quinta-feira, 27 de maio de 2010
I Universidade Federal Fluminense - UFF
II Universidade Federal do Pará - UFPA
Os neurônios espelho foram descobertos por Rizzolatti e colaboradores na área pré-motora de macacos Rhesus na década de 90 (Gallese, Fadiga, Fogassi, & Rizzolatti, 1996; Rizzolatti, Fadiga, Gallese, & Fogassi, 1996). Estes pesquisadores demonstraram que alguns neurônios da área F5, localizada no lobo frontal, que eram ativados quando o animal realizava um movimento com uma finalidade específica (tipo apanhar uma uva passa com os dedos) também eram ativados quando o animal observava um outro indivíduo (macaco ou ser humano) realizando a mesma tarefa.
A importância desta descoberta para a compreensão direta da ação e/ou da intenção do outro animal ou ser humano foi imediatamente percebida (Gallese et al., 1996; Rizzolatti et al., 1996; Rizzolatti & Craighero, 2004). Ou seja, os neurônios espelho, quando ativados pela observação de uma ação, permitem que o significado da mesma seja compreendida automaticamente (de modo pré-atencional) que pode ou não ser seguida por etapas conscientes que permitem uma compreensão mais abrangente dos eventos através de mecanismos cognitivos mais sofisticados (ver revisão em Gallese, 2005).
Além de um estímulo visual explícito (observação de uma ação), estes neurônios podem também ser ativados por eventos que possuem apenas relação indireta com uma determinada ação: (1) a partir de um som habitualmente associado a uma ação, como por exemplo o barulho da quebra da casca de um amendoim (Kohler et al., 2002) (2) pela dedução implícita da continuidade de uma ação, como, por exemplo, quando um macaco observa o movimento de uma mão na direção de um objeto oculto por um anteparo colocado posteriormente à apresentação do objeto ao animal (Umiltà et al., 2001).
Da mesma forma, não é só a ação manual que é capaz de ativar os neurônios espelho. Por exemplo, existem neurônios-espelho que são ativados quando o macaco executa e/ou observa ações relacionadas com a boca, tais como lamber, morder ou mastigar alimentos. Além disso, na mesma região onde são encontrados estes neurônios existe uma pequena percentagem de células que dispara quando macaco observa o experimentador fazer ações faciais comunicativas na sua frente (Ferrari, Gallese, Rizzolatti, & Fogassi, 2003). Em um outro estudo foram comparadas as regiões cerebrais ativadas pela observação de ações comunicativas da região orofacial de cães (latir), macacos (movimentos labiais) e humanos (fala em silêncio). Os resultados, em seres humanos, mostraram que a observação da fala em silêncio ativa a área de Broca no hemisfério esquerdo e a observação dos movimentos labiais de macacos ativa uma parte menor da mesma região cerebral em ambos os hemisférios, mas que a observação do latir do cão só ativa áreas visuais extra-estriadas (Buccino, Binkofski, & Riggio, 2004). Ou seja, quando a ação observada (o latir) não faz parte do repertório de ações do ser humano, os neurônios espelho não são ativados (Buccino et al., 2004, Gallese, 2005).
Os neurônios espelho foram associados a várias modalidades do comportamento humano: imitação, teoria da mente, aprendizado de novas habilidades e leitura da intenção em outros humanos (Gallese, 2005; Rizzolatti, Fogassi, & Gallese, 2006) e a sua disfunção poderia estar envolvida com a gênese do autismo (Ramachandran & Oberman, 2006). Além disso, considerando que a capacidade humana de abstrair intenção a partir da observação de conspecíficos é considerada crucial na transmissão de cultura (ver revisão em Tomasello, Carpenter, Call, Behne, & Moll, 2005), a descoberta dos neurônios-espelho é de importância fundamental para compreendermos o que nos faz diferente de outros animais, em termos cognitivos.
