behavioral problems in rett syndrome: an emerging issue · behavioral problems in rett syndrome •...

BehavioralProblemsinRettSyndrome:AnEmergingIssue

WalterE.Kaufmann,M.D.Dept.HumanGenetics,EmoryUniversitySchoolofMedicine

AnavexLifeSciencesCorp.

Disclosures

•  ChiefMedicalOfficer,AnavexLifeSciencesCorp.• MemberoftheNeurodevelopmentalDisordersWorkGroup,DiagnosticandStatisticalManualofMentalDisorders-FifthEdition(DSM-5).

BehavioralProblemsinRettsyndrome

•  ImprovementsinqualityoflifeinRTThavehighlightedtheimportanceofbehavioralproblems.

•  However,behavioralproblemshavebeenrecognizedsincetheearlydescriptionsofRTT.

A Progressive Syndrome of Autism, Dementia, Ataxia, and Loss of Purpos&l

Hand Use in Girls: Rett’s Syndrome: Report of 35 Cases

Bengt Hagberg, MD,” Jean Aicardi, MD,? Karin Dias, MD,S and Ovidio Ramos, MDI-

Thirty-five patients, exclusively girls, from three countries had a uniform and striking progressive encephalopathy. After normal general and psychomotor development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of higher brain functions. Within one-and-a-half years this deterioration led to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and acquired microcephaly. The destructive stage was followed by apparent stability lasting through decades. Additional insidious neurological abnor- malities supervened, mainly spastic parapareses, vasomotor disturbances of the lower limbs, and epilepsy. Prior exten- sive laboratory investigations have not revealed the cause. The condition is similar to a virtually overlooked syndrome described by Rett in the German literature. The exclusive involvement of females, correlated with findings in family data analyses, suggests a dominant mutation on one X chromosome that results in affected girls and nonviable male hemizygous conceptuses.

Hagberg B, Aicardi J, Dias K, Ramos 0: A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 14:471-479, 1983

In 1966 Rett IS, 6a1, in Vienna, described a syndrome of “cerebral atrophy and hyperammonemia” observed only in girls and characterized by autistic behavior and dementia, apraxia of gait, loss of facial expression, and stereotyped use of the hands. The syndrome had its onset toward the end of the first year of life or during the first half of the second year and had a slowly progressive course. The same author in greater detail reported on 21 cases of the same syndrome in 1974 [6].

Unaware of Rett’s descriptions, one of the present authors (B. H.) described similar patterns in 16 Swed- ish girls observed from 1962 through 1980 [3]. Fol- lowing this report, it emerged that the syndrome had been seen in several European countries but had not been recognized as an entity.

We report here on a pooled series of 35 French, Portuguese, and Swedish female patients with Rett’s syndrome.

Diagnostic Criteria and Clinical Material All patients fulfilled the following criteria: ( I ) normal neurological and mental development during their first 7 to 18 months of life, following normal prenatal and perinatal period; (2) stagnation of developmental acquisitions after this

7- to 18-month period, followed by a rapid deterioration of behavior and mental status, resulting in dementia with autistic features within less than 18 months; (3) loss of purposeful use of the hands, following the earlier acquisition of a normal grasp function; (4) jerky ataxia of the trunk and often of the limbs, ataxic gait, and acquired microcephaly; ( 5 ) a protracted period with a relatively stable mental status, marked, however, by the emergence over years of other neurological ab- normalities, mainly spasticity of the lower limbs and epilepsy.

The 14 French patients were seen by one of the authors (J. A.) between January 1, 1972, and June 30, 1982 at the HGpital Saint-Vincent-de-Paul and the HBpital des Enfants- Malades, Paris. Eleven of these 14 patients were found ret- rospectively by searching the medical records of the 152 patients who were given a diagnosis of progressive encephalopathy or psychosis during the period 1972 to 1980. Three patients were recognized as having Rett’s syndrome at their first attendance at the hospital and are being followed.

The 4 Portuguese patients were seen between 1978 and 1982 by a consultant child neurologist in Lisbon (K. D.) and were thought to have a special syndrome which was later recognized to be Rett’s syndrome. One of these patients, who came from a distant part of the country, was seen only once; the other 3 are being followed.

Six of the 17 Swedish patients were seen originally in Upp- sala between 1962 and 1971 and the remaining 11 were

From the ‘Department of Pediatrics 11, Ostra Sjukhuset, 416 85 Gothenburg, Sweden; tINSERM V12 and Clinique de Gen6rique

Received Nov 29, 1982, and in revised form Mar 8, 1983. Accepted for publication Mar 9. 1983.

Medicale, HGpital des Enfants-Malades, Paris, France; and $Hop;tal de Sinto Antonio dos Capuchos, Lisbon, Portugal. Address reprint requests Dr Hagberg,

47 1

A Progressive Syndrome of Autism, Dementia, Ataxia, and Loss of Purpos&l

Hand Use in Girls: Rett’s Syndrome: Report of 35 Cases

Bengt Hagberg, MD,” Jean Aicardi, MD,? Karin Dias, MD,S and Ovidio Ramos, MDI-

Thirty-five patients, exclusively girls, from three countries had a uniform and striking progressive encephalopathy. After normal general and psychomotor development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of higher brain functions. Within one-and-a-half years this deterioration led to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and acquired microcephaly. The destructive stage was followed by apparent stability lasting through decades. Additional insidious neurological abnor- malities supervened, mainly spastic parapareses, vasomotor disturbances of the lower limbs, and epilepsy. Prior exten- sive laboratory investigations have not revealed the cause. The condition is similar to a virtually overlooked syndrome described by Rett in the German literature. The exclusive involvement of females, correlated with findings in family data analyses, suggests a dominant mutation on one X chromosome that results in affected girls and nonviable male hemizygous conceptuses.

