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and her colleagues did indeed find that theEHMT1 gene in the middle of the 9q34.3region was disrupted. Then in the late1990s the first studies appeared showingthat the telomeres (ends) not only ofchromosome 9 but of many otherchromosomes are important in the cause of intellectual disability and thatrearrangements such as deletions in thesubtelomere regions of chromosomes cause a significant number of cases of intellectual

disability. One girl whose picture was published(far left) was one of the first childrenrecorded as having a 9q subtelomeredeletion. Later, more children werereported, like the two sisters (left) whoboth have a small 9q subtelomere deletion.Dr Kleefstra and her colleagueshypothesised that the EHMT1 gene wascausing the major abnormalities seen inthese children. So they searched for otherswith the same clinical features seen inchildren with a 9q deletion but who werereported as having normal chromosomestudies. In the first instance they found twochildren, a boy (above) and a girl (overleaf).Both had an intellectual disability as well ashypotonia (low muscle tone), a small headcircumference, delay in speech and motordevelopment and some recognisable facialfeatures. In both children Dr Kleefstra and hercolleagues found a disturbance (mutation) of

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From 16–18 April 2010, Unique hosted the first ever meeting of families,geneticists and scientists spearheading research into Kleefstra syndrome –earlier known as 9q34.3 deletion syndrome. The meeting in Coventry,United Kingdom coincided with a flight ban due to ash from a volcano inIceland, so Dr Tjitske Kleefstra and Dr Hans van Bokhoven gave theirtalks remotely. Dr Kleefstra also held 1:1 clinics remotely with families.

Kleefstrasyndrome

The story of Kleefstra syndrome: Dr Tjitske Kleefstra

Dr Kleefstra is aclinical geneticist atthe Department ofHuman Genetics,Radboud UniversityNijmegen MedicalCentre, theNetherlands, afterwhom the syndromeearlier known as9q34.3 deletion

syndrome, 9q- syndrome or 9q subtelomericdeletion syndrome, is now named.

She said how proud she was to open the day.You pronounce her first and family names,which derive from Friesland, north Holland,‘Chitsker Clayfstrer’.

Dr Kleefstra’s interest in the syndrome arose in 1999 when she met in clinic a girl with athen unexplained intellectual disability andfound that she was carrying a so-calledtranslocation between chromosomes X and 9. She was interested in the break points of this translocation because she and hercolleagues hypothesised that genes at the break points might be disrupted. Dr Kleefstra

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the EHMT1 gene: the children had a disruptionof only one base pair of one of the buildingblocks of DNA instead of an entire 9qdeletion. This study confirmed that the EHMT1gene was very important in causing the clinicalfeatures of the 9q deletion syndrome.

reported using FISH where there was noapparent 9q deletion but in fact while theregion targeted by FISH was intact, the regionincluding the EHMT1 gene was deleted, makingwhat is known as an interstitial deletion.

Studies todayChromosomal studies are hardly performedunder a microscope any more but instead usingmicroarrays, which allow one to identify muchmore and to pinpoint more exactly thelocation of the deletion.

Nijmegen databaseAt present on the database atNijmegen there are 17 patients with adisturbance (mutation) of EHMT1 and30 patients with a deletion thatencompasses at least EHMT1 or a partof EHMT1 and one other gene.Comparing the features in both groups,Dr Kleefstra and her colleagues see fewdifferences. Among individuals withEHMT1 mutations, there are differencesin the level of development andadditional congenital anomalies and thisis also true for those with deletions.

Major features in both groups includeintellectual disability, hypotonia andcharacteristic facial features. Remarkably,almost half of the babies in the EHMT1mutation group were born with a high

birth weight. Half of them also have childhoodobesity. Other features – microcephaly (smallhead), heart defects, seizures, genital defects inmales, gastro oesophageal reflux and urinaryreflux – seem to be found equally in bothgroups. At the moment, the clinicalconsequences of EHMT1 mutations anddeletions including EHMT1 seemindistinguishable.

The future? The nextquestionnaire…When Dr Kleefstra and her colleagues startedin 1999 they didn’t even know that the EHMT1mutation existed. Now they know a lot morebut many questions remain. Why do somechildren with the same genetic defect developbetter than others? What about theirbehaviour? What about additional clinicalfeatures? Why do some have heart defects,others not? Why do some develop epilepsyand others not? With a lot of reports thatchildren are prone to infection, what aboutimmune system defects? What aboutprogression into adolescence and adulthood?