Evidências da existência dos neurônios espelho em humanos
Estudos funcionais usando PET e fMRI
Desde a descoberta dos neurônios espelho em primatas não-humanos, vários estudos utilizando ferramentas de neuroimagem tentam localizar e mapear a presença desses neurônios em humanos. Os resultados sugerem que existe um sistema de neurônios espelho (SNE) em humanos distribuído em várias áreas corticais fronto-parietais. Recentemente, Buccino et al. (2004), através de um estudo com ressonância magnética funcional (fMRI), demonstraram a ativação de áreas frontais (giro frontal inferior e córtex pré-motor) em humanos durante a execução-observação de ações realizadas com a mão, com a boca e com os pés. Essas ativações ocorriam em diferentes setores corticais, de acordo com o efetor envolvido, e seguindo um padrão somatotópico. Mais importante ainda, estes autores demonstraram a ativação da área de Broca pela observação de ações, confirmando resultados anteriores de Rizzolatti e Arbib (1998) obtidos através de tomografia por emissão de pósitrons (PET). Outras funções do SNE foram observadas através do emprego da ressonância magnética funcional (ver revisão em Gallese, 2005; Rizzolatti et al., 2006). Por exemplo, a observação da expressão de nojo em uma outra pessoa que cheira um líquido de odor desagradável ativa a parte anterior da ínsula, estrutura que é também ativada quando a própria pessoa sente nojo (Wicker et al., 2003).
Estes resultados mostraram que a área de Broca não está somente envolvida com o processamento da linguagem oral e do significado de gestos linguísticos. A homologia proposta entre a área de Broca e a área F5 dos macacos, junto com a comprovação recente da participação da área de Broca no SNE sugere que os neurônios espelho podem ter contribuído para a gênese da linguagem humana, servindo de base para a apropriação simbólica de atos motores.
Estudos usando Estimulação Magnética Transcraniana (EMT)
Segundo Fadiga, Craighero e Olivier (2005), estudos de neuroimagem funcional como o fMRI permitem ao pesquisador localizar o SNE no cérebro humano, mas a demonstração de que o córtex motor é realmente ativado pela mera observação de movimentos somente pode ser obtida por técnicas como a estimulação magnética transcraniana (EMT), que permite estimar a modulação na excitabilidade da via cortico-espinhal decorrente da simulação mental. O SNE humano foi investigado através da EMT durante a observação de ações executadas por outros indivíduos. Os resultados demonstraram que o SNE realmente simula a ação observada, pois a transmissão neuronal é facilitada para os músculos associados com a realização dessa ação (Gangitano, Mottaghy, & Pascual-Leone 2001; ver revisão em Fadiga et al., 2005). Semelhante ao observado em estudos empregando ressonância nuclear magnética funcional (fMRI), outros sistemas, além dos envolvidos com a ação manual, mostraram uma facilitação devido à observação de ações. Por exemplo, Watkins, Strafella e Paus (2003) mostraram que a observação de ações buco-faciais da fala facilitam a excitabilidade do sistema motor envolvido com a produção das mesmas ações.
Possível papel dos neurônios espelho no reconhecimento da lateralidade de figuras da mão
Provavelmente, os neurônios espelho estão envolvidos com outras tarefas além do reconhecimento da ação e da intenção em seres humanos. Por exemplo, Parsons (1994) analisou o Tempo de Reação para a discriminação da lateralidade de figuras de mãos. Ele empregou 5 vistas da mão (dorso, palma, vista a partir do polegar, a partir do dedo mínimo e a partir do punho) e analisou a influência do ângulo de rotação sobre o Tempo de Reação separando as rotações realizadas no sentido lateral (afastando-se da linha média do corpo) e medial (na direção da linha média do corpo). Parsons (1994) verificou que o Tempo de Reação para decidir a lateralidade do desenho de uma mão não depende somente do ângulo de rotação do desenho, mas depende principalmente da dificuldade em colocarmos a nossa mão na orientação do desenho. Baseado nestes resultados, Parsons (1994) propôs que, nesta tarefa, a pessoa não gira o desenho para a posição vertical para então decidir a lateralidade. Ao contrário, a pessoa gira mentalmente a representação interna da sua própria mão de modo a fazer com que ela se encaixe no desenho da mão mostrado na tela.
Em resumo, na tarefa de decidir a lateralidade (esquerda ou direita) da figura de uma mão mostrada na tela de um computador, a pessoa deve imaginar implicitamente a sua mão movendo-se para assumir a postura apresentada na tela e, então, verificar se o desenho é da mão direita ou esquerda a partir da correspondência ou não entre a sua mão e o desenho. Cabe ressaltar que a pessoa, geralmente, projeta inconscientemente a mão correta (direita ou esquerda) para a tela e que esta escolha automática (pré-atentiva) é confirmada ou não por processos conscientes (atentivos) posteriormente.