Hagberg B, Aicardi J, Dias K, Ramos 0: A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 14:471-479, 1983

In 1966 Rett IS, 6a1, in Vienna, described a syndrome of “cerebral atrophy and hyperammonemia” observed only in girls and characterized by autistic behavior and dementia, apraxia of gait, loss of facial expression, and stereotyped use of the hands. The syndrome had its onset toward the end of the first year of life or during the first half of the second year and had a slowly progressive course. The same author in greater detail reported on 21 cases of the same syndrome in 1974 [6].

Unaware of Rett’s descriptions, one of the present authors (B. H.) described similar patterns in 16 Swed- ish girls observed from 1962 through 1980 [3]. Fol- lowing this report, it emerged that the syndrome had been seen in several European countries but had not been recognized as an entity.

We report here on a pooled series of 35 French, Portuguese, and Swedish female patients with Rett’s syndrome.

Diagnostic Criteria and Clinical Material All patients fulfilled the following criteria: ( I ) normal neurological and mental development during their first 7 to 18 months of life, following normal prenatal and perinatal period; (2) stagnation of developmental acquisitions after this

7- to 18-month period, followed by a rapid deterioration of behavior and mental status, resulting in dementia with autistic features within less than 18 months; (3) loss of purposeful use of the hands, following the earlier acquisition of a normal grasp function; (4) jerky ataxia of the trunk and often of the limbs, ataxic gait, and acquired microcephaly; ( 5 ) a protracted period with a relatively stable mental status, marked, however, by the emergence over years of other neurological ab- normalities, mainly spasticity of the lower limbs and epilepsy.

The 14 French patients were seen by one of the authors (J. A.) between January 1, 1972, and June 30, 1982 at the HGpital Saint-Vincent-de-Paul and the HBpital des Enfants- Malades, Paris. Eleven of these 14 patients were found ret- rospectively by searching the medical records of the 152 patients who were given a diagnosis of progressive encephalopathy or psychosis during the period 1972 to 1980. Three patients were recognized as having Rett’s syndrome at their first attendance at the hospital and are being followed.

The 4 Portuguese patients were seen between 1978 and 1982 by a consultant child neurologist in Lisbon (K. D.) and were thought to have a special syndrome which was later recognized to be Rett’s syndrome. One of these patients, who came from a distant part of the country, was seen only once; the other 3 are being followed.

Six of the 17 Swedish patients were seen originally in Upp- sala between 1962 and 1971 and the remaining 11 were

From the ‘Department of Pediatrics 11, Ostra Sjukhuset, 416 85 Gothenburg, Sweden; tINSERM V12 and Clinique de Gen6rique

Received Nov 29, 1982, and in revised form Mar 8, 1983. Accepted for publication Mar 9. 1983.

Medicale, HGpital des Enfants-Malades, Paris, France; and $Hop;tal de Sinto Antonio dos Capuchos, Lisbon, Portugal. Address reprint requests Dr Hagberg,

47 1


•  Severeautisticbehavior(compatiblewithDSM-5diagnosisofASD)isnotamajorconcernduringlifetime.Ittendstobepresentduringtheregressionperiod,affectingtransiently~40-50%ofpatients.

•  Mildautisticfeaturesmaybepresentlaterinlife.

PercyA,GlazeDG.NaturalHistory.RettSyndrome.Ed.KaufmannWE(w/PercyA,ClarkeA,LeonardH,NaiduS).MacKeithPress,2017.NeulJLetal.JNeurodevelopDisord6:20,2014.KaufmannWEetal.JIntellectDisabilRes56:233-247,2012.

Table 2.2 Features of autism in classic and variant Rett syndrome

Classic Rett syndrome Variant Rett syndrome n=765 n=140 Liked being held n (%)

Lost visual attention n (%)

Lost aural attention n (%)

Liked being held n (%)

Lost visual attention n (%)

Lost aural attention n (%)

714 (93) Acquired

409 (53) Lost

343 (46) Lost

126 (90)

Acquired 42 (30) Lost

38 (27) Lost

139 (18) Lost

309 (40) Regained

246 (32) Regained

15 (11) Lost

27 (19) Regained

21 (15) Regained

100 (13) Regained

40 (5.2) Lost again

26 (3.4) Lost again

8 (5.7) Regained

5 (3.6) Lost again

3 (2.1) Lost again

675 (88) Retained

625 (82)

Retained 642 (84) Retained

119 (85) Retained

120 (86) Retained

120 (86) Retained

Data obtained from the Natural History Study (Neul et al. 2014).


Firstlarge-scalestudy(Buchananetal.BrainDev41:123-134,2019)•  Mild-moderateinternalizingbehaviorsareverycommon.

or Neither. Overwhelmingly in RTT, participants dis-played internalizing behaviors; about half (52.0%) hadonly internalizing behaviors and half (45.1%) had con-current externalizing behaviors. Behavioral profiles didnot vary by RTT diagnosis, but a relationship withmutation severity was confirmed. Externalizing behav-iors were overrepresented in the mild MECP2 mutationgroup as compared to the severe mutation group(p < .05); the mild mutation group had more partici-pants profiled as Mixed (49.8% vs. 37.2%) and feweras Internalizing-only (48.0% vs. 61.0%). Because of thesmall number of participants with RTT in the Neither(n = 15) and Externalizing-only (n = 7) categories, weexcluded them from additional analyses.

The Internalizing-only and Mixed behavioral profileswere compared in terms of a variety of characteristics,including key features of RTT. The Mixed behavioralcohort was younger and had lower (i.e., less severe)CSS total scores than the Internalizing-only cohort(Table 6). The behavioral profiles showed no differencein MBA total scores (adjusted to remove externalizingitems), another indicator of overall severity. These find-ings held true in the classic RTT cohort, but no signifi-cant differences in age or overall severity were notedwithin the two atypical groups.