Brian Foley, a parent of a child with a 9qdeletion, has drawn up an extensivequestionnaire. For your own copy, emailb.foley1@ntlworld.com, call +28 9087 8847or write to Brian and Eileen Foley, 50 Somerton Road, Belfast, Northern Ireland BT15 3LG.

Finally Dr Kleefstra pointed out that a child isalso a mix of their mother and father and somefeatures are just not related to the 9q deletion.She offered to help any family with a child witha 9q deletion or EHMT1 mutation and pointedout the ways to contact her : through theKleefstra syndrome website; on Facebook; orbest by email.Tjitske Kleefstra849 Department of Human GeneticsPO Box 9101, 6500 HB NijmegenThe Netherlandst.kleefstra@antrg.umcn.nl

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Two strands of DNA are held together in the shape of a double helix by the bonds

between base pairs.

Base pairs

Later they identified more children, all withfacial similarities which parents might recognisein their own children. EHMT1 is just one genein the 9q34.3 region (above right). There aremany more and deletion sizes in individualchildren range from very small, encompassingonly EHMT1, to a lot bigger, including moregenes. At the moment, what the other genescontribute to the clinical features is still amatter of investigation.

Past studiesChromosomal studies in the past were largelydone by FISH analysis. Many cases were

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Modeling the 9q34deletion syndrome: Dr Hans van Bokhoven

Hans van Bokhovenis professor andleader of theMolecularNeurogeneticsresearch unit atRadboud UniversityNijmegen MedicalCentre, TheNetherlands.

Dr van Bokhoven is studying Kleefstrasyndrome using animals such as the Drosophilafruit fly and mice, hoping to gain more insightinto the biological mechanisms around theEHMT1 gene. He uses animals because theyallow him to do research that would beimpossible in humans and afford him insightsinto biological processes like organdevelopment that aren’t obtainable in humans.Animals also let him study the role of certaingenes and proteins like EHMT1 in the contextof a complete organism. Using animals alsoallows disease models to be created, with along-term aim of developing therapeuticinterventions. But this of course is a long wayoff.

Humans have about 20,000 genes. Surprisingly,the mouse has a remarkably similar set of20,000 genes, many essentially the same ashuman genes. Even the fruit fly is very similar,so many genes that humans have are also seenin fruit flies.

What does the EHMT1 genedo?What are genes? Genes contain instructions fordevelopment and function which are translatedinto the actual function in a two-step process.

First, DNA is transcribed into a molecule calledRNA. From the RNA, proteins are made whichare the working units of our bodies. So theDNA and genes contain the instructions butthe proteins do the real work. One of thesegenes and proteins is EHMT1, which isdisrupted in Kleefstra syndrome. Ourknowledge is still superficial but as far as weknow the function of EHMT1 protein is tocondense the DNA, making it inaccessible toother proteins. Thus, this protein suppresses theactivity of other genes by preventing thesynthesis of RNA and proteins (below left).

Dr van Bokhoven and his colleagues are tryingto identify the role of EHMT1 in the nervoussystem and in early development and discoverhow mutations in the gene cause Kleefstrasyndrome.

Researchers Dr Annette Schenck and Dr JamieKramer have studied what EHMT1 does in thefruit fly. With an inactivated (mutated) EHMT1gene, the fruit fly developed the equivalent ofKleefstra syndrome. Its brain cells (neurons)contained no EHMT1 protein. What was theeffect?

Abnormal brain cell networksin fliesIn many respects the neurons in the fly withthe mutation look the same as in a normal fly,except for the expected network of branches(dendrites). These dendrites are used forcommunication between brain cells and areneeded for learning and memory. WhenEHMT1 is missing, the network of connexionsappears to be disrupted (below).

Similar changes in the neuronal networks havebeen observed in many other similar humansyndromes where intellectual disability iscommon, such as Fragile X or Downsyndrome. The question is: Does the abnormaldendrite structure contribute to the intellectual

disability? After a lot of

assays in the Drosophila fruit fly, the answerseems to be ‘Yes’.