A nossa hipótese é que os neurônios espelho estejam envolvidos com esta tarefa detectando automaticamente tanto a postura quanto a lateralidade da figura da mão e desencadeando o movimento implícito da própria mão (ou seja, da representação mental da mão) em direção à figura. No momento, duas são as evidências (indiretas) suportando essa hipótese. A primeira é que, embora as figuras de patas/mãos de primatas antropóides (chimpanzé, gorila, orangotango e homem) sejam muito diferentes, a decisão sobre a lateralidade destas patas/mãos obedece às mesmas regras observadas na rotação mental de figuras da mão humana. Ou seja, para decidirmos se a figura de uma pata de orangotango é a esquerda ou a direita, projetamos mentalmente a nossa mão para a tela do monitor. Observou-se que é necessário algum tempo para que a orientação da representação mental da nossa mão se modifique até coincidir com a orientação da figura na tela. Isto é evidenciado pelo fato de que as posturas mais difíceis de serem reproduzidas resultam em um Tempo de Reação maior (Gawryszewski, Silva-dos-Santos, Santos-Silva, Lameira, & Pereira Jr., 2007)
A segunda evidência resulta da comparação entre as áreas corticais que são ativadas durante as tarefas clássicas dos neurônios espelho (observação de ações) e aquelas que são ativadas durante a rotação mental e a determinação da lateralidade de partes do corpo. Esta comparação é descrita no ítem a seguir.
Circuitos corticais comuns envolvidos com os neurônios espelho e com o reconhecimento da lateralidade da mão
Vários experimentos demonstram que os neurônios-espelho relacionados com a execução-observação de ações da mão, da boca e dos pés estão presentes também em humanos (Iacoboni, 2005). As áreas homólogas em humanos são o sulco temporal superior (STS), a parte rostral do lóbulo parietal inferior, e o córtex pré-motor ventral, incluindo a área de Broca (Iacoboni, 2005; Rizzolatti, 2005; Rizzolatti & Craighero, 2004; Rizzolatti et al., 2001).
Da mesma forma, a rotação mental de partes do corpo provoca a ativação de sistemas corticais e subcorticais envolvidos com o planejamento e a execução do movimento, tal como os gânglios da base, as áreas motoras e as pré-motoras. Especificamente, Parsons e Fox (1998), através de um estudo usando PET, mostraram que durante uma tarefa de discriminação da lateralidade manual, a área pré-motora suplementar (pré-SMA), as áreas de Brodmann (BA) 44/46 e 4 no hemisfério esquerdo e BA 6, 7 e 37 no hemisfério direito, estão envolvidas com o imaginário motor e a discriminação da lateralidade de partes do corpo.
Outros estudos de neuroimagem também demonstram a ativação do córtex pré-motor e do córtex parietal posterior durante o reconhecimento da lateralidade de figuras da mão (De Lange, Hagoort, & Toni, 2005; Vingerhoets, De Lange, Vandemaele, Deblaere, & Achten 2002).
Desta forma, podemos observar que ocorre uma sobreposição entre as áreas responsáveis por planejar ou simular ações da mão e as áreas do SNE. A nossa proposta é que o SNE esteja envolvido com a tarefa de discriminação da lateralidade da figura da mão, detectando a postura e a lateralidade automaticamente (reconhecimento pré-atencional), para haver depois o movimento implícito da própria mão do sujeito em direção à figura para comparar as formas e assim julgar (conscientemente) a lateralidade da figura.
Os neurônios espelho desempenham uma função crucial para o comportamento humano. Eles são ativados quando alguém observa uma ação de outra pessoa. O mais impressionante é o fato desse espelhamento não depender obrigatoriamente da nossa memória. Se alguém faz um movimento corporal complexo que nunca realizamos antes, os nossos neurônios-espelho identificam no nosso sistema corporal os mecanismos proprioceptivos e musculares correspondentes e tendemos a imitar, inconscientemente, aquilo que observamos, ouvimos ou percebemos de alguma forma.