To further investigate these characteristics in classicRTT, specific developmental and clinical features alongwith therapies commonly used in the disorder were com-pared between the Internalizing-only and Mixed behav-ioral profile cohorts (Table 7). All developmentalfeatures were more advanced in the Mixed behavioralcohort, with significant differences found in more com-plex gross and fine motor skills (‘‘Holds cup/bottle todrink”, ‘‘Walks unsupported”, ‘‘Hand use to feed self”,‘‘Standing unsupported”). ‘‘Self-Abuse” was stronglyrelated to behavioral profile, with a higher rate in theMixed behavioral cohort. While this association is

expected based on the definition of the Mixed behav-ioral profile, this provides consistent evidence from sep-arate data collection points within the RNHS (i.e., MBAand Current History). Although no other clinical featureor treatment was significantly different betweenInternalizing-only and Mixed behavioral profiles afterstringent correction for multiple comparisons, a fewapproached significance. Specifically, seizures, constipa-tion, and frequent daytime naps were more prevalent inthe Internalizing-only behavioral cohort.

3.4. Comparison of RTT with other cohorts

Compared to participants with classic RTT, individ-uals with MECP2 mutations who did not meet diagnos-tic criteria for RTT had similar internalizing andexternalizing item scores for nearly all items; only‘‘Acted bothered” was more common in this population(Table 1, Table 4). Non-RTT participants were catego-rized into Internalizing-only (65.7%) or Mixed (34.3%)behavioral profiles with rates similar to participants withRTT (p = 0.376).

CHQ MH subscale scores from other reportedcohorts were also compared to the classic RTT group(Fig. 3). Classic RTT participants had more frequentinternalizing behavior than the general pediatric popula-tion, the general population of females, and an epilepsygroup; on the other hand, participants with RTT hadscores similar to individuals with psychiatric disorders[31].

3.5. Behavioral profiles over time

Internalizing and externalizing behaviors were evalu-ated over time by combining all visits for participantswith RTT in linear regression models using age as theindependent variable (Table 8). Internalizing behaviors

Fig. 1. Frequency of internalizing behaviors from the CHQ Mental Health Subscale in RTT (all participants). Note. CHQ = Child HealthQuestionnaire. RTT = Rett syndrome.

C.B. Buchanan et al. / Brain & Development 41 (2019) 123–134 127


Firstlarge-scalestudy(Buchananetal.BrainDev41:123-134,2019)•  Externalizingbehaviorsaremildanduncommon.

RTT, and with the goal of developing behavioral pro-files that could be used clinically, we examined whetherinternalizing and externalizing behaviors associated indistinctive patterns. Indeed, two behavioral profilesemerged: Internalizing-only and Mixed (Internalizingand Externalizing). The two approximately equal-sizedgroups of individuals with RTT differed in age and clin-ical severity, with the Mixed cohort being younger andless affected clinically. This finding supported the notionthat motor and overall clinical severity have an impacton the expression of abnormal behaviors in RTT, which

could be reflected in the evolution of the disorder sinceclinical impairment worsens with age. This was con-firmed by an evaluation of behavioral changes overtime, which revealed a relatively more dynamic evolu-tion in the Mixed cohort. This group had a worseningof internalizing behaviors and an improvement in scoreson externalizing behaviors with age. These changesshould be interpreted with caution, as the decline inexternalizing behaviors may simply reflect progressivemotor impairment in RTT. Follow up studies areneeded to determine if the suggested greater similarity

Table 2Behavior scores based on MECP2 mutation severity categories.

Mutation severity Internalizing score (range 5–100)† Externalizing scores (range 0–4)

CHQ MH subscale Irritability Self-mutilation Aggressive behavior Biting self & others

Mild (n = 360) 66.15 ± 15.6 0.51 ± 0.9 0.33 ± 0.8 0.34 ± 0.8 0.33 ± 0.8Moderate (n = 87) 72.79 ± 13.3**; 0.47 ± 0.8 0.25 ± 0.7 0.15 ± 0.4 0.28 ± 0.6Severe (n = 348) 69.48 ± 14.6*; 0.43 ± 0.8 0.20 ± 0.6**; 0.11 ± 0.4***; 0.16 ± 0.5**;

Note. Analyses of entire RTT cohort, regardless of clinical presentation. All values are reported as mean ± SD. Severe mutations = R106W, R168X,R255X, R270X, insertions, deletions, large deletions, and splice site; Moderate mutation = T158M; Mild mutations = R133C, R294X, R306C, 30

truncations, and other point mutations. †Lower scores indicate more severe internalizing behaviors; higher scores indicate greater impairment forexternalizing items. Values in bold are significantly different from the mild group based on non-parametric Independent-Samples Kruskal-WallisTest; *p ! 0.05, **p ! 0.01, ***p ! 0.001. " = more severe, ; = less severe. CHQ MH = Child Health Questionnaire Mental Health Subscale.

Table 3Scores of internalizing behaviors based on SSRI use or any medication use for anxiety in RTT.

Clinical Feature Present CHQ MH (mean ± SD)

Anxiety – on any medication Yes (n = 118) 64.83 ± 16.5**

No (n = 590) 69.27 ± 14.6

Anxiety – on an SSRI Yes (n = 81) 63.40 ± 17.5**

No (n = 627) 69.19 ± 14.6

Any SSRI Use Yes (n = 106) 62.55 ± 17.5***

No (n = 602) 69.58 ± 14.3

Note. Sample: All RTT participants. Non-Parametric Independent Sample Mann-Whitney U Test *p < 0.05 **p < 0.01 ***p < 0.001. Bolded valuesare more severe than untreated counterparts. CHQ MH = Child Health Questionnaire Mental Health Subscale. RTT = Rett syndrome.

Fig. 2. Frequency of externalizing behaviors from the MBA in RTT (all participants). Note. MBA =Motor Behavioral Assessment. RTT = Rettsyndrome.

C.B. Buchanan et al. / Brain & Development 41 (2019) 123–134 129


Firstlarge-scalestudy(Buchananetal.BrainDev41:123-134,2019)•  Twogroups(approx.50%each):

internalizingonly&mixedinternalizing+externalizing.•  Girlswithmixedprofileareyoungerand(overall)less

affected,withprominentself-injuryandworseninginternalizingbehaviorsovertime.

between the two behavioral profile groups over time ispart of the natural history of RTT.