What about the future?In future the researchers want to expand themolecular mechanisms that result in theabnormal dendrite structure. They will theninvestigate whether they can influence thesemechanisms. Can they repair the abnormalities?They could for example use drugs to return amutant fruit fly to normal. But this has not yetbeen tried.

And in mice?Dr van Bokhoven is also looking at the mouse,a mammal whose body closely resembles theshape and function of our own. A mouse has

been created with an Ehmt1mutation that resembles themutation in people with Kleefstrasyndrome.

Many investigations into thebehaviour of mice, including learningand memory, have concluded thatmice have behavioural features thatresemble humans. For example,autistic-like features are seen in themutant animals. Learning and memoryperformance and the brain anatomy ofthe Ehmt1 mutant mouse is currentlybeing studied to see whether themutant mice resemble also in thisrespect the brain phenotype of thehuman syndrome.

Dr van Bokhoven and his group have alsolooked at the skull and brain shape inEhmt1 mutant mice. Although a mouse

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looks very different from a human, thedevelopment and architecture of its skull aremuch the same. They compared non-mutatedmouse skulls with Ehmt1 mutated mice,measuring the length of the skull, its width andthe distance between the eye sockets – andfound several differences.

The Ehmt1 mutated mice have a shorter, widerskull, resembling the head shape seen inKleefstra syndrome and known medically asbrachycephaly. They also have a shorter nasallength, reflecting the short nose seen in manypeople with Kleefstra syndrome. In addition theeye sockets are further apart than normal(hypertelorism) just as in Kleefstra syndrome. Inthese respects the human phenotype seems tobe mirrored in the mouse.

In summarySo why are Dr van Bokhoven and his groupstudying Kleefstra syndrome in animals? Theyhave fly and mouse models of Kleefstrasyndrome that share several aspects of thehuman condition. They now want to learnmore about the biology of EHMT1 protein in awhole organism. Very likely they will learnabout other molecules that interact withEHMT1 protein or are regulated by it and thismay reveal that these molecules are involved insyndromes resembling Kleefstra syndrome. Thiscould open up possibilities for diagnostic testingin these other syndromes.

The researchers’ ultimate goal is to developtherapies. Although it will not be possible tocure Kleefstra syndrome completely, they cantry to find drugs and compounds to alleviatesome of the symptoms.

Question TimeHvB = Dr Hans van Bokhoven

Cytogenetic andmolecular analysis inpeople with 9q34.3microdeletion syndrome:Dr Svetlana Yatsenko

Dr Yatsenko, aformer researchassociate at Baylor College of Medicine,Houston, Texas, USA has a specialinterest in 9q34.3deletions.interest in 9q34.3 deletions.

Q Would any therapy have to beapplied at a particular stage ofdevelopment?

HvB It would be very difficult if notimpossible to apply therapy to curethe condition completely because it isa developmental condition that hasalready affected the very earlydevelopment of the human embryoand fetus. But we can hope to finddrugs that improve the quality of lifefor young children at a later stage,symptoms like the epilepsy or otherfeatures that go with the conditionand for now are impossible to treat.

Dr Yatsenko introduced chromosomes,explaining that while the end of a chromosome(telomere) is just a protective cap, the regionjust before the end (subtelomere) containsunique information and genes. Most deletionsvisible under a microscope occur at the ends ofchromosomes: about 70 per cent of childrenwith a chromosomal condition have a deletion,duplication or translocation at the end of achromosome. Around one newborn baby in5000 has a terminal deletion of onechromosome or another, so it’s notuncommon. Subtelomeres have a very largegene content so rearrangements are likely tohave an impact. Many recognisable geneticsyndromes result from subtelomeric deletions(below).

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29 patients studiedDr Yatsenko’s team has studied 29 patientsusing these arrays. Broadly speaking, they havefound four types of deletion:

1. Terminal deletions of different sizes. Onlythree patients studied have the same sizedeletion, suggesting in these cases that theDNA there may have some feature thatpredisposes it to break. The team is nowstudying if any DNA assembly there hasdifficulties repairing itself, perhapscontributing to the chromosome breakingthere more commonly than elsewhere.

2. Interstitial deletions of different sizes, butencompassing part or all of the EHMT1gene.

3. Complex rearrangements, with doubledeletions or extra duplications ortriplications.

4. Derivative chromosomes with both adeletion from 9q and a duplication fromanother chromosome arm, either inheritedfrom a parent or as a new (de novo)occurrence.