Mas esses neurônios-espelho permitem não apenas a compreensão direta das ações dos outros, mas também das suas intenções, o significado social de seu comportamento e das suas emoções. Iacoboni et al. (2005) usaram a fMRI para demonstrar que os neurônios-espelho não codificam somente ações, mas também a intenção da ação. Nesse estudo foram apresentados três vídeos: “ação”, “contexto (sem ação)” e “intenção”. O vídeo “ação” mostrava uma mão pegando uma xícara de duas formas (preensão em pinça e em garra). O vídeo “contexto (sem ação)” mostrava uma cena com a mesa preparada para se fazer um lanche ou uma mesa com o cenário após o lanche. Os vídeos “intenção” eram a união dos vídeos “contexto” e “ação”. Ou seja, um vídeo mostrava a ação da mão (pegar uma xícara) no contexto de fazer o lanche e outro vídeo, a ação da mão no contexto de arrumar a mesa. Assim, os vídeos forneciam as pistas necessárias para entender a intenção da mão pegando a xícara. Mais especificamente, a mesa preparada para se fazer um lanche (ou após o lanche) e a mão pegando a xícara com uma determinada preensão, sinalizava que “alguém” se preparava para beber (ou para limpar a mesa). A observação de ações realizadas em contextos determinados, comparadas com as outras duas (só ação ou só o contexto), provocaram uma ativação significativamente maior no giro frontal inferior e no córtex pré-motor ventral, onde as ações da mão estão representadas. Desta forma, as áreas pré-motoras com neurônios espelho estão também envolvidas com a compreensão da intenção da ação (Iacoboni et al., 2005 ).
As emoções também podem ser espelhadas pois, quando vemos alguém chorar, por exemplo, nossas células refletem a expressão do sentimento que pode estar por trás das lágrimas e trazem de volta a lembrança de momentos que já vivenciamos. A essa capacidade dá-se o nome de empatia, uma das chaves para decifrar o comportamento e a socialização do ser humano. Essas células também refletem uma série de elementos da comunicação não verbal, como por exemplo, pequenas mudanças na face e no tom de voz nos ajudam a compreender o que o outro está pensando ou sentindo (Dobbs, 2006).
De acordo com Rizzolatti e Craighero (2004), o que caracteriza e garante a sobrevivência dos seres humanos é o fato de sermos capazes de nos organizar socialmente, e isso só é possível porque somos seres capazes de entender a ação de outras pessoas. Além disso, também somos capazes de aprender através da imitação e essa faculdade é a base da cultura humana (Ramachandran & Oberman, 2006; Rizzolatti et al., 2006)
Crianças com autismo têm grande dificuldade para se expressar, compreender e imitar sentimentos como medo, alegria ou tristeza. Por isso se fecham num mundo particular e acabam desenvolvendo sérios problemas de socialização e aprendizado. O comportamento autista reflete um quadro compatível com a falha do sistema de neurônios-espelho. O entendimento de ações (essencial para a tomada de atitude em situações de perigo), a imitação (extremamente importante para os processos de aprendizagem) e a empatia (a tendência em sentir o mesmo que uma pessoa na mesma situação sente, a qual é fundamental na construção dos relacionamentos) são funções atribuídas aos neurônios-espelho e são exatamente essas funções que se encontram alteradas em pessoas autistas (ver revisão em Ramachandram & Oberman, 2006).
Os neurônios-espelho podem explicar muitas habilidades mentais que permaneciam misteriosas e inacessíveis aos experimentos e os neurocientistas acreditam que o aparecimento e o aprimoramento dessas células propiciou o desenvolvimento de funções importantes como linguagem, imitação, aprendizado e cultura.
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sábado, 22 de maio de 2010
M Acampa and F Guideri
M Acampa, Section of Internal Medicine, Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy
F Guideri, Section of Clinical Immunology, Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy
Correspondence to: Dr M Acampa
Dipartimento di Medicina Clinica e Scienze Immunologiche, Sezione di Medicina Interna, Policlinico 'Le Scotte', viale Bracci, 53100 Siena, Italy; M.Acampa@ao‐siena.toscana.it
Accepted January 26, 2006.