A detailed comparison of key features of RTTrevealed that the distinction between Internalizing-onlyand Mixed behavioral profiles was related to certainclinical features. The Mixed group showed moreadvanced gross and fine motor skills at baseline. Sup-porting the relevance of two behavioral profiles, theInternalizing-only cohort had slightly greater severityof major clinical problems in RTT, namely constipation,seizures and daytime sleepiness. In contrast, the Mixed

group had highly prevalent self-injurious behaviors.These initial clinical behavioral associations have impli-cations in terms of RTT management, suggesting targetsfor prevention or more aggressive treatment.

While some differences exist in specific internalizingand externalizing behaviors among RTT subgroups,these appeared to be rather a reflection of clinical sever-ity. Similarly, comparisons between RTT and non-RTTindividuals with MECP2 mutation indicate that thereported behavioral profiles are present in general inindividuals with MECP2 mutation and not exclusively

Table 4Scores of externalizing behaviors from the MBA in RTT.

Externalizing BehaviorsMBA Individual Items (Range 0–4)

Diagnosis Group Irritability Self-mutilation Aggressive behavior Biting self & others

Classic (n = 736) 0.46 ± 0.9 0.26 ± 0.7 0.21 ± 0.6 0.24 ± 0.6Atypical Mild (n = 66) 0.53 ± 0.9 0.36 ± 0.8 0.52 ± 1.0**" 0.30 ± 0.8Atypical Severe (n = 59) 0.63 ± 1.0 0.34 ± 0.8 0.10 ± 0.4 0.31 ± 0.7Non-RTT (n = 48) 0.25 ± 0.7 0.38 ± 1.0 0.08 ± 0.3 0.02 ± 0.1

Note. All values are reported as mean ± SD. Scores are directly related to severity. All score comparisons are in reference to classic RTT cohort usingthe non-parametric Independent Samples Kruskal-Wallis Test. Bolded values are significantly " higher than classic RTT; **p-value < 0.01. Signif-icance values have been adjusted by the Bonferroni correction for multiple comparisons. MBA =Motor Behavioral Assessment. RTT = Rettsyndrome.

Table 5Spearman’s Rho correlations of internalizing and externalizing behavior scores in RTT.

Internalizing Externalizing

Behavior Subscale or Item CHQ MH Irritability Self-mutilation Aggressive behavior Biting self & others

Internalizing CHQ MH 1 !.141** !.086* !.080* !.126**

Externalizing Irritability !.141** 1 .228** .220** .238**

Self-mutilation !.086* .228** 1 .293** .468**

Aggressive behavior !.080* .220** .293** 1 .308**

Biting self & others !.126** .238** .468** .308** 1

Note. *p " 0.05, **p " 0.01; !0.3 to 0.3 = negligible correlations, 0.3 to 0.5 = low positive correlations (also shown in bold print); no moderate orhigh correlations were found. CHQ MH = Child Health Questionnaire Mental Health Subscale. RTT = Rett syndrome.

Table 6Differences in age and clinical severity between behavioral cohorts in RTT overall and by diagnosis group.

Diagnosis Group Behavioral Profile Age(Range 3–49 years)

CSS Total(Range 1–47)

MBA Total [excludingexternalizing items](Range 7–92)

All RTT Internalizing-only (n = 368) 12.03 ± 8.9 23.61 ± 8.4 47.03 ± 15.3Mixed (n = 319) 9.86 ± 7.8**; 20.84 ± 8.1***; 46.92 ± 15.1

Classic Internalizing-only (n = 319) 12.06 ± 8.9 24.11 ± 7.9 48.13 ± 14.5Mixed (n = 271) 10.12 ± 8.1**; 21.27 ± 7.6***; 50.47 ± 15.1

Atypical Mild Internalizing-only (n = 27) 10.09 ± 6.6 11.78 ± 4.4 25.65 ± 10.9Mixed (n = 28) 8.65 ± 5.2 10.86 ± 4.8 28.78 ± 11.2

Atypical Severe Internalizing-only (n = 22) 13.92 ± 11.4 31.00 ± 5.8 56.32 ± 11.1Mixed (n = 20) 8.02 ± 6.2 29.05 ± 5.2 56.35 ± 11.5

Note. All values reported as mean ± SD. Bolded values are significantly different from Internalizing-only cohort based on non-parametric Inde-pendent Samples t-test; *p-value < .05 **p-value < .01 ***p-value < .001; "=higher ;=lower. CSS = Clinical Severity Score. MBA =Motor Behav-ioral Assessment. RTT = Rett syndrome.

130 C.B. Buchanan et al. / Brain & Development 41 (2019) 123–134


Firstlarge-scalestudy(Buchananetal.BrainDev41:123-134,2019)•  BehavioralproblemsinRTTarecomparabletopopulation

withpsychiatricdisorders(i.e.psychosocialQOL).

Fig. 3. Mean CHQ Mental Health Subscale scores from the RNHS and other reported cohorts (HealthActCHQ, 2013). Note. *p < .05 **p < .01***p < .001 in comparison to the classic RTT group. Error bars indicate standard deviation of the mean. CHQ = Child Health Questionnaire.RNHS = Rett Natural History Study.

Table 8Linear regression analyses of behavioral items and profiles in RTT.

Cohort Behavior item or subscale R2 F Standardized b Sig.