Overall terminal deletions account for 50 percent of the patients studied. Interstitial deletionsand other rearrangements account for theother 50 per cent. Apart from some largetranslocations, none of those would bedetected on a conventional chromosome test(above).

Differences if the deletion ison the chromosome 9 fromthe mother or father?Dr Yatsenko’s team have found that 62 percent of the deletions occurred on thechromosome that came from the father.Rearrangements on the paternal chromosomewere usually small. In contrast, the 38 per centof rearrangements on the chromosome fromthe mother were usually big. They found nodifferences between the children when the

deletion was on the maternal or the paternalchromosome and concluded that all childrenwill probably be affected similarly regardless ofthe origin of chromosome.

In summaryRearrangements of 9q are frequentchromosome disorders. Deletions from nearthe end of 9q are small: Dr Yatsenko’s teamfound none larger than 4 Mb (1Mb ormegabase is one million base pairs),although much larger deletions are foundon other chromosomes. They cannot yetexplain why this is the case. There is noobvious region where they see consistentbreaks, unlike in other chromosomedisorders where there are hotspots forbreakage. In any case of 9q34.3 deletion,

array CGH analysis should be considered notonly to define the deletion size but also to pickup any complex rearrangements that may bemaking a difference.

Next directionsOne of Dr Yatsenko and her colleagues’ furtheraims is to match the phenotype with the sizeof the deletion. The 9q34.3 region is particularlyrich in genes and using array CGH they cancompare the clinical features between thechildren and see if there are genes other thanEHMT1 that are playing a role.

Dr Yatsenko’s email addresssayatsenko@gmail.com

Behaviour in 9q34deletion syndrome:Professor Chris Oliver

Chris Oliver isProfessor ofNeurodevelopmentalDisorders at theUniversity ofBirmingham andDirector of theCerebra Centre forNeurodevelopmentalDisorders.

Professor Oliver’s team is interested in thebehavioural phenotypes of chromosomal andgenetic disorders and researcher TraceyGrandfield is studying the behaviour of peoplewith 9q34 deletions. Professor Oliver warnedagainst treating everyone with a particulardisorder the same: not only is each childunique, but children with 9q34 deletions have alot in common with other children.

Genetics and behaviourGenes affect behaviour in a less obviouslydirect way than they affect, for example,appearance. There probably isn’t a gene for aparticular behaviour, any more than there is a

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Kleefstra syndromeUsing chromosome (cytogenetic) analysis, it’s difficult even for a good technologist toprecisely define some abnormalities, including in the 9q34.3 subtelomere region. For more precise definition, molecular analysis is needed. This is probably why the 9q microdeletion syndrome went unrecognised for many years. Even today many people remain undiagnosed becauseidentifying the deletion is so difficult.

Much remains unknown: it’s unknown howcommon the 9q microdeletion syndrome is. It’sunknown if there is a correlation between thephenotype and the deletion size. But otherthings are known: such as whether the deletionis on the mother’s or the father’s chromosome.Some reasons why the chromosome becamedeleted are also known.

People have different types of deletion. One isa simple terminal deletion when onechromosome 9 breaks and the chromosomeend heals with a new telomere. Another iswhen there are two breaks in the chromosomeand the ends fuse, giving an interstitial deletion.Interstitial deletions can be missed by asubtelomere FISH study because the probe islocated close to the telomere but not in thedeleted region. Another possibility is when atranslocation between chromosome 9 andanother chromosome occurs in a parent. Theparent would have no signs of abnormalities –but when a child is conceived, the child canhave a deletion from chromosome 9 and anextra part of the other chromosome. A similarprocess can happen without a parentaltranslocation: a deletion occurs, then thechromosome needs an end but instead ofsynthesising a new telomere, it attaches a partof another chromosome containing a telomere.That creates the same situation as in a parentaltranslocation but this type of translocation iscalled de novo. Many other complexrearrangements can also occur.

Ultra high resolution arrayCGHArray CGH gives a much more preciselydefined deletion size: a high resolution arraycan define where breaks happen and whichgene or genes are affected. Some arrays havegaps so array results sometimes give maximumand minimum deletion sizes, the minimumshowing the probes that are definitely deletedand the maximum showing the probes thatmay be deleted.