Keywords: QT interval prolongation, Rett syndrome, cardiac arrhythmias, heart rate variability, sudden death
Mutations in the methyl‐CpG‐binding protein 2 gene (MECP2) are present in the majority of cases of RS, but a proportion of atypical cases may result from mutations in CDKL5, particularly the early onset seizure variant.4 MECP2 was originally thought to be a global transcriptional repressor, but recent evidence suggests that it may have a role in regulating neuronal activity dependent expression of specific genes such as brain derived neurotrophic factor (BDNF) which is important in synapse development and neuronal plasticity.4 MECP2 absence or reduction in neurones of Rett children may account for the failure of structural maturation in the brain and for the alterations in neurotransmitters, required for the regulation of normal brain development.5 Neurometabolic alterations include reduced levels of dopamine, serotonin, noradrenaline, choline acetyltransferase, nerve growth factor (NGF), endorphines, substance P, glutamate, and other aminoacids and their receptor levels in the brain.3
Rett patients may survive into middle and old age, but their life expectancy is reduced and the incidence of sudden death (SD) is greater than that of the general population. The mortality rate in RS is 1.2% for year; of these deaths, 48% occur in debilitated people, 13% are from natural causes, 13% occur in those with prior severe seizures, and 26% were SD.6 In comparison, the incidence of SD in the general population, between 1 and 22 years of age, is 1.3 per 100000 patient‐years.7 Possible causes of SD in RS include brain stem autonomic failure (respiratory failure, apnoea, cardiac arrhythmias);8 the possibility that cardiac electrical instability might be the underlying pathogenetic mechanism has prompted efforts to determine the cardiac alterations in RS.
Measurement of organ weights, as recorded in 44 postmortem examination studies, suggests that the heart grows normally until 8 years of age; thereafter the weight is less than the normal range, but it continues to increase, reaching a plateau between 16 and 20 years of age.9
Kearney and colleagues10 examined the cardiac conduction system from postmortem hearts of six RS patients (aged 7–27 years), five of which had suffered from SD. Histological examination showed a significant dispersion of conduction system fibres within the central fibrous body (archipelagos), with focal premature connections to the crest of the ventricular septum (Mahaim fibres). The "archipelagos" of the conduction system in RS resemble the immature configuration of the conduction system in the newborn and young infant, suggesting a possible development arrest in this region of the heart.
In a recent study,11 32 girls with Rett syndrome were evaluated by echocardiography: all had normal cardiac structures, dimensions, and function, suggesting that in RS there are no cardiomyopathies or cardiac valve alterations.
- Anatomical findings
- Electrocardiographic findings
- Treatment of cardiac alterations
In recent years, many studies have shown the presence of risk factors for life threatening cardiac arrhythmias in RS; in particular, a prolongation of QT corrected interval (QTc)—that is, the QT interval divided by the square root of the preceding RR interval (normal values <440 msec).12
Sekul and colleagues13 evaluated a total of 61 standard 12‐lead electrocardiograms (ECGs) in 34 individuals with RS aged 2–22 years: sinus tachycardia was observed in 6% of patients (2/34), but no other cardiac arrhythmias were observed.
Madan and colleagues14 described a case of severe sinus bradycardia in a 2 year old girl with RS, suggesting that this cardiovascular manifestation may provide an explanation for SD in these patients.
Ellaway and colleagues15 investigated the presence of cardiac tachyarrhythmias in 24 hour Holter ECG monitoring in a cohort of 34 Rett girls, and found no significant arrhythmias.
Guideri and Acampa16 studied 214 Rett girls with a 10 minute 12‐lead ECG. In one patient an asymptomatic grade 2 sinoatrial block was observed, and in another patient a ventricular tachycardia was documented before death.
Panossian and Duro17 described a case of atrioventricular dissociation with third degree atrioventricular block in a 6 month old girl with Rett syndrome.
Sekul and colleagues13 were the first to show alterations of ventricular repolarisation in RS, observing a prolongation of QTc interval (>0.45 sec) in 14/34 Rett girls (table 1), significantly more prolonged across clinical stages. They also showed non‐specific T wave changes in 18/34 Rett girls and other ECG abnormalities such as a right ventricular conduction delay (7/34), and a counterclockwise loop in the frontal plane (2/34).
Johnsrude and colleagues18 evaluated routine ECGs in 25 RS females, confirming a prolongation of QTc interval (table 1).