All RTT CHQ MH 0.000 0.495 !0.013 0.482Felt like crying" 0.006 18.367 0.079 0.000***

Felt lonely; 0.002 6.470 !0.047 0.011*

Acted nervous" 0.003 9.257 0.056 0.002**

Acted bothered or upset 0.001 1.742 0.024 0.187Irritability; 0.011 54.597 !0.107 0.000***

Self-mutilation 0.000 0.497 !0.010 0.481Aggressive behavior; 0.006 27.593 !0.076 0.000***

Biting self & others; 0.013 59.958 !0.112 0.000***

Internalizing-only CHQ MH 0.003 3.699 0.052 0.055Felt like crying" 0.015 20.208 0.121 0.000***

Felt lonely 0.002 2.669 0.044 0.103Acted nervous" 0.010 14.463 0.102 0.000***

Acted bothered or upset" 0.004 5.413 0.063 0.020*

Irritability 0.001 1.577 !0.028 0.209Self-mutilation" 0.004 7.144 0.059 0.008**

Aggressive behavior 0.000 0.605 !0.017 0.437Biting self & others 0.001 2.607 !0.036 0.107

Mixed CHQ MH; 0.015 19.880 !0.124 0.000***

Felt like crying 0.000 0.057 0.007 0.812Felt lonely; 0.173 39.174 !0.173 0.000***

Acted nervous 0.012 0.180 !0.012 0.671Acted bothered or upset 0.002 2.414 !0.043 0.121Irritability; 0.012 21.937 !0.107 0.000***

Self-mutilation 0.001 1.827 !0.031 0.177Aggressive behavior ; 0.005 8.999 !0.069 0.003**

Biting self & others; 0.015 28.546 !0.122 0.000***

Note. Analyses of entire RTT cohort, regardless of clinical presentation. Bold text indicates significance. *p < .05 **p < .01 ***p < .001; " = increaseover time, ; = decrease over time for significant items.

132 C.B. Buchanan et al. / Brain & Development 41 (2019) 123–134


CommonAbnormalBehaviorsinNeurodevelopmentalDisorders

1.   Disruptive/aggressive/self-injuriousbehavior(IAAS)2.   ADHD-like(attentionaldifficulties,hyperactivity,impulsivity)3.   Anxiety-like4.  Moodabnormalities5.  Abnormalsocialcommunication&interaction(Autistic

behaviorduringregressionperiod)6.   Stereotypic/repetitive/OCD-like

Sansometal.DevMedChildNeurol35:340-345,1993Mountetal.JIntellectDisabilRes46:619-624,2002Mountetal.AmJMentRetard108:1-12,2003Cianfaglioneetal.JNeurodevelopDisord7:11,2015Cianfaglioneetal.JDevPhysDisabil28:425-441,2016Cianfaglioneetal.JIntellectDisabilRes60:182-190,2016Mundeetal.JIntellectDisabilRes60:43-53,2016


•  Moststudiesarebasedonsmallsubjectsamples.•  Behavioraldomainsaremeasuredwithasingleinstrument.•  Moststudiesarecross-sectional.•  Onlyafewreportshaveincludedadults.•  Virtuallynodataonpsychiatricdiagnoses.•  Unknownrelationshipwithrelatedimpairments(e.g.,

communication,sleep).•  Limiteddataonimpactonqualityoflife.•  Instrumentsarenotadequateforindividualswithmotor

impairmentand/orminimalverbalfunction.


median slightly above the measure’s median. Scores onthe ADAMS were relatively low but comparativelyhigher than those on the ABC-C, with only two scales,Manic/Hyperactive Behavior and General Anxiety, withmedians approaching the measure’s median and valuesin the upper range. In general, distribution of scores forthe anxiety-related subscales was comparable to that ofmood subscales and intermediate between those forstereotypic behavior (upper end) and disruptive behavior(lower end).

Internal structure of anxiety scales in RTTWe examined the distribution of scores for each of thesubscales using percentile ranks for the scores (Table 1).The percentile rank of a measure’s score is the percent-age of scores at the same level or below it [51]. Percent-ile ranks are useful in demonstrating score distributionbeyond the median, particularly the level of upper range

skewing. In terms of the RSBQ, the Fear/Anxiety sub-scale showed a comparable percentile rank distributionto other subscales, whether they measured mood abnor-malities or other behaviors. The ADAMS Social Avoid-ance displayed a wide range of scores between themedian and percentile 85 comparable to other ADAMSsubscales but different from the General Anxiety sub-scale, which had a more even distribution of upper rangescores. The two social anxiety-related ABC-C subscalesshowed a similar pattern of score distribution to the AD-AMS Social Avoidance, which was comparable to otherABC-C subscales with exception of the Stereotypy(probably reflecting the relatively high scores on thissubscale in the entire RTT cohort). To our knowledge,no percentile rank distribution has been reported for theRSBQ and ABC-C score distribution is quite variable be-tween and within genetic disorders depending on theproportion of individuals with severe autistic behavior as

Table 1 Descriptive statisticsCSS Number Min. Max. Skewness SE Kurtosis SE 25th 50th 75th 85th 95th Items α

Total 51 5 32 −0.1 0.3 −0.3 0.7 16.00 20.00 25.00 27.00 30.40 13 –

RSBQ

General Mood 74 0 16 0.5 0.3 −0.6 0.6 4.00 6.00 9.50 13.00 15.30 8 0.88

Body Rocking 74 0 14 0.6 0.3 0.1 0.6 4.00 6.00 8.00 9.00 12.30 7 0.67

Hand Behaviors 74 3 12 −0.5 0.3 −0.5 0.6 6.00 8.00 10.00 10.00 12.00 6 0.63

Fear/Anxiety 74 0 8 −0.1 0.3 −0.7 0.6 3.00 5.00 6.00 7.00 8.00 4 0.73

Breathing Problems 72 0 10 0.3 0.3 −0.9 0.6 2.00 4.50 7.00 8.00 10.00 5 0.76

Repetitive Face Movements 74 0 8 0.0 0.3 −0.8 0.6 2.00 4.00 5.00 6.00 7.00 4 0.53