Dr Yatsenko’s team has designed a highresolution array covering the end of 9q andother subtelomeric regions. The array contains44,000 probes just for the 9q region, with 2–3probes per one kilobase (1000 base pairs). Sothis array can define a deletion with a precisionof about 400 base pairs. This has revealed manyunpredicted events and some complexrearrangements.

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particular part of the brain associated with aparticular behaviour, but if genes contain codedinstructions for development, then the codehas to be complete and in the right order. Ifsome of the code is missing, the developmentof the nervous system and the connectionsbetween the brain cells that underlie behaviourwill be disrupted.

9q34 surveyProfessor Oliver has sent out a 9q34 deletionbehaviour survey. Early results from the first 15responses give a snapshot of the syndromethat allows it to be compared with othergenetic syndromes to understand features thatare shared and features that are unique to9q34. About 4/10 of the children have whatcan be thought of as autism – but autism ingenetic syndromes is not always the same asautism in other contexts, perhaps particularly inpeople with 9q34 who have a surprisingly highlevel of sociability, above all other syndromes(below). This level of sociability isn’t seen inautistic spectrum disorders. Indiscriminatesociability can be a problem in more ablepeople because it makes them more vulnerableto exploitation. In 9q34, strategies that help inbetter characterised syndromes like Angelmansyndrome (also with a high level of sociability)could also help people with 9q34.

About 4/10 show some form of self injury,compared with only about a quarter of peoplewith an intellectual disability generally, andnearly two thirds show aggression – a highlevel. Pain is associated with self injury: amongtypically developing children, around 1.5/10headbang, about half of whom have a middleear infection. So Professor Oliver suggestedthat families are alert to signs of ‘hidden’ pain,especially gastrointestinal reflux, reported byabout half the families. Once reflux in a childwith Cornelia de Lange syndrome was treated,her self injury plummeted: she was a lothappier. Reflux, tooth decay and middle earinfection go together, Professor Oliver pointedout, because reflux contains acid which erodestooth enamel causing decay.

Forty per cent of families said their child had

gastrointestinal problems but Professor Oliverwondered if there might be moreunrecognised problems. How does someonewith a severe disability and poorcommunication let you know they are in pain?Many of the behaviours that familiesreported in the survey could be associatedwith reflux, such as tooth grinding (in 7/15),chewing on clothes, drinking excessively orconstantly growling. In Cornelia de Lange,children with reflux drink a lot in themorning, perhaps to wash away the painand irritation built up by reflux overnight.Other behaviours to watch for includesleeping sitting or propped up andfrequent night waking. These behavioursshould prompt families to consult agastrointestinal specialist.

Every child also has their own ‘pain signature’,identifiable following the acronym FLACC.F = Facial expression, usually two lines down

the middle of the forehead, a sign of painacross all cultures

L = Legs tend to moveA = Active – children don’t stay stillC = CryingC = Consolability – you usually can’t console

them

Learned behaviourThe most important thing about any problembehaviour is how it makes other peoplerespond. Self injury or aggression can become alearned behaviour because it’s often rewarded,albeit unintentionally, with increased attention.This can act as a positive reward, making thebehaviour more likely to be repeated.Speculatively, attention may be particularlyimportant for sociable children with 9q34.Alternatively, faced with a child who showschallenging behaviour when asked to dosomething they don’t want to, the adult maystop making that demand. This too is a reward.Both situations can create a learning trap, withan increase in the behaviour over a two yearperiod.

So parents need to be aware of how theyrespond. Faced with problem behaviours,

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Professor Oliver suggested that parents play fortime by thinking ‘One two, what should I do?’Does it need a big row and lots of eye contactor a very cool response without muchattention? If parents choose to ignore thebehaviour, they need to be aware that the earlystages of ignoring behaviours increase thebehaviour in what is known as an ‘extinctionburst’. Responding then merely teaches thechild to ‘ratchet it up a bit’ to get the responsethey desire.

Behaviour as communicationA typically developing child has a wide range ofcommunication strategies but a child with alearning or physical disability has a smallerrepertoire and may resort to some really trickybehaviours to convey messages. Functionalcommunication training (available via clinicalpsychology) and applied behavioural analysisshow very good evidence that they can help.Using this approach and giving children thecapacity to control their immediateenvironment, Professor Oliver’s team hasshown a decrease in aggression and a rise infunctional communication in six children withAngelman syndrome, showing that children canunlearn one (problematic) behaviour and learnanother (acceptable) one.