Guideri and colleagues19 showed in 74 Rett children a prolongation of QTc interval without any progression across the clinical stages (table 1); in Rett girls with preserved speech, QTc prolongation was only observed in 20% of patients, but QTc interval was significantly longer than in the control group (0.42±0.03 v 0.40±0.01 sec).
Ellaway and colleagues15 showed, in a cohort of 34 Rett girls, QTc values ranging from 0.38 to 0.53 sec (mean value 0.44 sec), identifying a prolonged QTc interval in 9/34 patients (table 1) without T or U wave abnormalities.
Recently, in RS, alterations of ventricular repolarisation were evaluated by means of magnetocardiographic mapping,20 showing in nine Rett girls an abnormal magnetic field gradient orientation, more altered with clinical stage and a prolongation of JT peak, JT end, QT end, T peak‐end intervals, and QT dispersion.20
Pathogenesis of QTc prolongation is still unknown; but it is well known that cardiac autonomic dysfunction may influence QTc interval duration, in particular sympathetic imbalance may increase QTc interval.21 However, Johnsrude et al showed that Rett children with QTc >0.45 sec and those with QTc <0.45 had similar heart rate variability (HRV) parameters18 (HRV represents the variation of both instantaneous heart rate and RR intervals and is considered a marker of cardiac autonomic nervous system activity22). Similarly, our group did not observe any correlation between sympathetic hyperactivity and QTc prolongation.19
Recently, we observed low NGF plasma levels in RS patients with prolonged QTc and higher QTc dispersion suggesting a role for neurotrophic factors in the alterations of ventricular repolarisation; low NGF plasma levels may cause an abnormal heart innervation pattern and an increased in QTc interval through a delayed pattern of both nexal and desmosomal junction formation and by the dispersion in the action potential duration23 (fig 11).
In particular, desmosome alteration may cause the destabilisation of myocardial cell adhesion complexes, inhibiting preservation of normal numbers of gap junctions resulting in heterogeneous conduction and significantly contributing to arrhythmogenesis.24
Cardiac autonomic nervous system
There is clinical and experimental evidence that in RS, the autonomic nervous system is abnormal at various levels.25 Julu and colleagues26 measured the autonomic reactions to hyperventilation in RS to understand the interactions between medullary autonomic and cardiorespiratory neurones, suggesting that medullary cardioinhibition is immature in RS; in particular, measuring the cardiac response to the baroreflex, he observed a reduced cardiac vagal tone, leading to sympathovagal imbalance with higher risk of cardiac arrhythmias and possibly SD.
It is well known that cardiac dysautonomia has a role in the pathogenesis of lethal ventricular arrhythmias: sympathetic stimulation lowers the ventricular fibrillation threshold, whereas vagal stimulation antagonises sympathetic activity and decreases the ventricular fibrillation threshold.27
Johnsrude and colleagues18 studied HRV parameters from 24 hour ECG ambulatory monitoring in 25 females with RS (aged 3–27 years). Diminished HRV was shown in RS with respect to the mean and standard deviation of normal RR for all 5 minute segments, root mean square successive differences, difference percentage between normal RR >50 msec, and high frequency spectral component power.
Guideri and colleagues19,28 studied the cardiac autonomic nervous system by means of HRV, and found that: (1) the total power spectrum of HRV was significantly lower in children with RS and this alteration progresses with age and with clinical stages; (2) the sympathovagal balance expressed by the ratio LF/HF (low frequency/high frequency) was significantly higher in RS, reflecting the prevalence of sympathetic activity; and (3) the girls with preserved speech variant show a slight increase of sympathetic tone but a normal values of total power of HRV (fig 22).
These results suggested that loss of physiological HRV associated with an increase of adrenergic tone and QTc prolongation may represent the electrophysiological basis of cardiac instability and SD (fig 11).
The pathogenesis of cardiac dysautonomia in RS is not well known; Julu and Witt‐Engerström observed that baseline brain stem functions (breathing rhythm, cardiac sensitivity to baroreflex, and cardiac vagal tone, which are maintained by complex integrative inhibition) are affected in RS, with heterogeneous clinical phenotypes,29 suggesting an insufficient reciprocal innervation and a leak of integrative inhibition within the cardiorespiratory neurones of the brain stem.