Night-time Behaviors 72 0 6 0.9 0.3 −0.1 0.6 0.00 1.00 3.00 4.00 5.30 3 0.75

Walking/Standing 73 0 4 −0.1 0.3 −1.3 0.6 1.00 2.00 3.00 4.00 4.00 2 0.62

Total 45 0.88

ADAMS

Manic 74 0 14 0.3 0.3 −0.8 0.6 3.00 6.00 9.00 10.90 13.00 5 0.77

Depressed 74 0 19 1.3 0.3 2.6 0.6 1.00 4.00 6.00 8.00 11.40 7 0.76

Social Avoidance 74 0 16 1.1 0.3 1.3 0.6 2.50 4.00 7.00 8.00 15.30 7 0.80

General Anxiety 74 0 20 1.0 0.3 0.4 0.6 3.00 5.00 9.00 12.20 18.40 7 0.91

Obsessive Behavior 73 0 7 0.7 0.3 −0.4 0.6 1.00 2.00 4.75 6.00 7.35 3 0.60

Total 28 0.92

ABC-C

Irritability 47 0 29 1.3 0.4 1.1 0.7 3.75 7.00 12.00 17.95 27.60 15 0.89

Lethargy/Social Withdrawal 47 0 22 0.7 0.4 −0.4 0.7 4.00 8.00 13.25 16.00 21.30 16 0.78

Stereotypy 47 1 18 −0.2 0.4 0.9 0.7 9.00 11.00 13.25 14.95 17.30 7 0.68

Hyperactivity 47 0 36 1.4 0.4 1.6 0.7 5.00 8.00 14.50 22.00 34.60 16 0.93

Inappropriate Speech 47 0 10 4.4 0.4 23.0 0.7 0.00 0.00 0.00 1.95 3.00 4 0.86

Social Avoidance 47 0 10 1.6 0.4 3.0 0.7 0.00 0.50 3.25 4.00 5.65 4 0.86

Total 58 0.94

There were no differences in the mean/median scores in any of the five anxiety-related scales (in italics), when the nine subjects in the regression stage werecompared with the 65 individuals post-regression. Interpretative guidelines for internal consistency by Cortina [53]: 0.90 or above = excellent; 0.80–0.89 = good;0.70–0.79 = fair; below 0.70 = unacceptable. In italics are descriptive statistics for the five anxiety-related measures

Barnes et al. Journal of Neurodevelopmental Disorders (2015) 7:30 Page 5 of 14

Barnesetal.JNeurodevelopDisord7:30,2015

Studyof74girls,2-11years:ADAMSwasthestrongestmeasurefor(social)anxiety


The Rett Syndrome Behaviour Questionnaire (RSBQ):re¢ning the behavioural phenotype of RettsyndromeRebecca H. Mount,1 Tony Charman,1 Richard P. Hastings,2 Sheena Reilly,3

and Hilary Cass41Behavioural and Brain Sciences Unit, Institute of Child Health, University College London, UK; 2Centre for

Behavioural Research Analysis and Intervention in Developmental Disabilities, University of Southampton, UK;3LaTrobe University, Australia; 4Neurosciences Unit, Institute of Child Health, University College London, UK

Background: Although physical features, including loss of hand skills, deceleration of head growth,spasticity and scoliosis, are cardinal features of Rett syndrome (RS), a number of behavioural featuresare also associated with the disorder, including hand stereotypies, hyperventilation and breath holding.No study has tested the specificity of these behavioural features to individuals with RS, compared toindividuals with severe to profound mental retardation (SMR). Method: A novel checklist of charac-teristic RS behavioural and emotional features, the Rett Syndrome Behaviour Questionnaire (RSBQ),was developed to test the type and specificity of behavioural features of RS against those found in girlswith SMR. Results: After controlling for the effects of RS-related physical disabilities, the RSBQ dis-criminated between the groups. Some aspects of the behaviours found to be specific to RS are includedin the necessary or supportive RS diagnostic criteria, notably hand behaviours and breathing problems.Additional behavioural features were also more frequently reported in the RS than the SMR group,including mood fluctuations and signs of fear/anxiety, inconsolable crying and screaming at night, andrepetitive mouth and tongue movements and grimacing. Conclusions: Full validation of the scalerequires confirmation of its discriminatory power and reliability with independent samples of individ-uals with RS and SMR. Further delineation of the specific profile of behaviours seen in RS may help inidentification of the function of the MECP2 gene and in improved differential diagnosis and managementof individuals with RS. Keywords: Rett syndrome, behavioural phenotype, mental retardation, MECP2,diagnosis, questionnaire.

Rett syndrome (RS) is a profoundly disabling neu-rological disorder predominantly affecting females(Rett, 1966; Hagberg, Aicardi, Dias, & Ramos, 1983;Kerr & Witt Engerstrom, 2001). The prevalence isestimated to be between 1 in 10,000 and 1 in 15,000females (Hagberg & Hagberg, 1997; Kerr, 1992;Kozinetz et al., 1993; Witt Engerstrom, 1990). Themajority of cases are thought to be the result ofsporadic mutations. Recently Amir et al. (1999)identified mutations in the gene (MECP2) encodingX-linked methyl-CpG-binding protein 2 (MeCP2) asthe cause of some cases of RS. More than 60 differentmutations have been found in patients so far and itappears that as many as 85% of sporadic classic Rettcases, as well as 50% of familial cases, are the resultof coding mutations in MECP2 (Clarke, Schanen, &Anvret, 2001; Dragich, Houwink-Manville, & Scha-nen, 2000; Shahbazian & Zoghbi, 2001). The normalfunction of MECP2 has not been easy to dissect, andresearch to elucidate the role of mutations in the genein the pathological brain development that underliesthe RS phenotype is ongoing (Chen, Akbarian, Tudor,& Jaenisch, 2001; Guy, Hendrich, Holmes, Martin, &Bird, 2001; see Clarke et al., 2001, for a review).