In summaryThere’s variability, of course, betweenindividuals. Professor Oliver remainedunconvinced that 9q34 is best thought of as anautism spectrum disorder. Some behaviours inpeople with 9q34 may look like autism butthey have a different derivation and need to bebetter understood. He recommended thatfamilies resolve any health problems first.Clinical psychology and applied behaviouranalysis may both be helpful. And effectivecommunication systems are really important.

‘Finally, in trying to lobby for your children chainyourself to the doctor’s desk and refuse toleave until you’ve got a bit further. Speak softlybut carry that big stick.’

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Question TimeCO = Professor Chris OliverHM = Hélène MilesSA = Simon AshbyES = Dr Eugen StrehleSY = Dr Svetlana Yatsenko

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Biting

Q How do you discourage a child frombiting and once they have bitten, howdo you release their jaws?

CO When people are fighting, typically youtry to separate them, which is never agood idea. You actually push againstand keep everything exactly where it isuntil eventually they let go. As for theunderlying frustration, there are usuallytwo reasons. One is impulsivity. You can’twait, so if you are asked to wait or todo something you don’t want to, thatappears to be a bit of a trigger. Back ofthe hand biting is not uncommonacross people with a severe disabilityunder those circumstances.

We would first say: are there situationswhere we can reliably trigger thatbehaviour? Then we would decide whatwe would rather the child did in thatsituation. Then we’d set situations upand encourage the alternative responseand reward it heavily, artificially initiallybut fading with time.

HM We’d also look at the child’s sensoryneeds. What is the child withoutcommunication getting out of biting?Children with a learning disabilityreceive and process stimulation verydifferently. The pressure may be quitenice and we wouldn’t want to stop aneed to bite. We’d maybe incorporatesome sensory experiences throughoutthe day, some calming strategies,maybe some deep pressure-typemassage and activities – and make theneed to get something out of the deepchewing and biting more appropriate.We also use things like chewy sticks orfirm dog toys.

SA If ever he manages to communicate hisfrustration in an appropriate way, it’salso validating that communication andrewarding it heavily.

Self stimulation

Q The nicest way to put this is my daughter does self-stimulating. It can be so extreme, itlooks as if she’s fitting. When she’s unwell it gets excessive and she can be quite aggressiveif you don’t let her. Sometimes it can get excessive when she’s tired and can’t sleep. While Idon’t mind if she does it around sleep time, it upsets me when it’s intense.

HM It’s not uncommon. We’ve found we need to work on it early because the longer it goes on,the more entrenched it becomes and the more difficult to break. If you can intervene andredirect the behaviour, that’s fine. If your child gets really distressed when you do that, thebehaviour is quite entrenched. It is sensory; it starts off as a sensory need but when the childrealises the behaviour is quite nice, it then can become entrenched. If you try to redirect heronce it gets into that intense stage, then you’ll get aggression. Looking at the socialenvironment, it’s also giving the message that it’s not OK to do it in front of other people. Assoon as the child can differentiate, they can learn that they can only do it in the bedroom orin the bathroom.

Parent We’ve had a couple of strategies that worked at school where they say ‘Hands on knees’.We haven’t tried to stop it at home, but she knows it’s a private thing, not to be done infront of others and she goes upstairs and closes the door.

HM At 3½ it’s still easy to move her and as she grows up she will make the association that it’sno on the settee but OK in my bedroom. Maybe some more sensory experiencesincorporated in her day so she’s getting the same feelings without having to self stimulate. Itmay be worth having a sensory assessment in case she has some hypersensitivity needs.She might be able to do some exercises that would give her the same feeling but not in thesame way. And try keeping a diary of when she does it. We would first check out therewasn’t any urinary infection or thrush and possibly ask the paediatrician if there are anyother physical causes.

Life expectancy

Q Are we looking at a normal life expectancy for these children?

CO We don’t know because the diagnosis is quite recent. Generally if you look at the lifeexpectancy of someone with a severe intellectual disability, it’s around 55. One wouldassume that if you have more health conditions then you are more at risk.

