosomes. 

DNA (left), Chromatin (right)

Each nucleosome comprises a group of four histone protein pairs named: H2A, H2B, H3 and H4. The DNA winds twice around a nucleosome, gets 'fastened' by a H1 histone and then moves on to the next nucleosome.  

Nucleosome

The DNA of each chromosome is partitioned into genes - hundreds of them on each chromosome. Each gene encodes a unique sequence of amino acids which, in turn, define a specific protein in the cell. Our chromosomes contain about 26,000 genes, giving us a potential library of tens of thousands of proteins - each performing a special, often crucial, function. 

To be able to use a gene it needs to be switched-on or "expressed". This is done by unwinding the chromatin "string of beads", as shown in the middle of the Chromatin diagram above. When the beads are clumped together, as on the right of the diagram, the gene is made inaccessible and effectively switched-off or "silenced".

Usually, RTS is caused by the random mutation of one gene on a chromosome. About 60% of RTS cases are because the CREBBP gene on chromosome 16 mutates; about 3% of RTS cases are because the EP300 gene on chromosome 22 mutates. That leaves 37% of RTS cases for which the cause is, as yet, unknown. Clearly scientists need to do a bit more work before they understand the whole picture. 

Another cause of RTS is through family inheritance. If Maria were ever to have children with a non-RTS father, there'd be a 50% chance the offspring would have RTS. If the father had RTS then there'd be a 75% chance their children would have RTS. Even though RTS families are very rare, it made me wonder how Maria would feel about having children when she's an adult.

The more you learn about genetics, the more you discover that mutations are not uncommon. Some genetic mutations go unnoticed from birth but some, like mutations in the CREBBP gene, have a significant impact on the child because they affect several important body functions. 

Random mutations are just that, random. That means it's not my fault, it's not Joan's fault and it's certainly not Maria's fault that this arbitrary thing happened. It would be irrational to blame ourselves for the fact that Maria has RTS; doing that would be like blaming ourselves for not winning the Lottery. If I needed to blame something then its got to be God, or chance. Either way I'd be failing to appreciate the wonderful gift that chance or God has given us. Maria can't be helped by blame; she thrives when she's loved, and love is a potent epigenetic factor.

When a baby's born, the results are always a bit of a gamble: it may be a boy instead of a girl; it may look like your partner instead of you. Most of us expect these differences and accept them. We're surprised only when something unexpected happens. This can turn to shock when the unexpected becomes the unwanted; nobody wants a child to have RTS. 

For me, the shock was realising that Maria had a syndrome I knew nothing about and, as a consequence, she might never be "normal". I wondered which of the list of possible RTS symptoms Maria would potentially develop. 

But sometimes it just doesn't pay to be over-analytical. At present, Maria is actually quite fit medically. She's a very happy child (when she's not fighting with her sister) and has a great sense of empathy and humour. She loves to dance and sing. She's a walking dictionary of sign language (Makaton) and is slowly learning to speak. She's beautiful, both inside and out; and despite all the implications of the term "mental retardation", she's actually very clever. What more could you ask of a five year old child?

I always like to remind myself that if computer scientists were able to build a computer as "intelligent" as Maria, they'd be hailing it as probably the greatest breakthrough in engineering history. Unfortunately they can't. Neither can the medics and biologists model how the brain works to create intelligence and consciousness. The fact is, something astonishing happens in Maria's head that still defies description by our brightest minds. 

When that wonderful day comes - when scientists find a way to counter the effect of the CREBBP or EP300 mutation - chances are they won't know how it works on the brain. Nevertheless, I'll be one of the first to praise the wonders of science, even though we might be none-the-wiser about the nature of intelligence.