The neurodevelopmental course of regression andloss of hand skills, apraxia, deceleration of headgrowth, and increasing spasticity and scoliosis are

cardinal features of the syndrome (Cass et al., inpreparation; Kerr & Witt Engerstrom, 2001). In addi-tion, a number of behavioural features have beenreported as being associated with RS (see Coleman,Brubaker, Hunter, & Smith, 1988; Mount, Hastings,Reilly,Cass,&Charman,2001; for a review). Themostprominent behaviours reported in the literature werehand stereotypies, hyperventilation and breath hold-ing. These behaviours are currently part of the nec-essary and supportive diagnostic criteria for RS (RettSyndrome Diagnostic Criteria Work Group, 1988;Hagberg, 1995). However, behaviours not currentlypart of the diagnostic criteria were also frequentlyreported in the literature reviewbyMountetal. (2001).These included a number of autistic-like behaviours(e.g., indifference to persons, poor eye contact), sleepabnormalities, and features of anxiety and low mood.

There is increasing recognition that genetic disor-ders may have specific effects on behaviour (Dykens,1995, 1999; Flint, 1996; Hodapp, 1997; O’Brien &Yule, 1995). Behaviours that are common and spe-cific to a genetic disorder are assumed to share anunderlying genetic origin and have been termed‘behavioural phenotypes’. Previously it was arguedthat some behaviours might be specific to particularsyndromes. However, there is an emerging consen-sus that such behaviours are not unique, nor nec-

Journal of Child Psychology and Psychiatry 43:8 (2002), pp 1099–1110

! Association for Child Psychology and Psychiatry, 2002.Published by Blackwell Publishers, 108 Cowley Road, Oxford OX4 1JF, UK and 350 Main Street, Malden, MA 02148, USA

45items,8subscales,5“pure”behavior

•  RettBe2.0,anew,morecomprehensivebehavioralinstrument.•  40itemscovering:Anxiety,EmotionalBehaviorNon-Anxiety,

SocialBehavior,AttentionalDifficulties,SensoryStimulation,Repetitive-StereotypicBehaviors,RestrictedBehaviors,DisruptiveBehaviors,BreathingProblems.


•  Interventionstargetingcommunicationandotherskills.•  Treatmentofsleepdifficulties.•  Behavioraltherapy,includingABA.•  Psychopharmacology:1.   SSRIsforanxiety.2.   Atypicalneurolepticsfordisruptiveandself-injuriousbehaviors

(IAAS).3.   Lessfrequentuseofalpha-agonistsforADHD-likesymptoms,

anxiolytics,andAEDsasmoodstabilizers.4.   Combinedtreatmentofbehavioralandsleepproblems(e.g.,

alpha-agonists,mirtazapine)orbehavioralandbreathingproblems(e.g.,buspirone).

ClinicalTrialsinRettSyndrome:Howtodothem?

ClinicaltrialsinRettsyndrome:Principles

•  Clinicaltrialsareresearchstudies:drugsaretestedforsafetyandefficacy.

•  Safetyand(adverseevent)tolerabilityareprimarygoals:rulingoutnegativeeffects.

•  Efficacyissecondarygoal:demonstratingpositiveeffect.•  Usuallyseveralstudiesinsequence(drugdevelopment

program).•  Replicationisessential.•  Comparisonbetweendrugandplacebo(nodrug)isideal.•  Efficacyoutcomemeasuresneedtobesensitivetodetect

”signal”atthebeginningofprogram(earlyphasetrials).•  Biomarkers(objectivemeasures)cansupportpositivesignal.

LearningAsMuchasPossibleatEachStep:Safety,Efficacy,ReplicationTraditionalApproachfromPhaseItoPhaseIII

Safety(S)Tolerability(T)

EfficacyS+T

EfficacyReplication

S+T

EfficacyS+T

Surveillance


LearningAsMuchasPossibleatEachStep:Safety,Efficacy,ReplicationNovelApproaches:AdaptiveDesigns

Spinelietal.OrphanetJRareDis12:140,2017

FellH.RheinischenFriedrich-Wilhelms-UniversitätBonn,2014

Investigating the sample size requirements using a real-life exampleDelaying assignment to A1PI by 12 months leads to asmaller annual rate of lung density change from baselineto 24 months under the delayed-start design and thesample size required to achieve this change is tremen-dously large (Table 1). Contrariwise, a standard RCT canachieve larger effect in the 2-year time-frame with muchsmaller sample size requirements.In the next section we illustrate schematically the sam-

ple size and treatment effect considerations that havebeen demonstrated with the real-life example.

ExamplesSuitability of the delayed start designFigure 3 schematically illustrates three different scenar-ios of treatment-effect development over time under thedelayed-start design in order to understand the impactof how the treatment effect develops over time. Time isdepicted on x-axis, whereas the treatment efficacy is

presented as percentage on y-axis. The early-start group(i.e. the group directly assigned and maintained to theactive treatment until trial completion) and the delayed-start group (i.e. the group initially assigned to placeboand then switched to the active treatment at some pointin time) are defined by the black and green dotted line,respectively.In Fig. 3a, a few time units after taking the active treat-

ment (for instance, aspirin), an immediate effect is ob-served in the early-start group and achieves 100% of itsefficacy at t1. The delayed-start group responds also im-mediately, but at a later timepoint t2 (t2 > t1) reachingalso 100% of efficacy. Inferences can be made only onthe immediate effect of these treatment groups withinthe time frame as indicated by the parallel vertical lines(i.e., between t1 and t2); the efficacy of the early-startgroup compared to that of the delayed-start groupremains constant.A careful investigation of Fig. 3a reveals that the

delayed-start design is not suitable for drugs that estab-lish an immediate treatment effect. If the treatmenteffect is investigated too early, it would be zero but thenwould be observed for the very short period that isrequired to establish the immediate effect, followed byzero effect, thereafter. As outlined above, the advantageof the design to limit duration on placebo is onlybecoming effective if the treatment effect is developingslowly over time. As a result, assumptions about thedevelopment of the treatment effect over time are impli-cit to this design approach.