ES Underlying health issues like heart disease can have an effect, depending on whether it isfully corrected or not. Also children are more prone to infections perhaps because theirmuscle tone is reduced and their breathing is not so strong and they cannot cough upsecretions as easily. The chromosome disorder does not necessarily have an effect on lifeexpectancy and while the overall life expectancy for someone with a severe learningdisability may be reduced to 55, it will depend on the individual and their situation.

SY We know about four patients beyond their 40s, but that doesn’t mean that others don’texist. It’s because genetic tests are mostly done on children. We don’t know how many olderpatients there are.

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Possibilities of treatment

Q Before this weekend I worked on the assumption that having a genetic disorder was sofundamental that it wasn’t treatable but in the session this morning there was some talkabout drugs that might be able to repair neurons in the brain. Do you know how long itmight be before such a therapy is available and what the expectation might be of howsuccessful it could be?

SY Deletions can be variable in size and we know that the critical gene EHMT1 is deleted inall patients but there are additional genes that may play a role, triggering seizure disordersor other features. We have no idea yet which genes are responsible for the other features. Itis a developmental defect so you cannot reverse all the features but some of them likeseizures can be treated by knowing which gene is responsible because potentially it can beblocked at some point and the seizures prevented. Treatment can change the quality of lifefor children but it will not treat the situation or the condition.

Q I had the impression this morning that you couldn’t replace or correct the gene but mydaughter has perivascular dysplasias throughout the brain and one large lesion. It soundedas if there might be some treatment in the future to repair some of the damage. Neuronsand drug therapy was something I hadn’t considered before.

SY I would not be so positive about the early possibility of treatment, especially with neurons inthe brain. The damage is done. Research now is increasing rapidly: five years ago we had noidea about this condition and now we know the genes that cause it. I hope we will knowmuch more not only about the critical genes that are responsible, but maybe other genes aswell. A better understanding may bring ideas for treating certain things, but not all.

Toilet training

Q My son has a problem with toilettraining. I’m not sure whether it’s abehaviour problem or whether it’s alearning problem. He’s nearly 10 andwe’ve been trying since he was about5. He now holds his wee when youtry and teach him how to go to thetoilet. He also does that in times ofstress or excitement. Hispaediatrician assures us that he hasgood sensation and that it’s a goodsign that he can hold on. But heholds it to the point where he iscontorted and he must clearly be indiscomfort and will only let go whenhe is in bed. We’re at a loss as tohow to help him. We’ve spoken tocontinence advisory and ourpaediatrician.

CO It sounds as if he has rules aboutwhere he goes to the toilet andwhere he doesn’t. It sounds like oneof those things you see in peoplewith an autism spectrum disorderabout developing rules and beinganxious or in typically developingchildren about being anxious aboutgoing to the toilet in different places.You might think about it as a kind ofanxiety-related behaviour.

Q I can see that as he is getting olderthat level of noticeable anxiety isincreasing.

CO I would seek referral to clinicalpsychology via your GP because itsounds as if it’s downstream of ananxiety disorder and clinicalpsychology may be able to help intrying to understand why he hasdeveloped those particular rules.

SA We helped one autistic lad with asocial story. Essentially we gave him anew script to replace his previous setof rules and that helped.

Parent He has quite set rules for things thathappen on a day-to-day and week-to-week basis. He holds a two weektimetable in his head even for thingshe doesn’t like.

CO The general advice about changingthose rules is not to make hugechanges. People respond better to avery gradual change. I might go tothe National Autistic Society (NAS)website (www.nas.org.uk).

HM On the NAS website there are storiesthat you can download. Also there aresome brilliant books for a child whorelates to pictures. It may help toreintroduce pictorial sequences.

This report includes the presentations that werespecific to Kleefstra syndrome and families’ questions.The other speakers, whose presentations were moregeneral, were: Professor Peter Hammond, professor ofcomputational biology at the molecular medicine unitat the Institute of Child Health, University CollegeLondon, on Creating a 3D model of typical faces in 9q34deletion syndrome; Dr Eugen Strehle, consultantpaediatrician at North Tyneside General Hospital, onThe Child with a Chromosomal Disorder from aPaediatric Perspective; Hélène Miles and Simon Ashbyfrom the Coventry Children’s Community LearningDisability Team on Realistic expectations ofdevelopment and Marion Miller, sleep counsellor, onSleep issues and how to tackle them.

Professor Peter Hammond

Dr Eugen Strehle

Marion Miller

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