Treatment-effect development over timeIn Fig. 3b, the treatment-effect of the early-start groupstarts immediately to develop and it reaches 100% of itsefficacy at t1. The treatment-effect of the delayed-startgroup starts developing before early-start group reaches100% of its efficacy and it arrives also at 100% efficacylater at t2. Inferences can be made only on the symptom-atic effect of these treatment groups within the timeframe as indicated by the parallel lines. Now considerthe case of a parallel RCT instead of a delayed-startdesign; the active treatment (black dotted line) developsimmediately and reaches 100% efficacy at t1, whereas theplacebo group (red dotted line) has not responded yet.At t1 the treatment effect is smaller under delayed-startdesign than the standard parallel-group RCT, and as aresult, the former fails to achieve proof of efficacy. Thetreatment-effect increases but remains smaller under thedelayed-start design. The treatment-effect developmenthas a different impact on the sample size of these twodesigns; a parallel RCT has smaller sample size require-ments than a delayed-start design to capture a largertreatment effect than the latter.

ACTIVE

ACTIVEPLACEBO

RandomizationDelayed-group starts

active treatment Final visit

Placebo-controlled phase Active treatment phasetime

0

Fig. 2 Graphical display of the delayed-start design. At baseline (time 0),patients are randomly assigned to receive either placebo (delayed-startgroup) or the investigational treatment (early-start group) and they arefollowed over an extended period of time. Then, patients in the placebogroup switch to the investigational treatment until the end of the trial(active treatment phase)

Table 1 Calculated sample size requirementsParameters Double-blinda Open-label extensionb

A1P mean (SE) −1.45 (0.23) −1.45 (0.23)

Placebo mean (SE) −2.19 (0.25) −1.74 (0.25)

Difference 0.74 0.29

Common SD 2.25 2.25

Effect size 0.32 0.13

N per group 147 946

SE standard error, SD standard deviation, N number of patientsaAnnual rate of lung density change from baseline to 24 months (A1PIversus placebo)bAnnual rate of lung density change from baseline to 24 months (A1PI versusdelayed-start A1PI)

Spineli et al. Orphanet Journal of Rare Diseases (2017) 12:140 Page 4 of 7

Adaptive Design Clinical Trials Heike Fell

13

Figure 3 - Seamless Phase II/III design

Two different scenarios are possible for seamless designs. One is the operationally

seamless design, which mainly aims at saving the time that is needed in a conventional

setting for the evaluation of the Phase II data as well as the planning and setting up of the

Phase III trial. The other one is the inferentially seamless design where the final analysis is

done on the complete population treated in both stages. There are statistical methods

available to control the Type I error, however final analysis might be challenging when the

objectives/endpoints in the two stages are different (for example dose finding for the Phase II

stage and efficacy confirmation in the Phase III stage) [10].

2.6 Group sequential design

Group sequential designs are used to allow stopping a clinical trial either for futility, safety or

efficacy. The principle behind group sequential designs is to first only recruit a fraction of the

initially calculated sample size. In a first interim analysis the treatment effect on this subgroup

will be determined. If the treatment effect is greater than the treatment effect that had been

anticipated in the planning stage, the study might be stopped at this point with an early

rejection of the null hypothesis. If, however, the treatment effect is much lower than

anticipated, the trial might also be stopped for futility with accepting the null hypothesis, thus

avoiding exposing further patients to a treatment that isn´t as effective as the comparator and

spending money on a trial that will not reach its primary endpoint. In case the treatment effect

is as large as anticipated, the second fraction of patients will be recruited until a further

interim analysis. These steps will be repeated as pre-specified in the planning stage. A

diagram depicting the flow of actions within a group sequential design is shown below.

Treatment/Dose A

Treatment/Dose B

Placebo

Interim Analysis Final Analysis

Phase III Phase II



•  Global:measuringmultipleclinicalmanifestations.Pros:TheycapturethevariabilityofRTT.Cons:Theymaynotbesensitiveenoughbecausetheymeasuremanyfeatures;theydon’tmeasurepreciselyspecificsymptoms.•  Specific:measuringasingledomain/symptom(e.g.,behavior,

sleep).Pros:Theymeasurepreciselyspecificsymptoms.Cons:Theymaynotdetectefficacyinagroupofpatients.•  Itisdifficulttodevelopsensitive,precise,meaningfulmeasures.•  Theycanbesupportedbybiomarkers(alsodifficulttodevelop).


•  Shortertrials(upto3months).Pros:Easytocomply,fewerunexpectedsituations.Cons:Onlysomesymptomschange:behavior,autonomic,sleep,somemotorfeatures,fluidcognition,seizures.•  Longertrials(longerthan3months).Pros:Theycandetectmultiplepositiveeffects,aswelllonger-termsafety.Cons:Difficulttocomply,greaterchanceofunexpectedsituations.•  Design,assimpleaspossible.•  When,ideallyasearlyaspossible.However,Adultsmayneed

theirowntrials.•  Whoshouldbeincluded,tooptimizeoutcomes.

WeNeedtoAnswertheWhat,How,When&Who

ACommunityEffort


AcknowledgementsRettsyndrome.org(RSO)AutismSpeaksRSAMTranslationalResearchProgram(BCH)DukeEndowment(GGC)NIHP30HD18655NIHUL1RR025758NIHR03HD082561NIHU54HD061222NIHU01NS096767CDCU01DD001189IpsenEloxxNeurenAnavex

•  FXCRCcolleagues:RandiHagerman,Len

Abbeduto,DavidHessl,CraigErickson,LizBerry-Kravis,DejanBudimirovic,andFORWARDteam.

•  RettSyndromeNaturalHistorycolleagues:AlanPercy,JeffNeul,GaryCutter,LindsayOberman,LuigiBoccuto,GreenwoodGeneticCenter’steam&colleaguesinRTTcommunity.

•  BostonChildren’sHospitalcolleagues:KateBarnes,HeatherO’Leary,ChuckNelsonandBCHteams.

•  MITSimonsCentercolleagues:MrigankaSur,Chi-SangPoon&MarkBear.

•  ColleaguesatNCATS,NINDS,NICHD&CDC.

•  SteveKaminsky,PaigeNues,andRSOteam.

•  Anavexteam.

behavioral problems in rett syndrome: an emerging issue · behavioral problems in rett syndrome •...

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