Neurotransmitters may also have a role in the pathogenesis of cardiac dysautonomia (fig 11):): in RS, substance P is deficient in the central nervous system, contributing to the impairment of autonomic nervous system resulting in cardiac dysautonomia.30
Furthermore, Guideri and colleagues31 observed that serotonin plasma levels are low in RS and correlated positively with sympathovagal balance (LF/HF ratio), suggesting a link between cardiac dysautonomia and serotoninergic dysfunction. Central serotoninergic pathways innervate autonomic areas involved in cardiovascular regulation;32 in particular, an increase in central nervous system serotoninergic neurotransmission reduces the susceptibility to ventricular fibrillation, because the increase in central serotonin produces a decrease in sympathetic nerve traffic to the heart.32 Therefore, it seems likely that the brain's control of sympathetic output is closely linked with central serotoninergic mechanisms (high serotonin/low sympathetic output; low serotonin/high sympathetic output).32 Recently Paterson and colleagues33 observed an altered serotonin innervation and/or uptake in the dorsal motor nucleus of the vagus (preganglionic parasympathetic outflow), suggesting a potential implication for clinical autonomic dysfunction; this alteration may be caused by an overexpression of BDNF that may potentially cause a general disruption of serotoninergic neuronal development and a specific abnormality in serotoninergic synapse formation.
An alteration of NGF levels may also contribute to an altered sympathovagal balance, because NGF also functions as a modulator of synaptic transmission between sympathetic neurones and cardiac myocytes34 (fig 11).
In RS, alterations of ventricular repolarisation and cardiac dysautonomia may contribute to life threatening cardiac arrhythmias and probably to the high incidence of SD. QTc prolongation and sympathetic hyperactivity in RS may be reduced by the use of β blockers; however, this does not represent a strong recommendation as in the inherited forms of long QT syndrome in where QT intervals reach much longer values (>500 msec). Furthermore, prokinetic agents (such as cisapride), antipsychotics (such as thioridazine), tricyclic antidepressants (such as imipramine), antiarrhythmics (such as quinidine, sotolol, amiodarone), and antibiotics (such as erythromycin, ketoconazole) should therefore be avoided because of the possibility of precipitating QT abnormalities.
Julu and Witt‐Engerström29 suggested that the pharmacological manipulation of brain stem neurotransmitters may offer a means of clinical intervention: L‐glutamate is required for baroreceptor input; serotonin receptor type 5‐HT4, angiotensin II, and enkephalin are all modulators of cardiac sensitivity to baroreflex at the nucleus of tractus solitarius; γ‐aminobutyric acid is used also to modulate cardiac sensitivity to baroreflex and cardiac vagal tone by supramedullary centres. Treatment with serotonin analogues or serotonin reuptake inhibitors may be useful in improving serotoninergic neurotransmission as well as sympathovagal imbalance. A case report of a Rett girl treated with a serotoninergic type 2A agonist (buspirone) showed a dramatic improvement in breathing pattern, but no data were reported on cardiac alterations.35
Recently Guideri and colleagues36 observed a potential pharmacological role for acetyl‐L‐carnitine, which, by exerting neurotrophic properties, may improve cardiac dysautonomia in RS; in particular, acetyl‐L‐carnitine produces a significant increase of HRV total power and a slight reduction of sympathetic overactivity.
However, large trials looking at mortality or occurrence of arrhythmias should be carried out in order to determine the role for this type of drug in protecting these patients from the risk of lethal arrhythmias and SD.
HRV - heart rate variability
RS - Rett syndrome
SD - sudden death
Competing interests: none declared
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Articles from Archives of Disease in Childhood are provided here courtesy of
Robert Didden,1 Hubert Korzilius,2 Eric Smeets,3 Vanessa A. Green,4 Russell Lang,5 Giulio E. Lancioni,6 and Leopold M. Curfs3
1Behavioural Science Institute, Radboud University Nijmegen, P.O. Box 9104, 6500 HE Nijmegen, The Netherlands
2Institute for Management Research, Radboud University Nijmegen, Nijmegen, The Netherlands
3University of Maastricht, Maastricht, The Netherlands
4Victoria University of Wellington, Wellington, New Zealand
5The Eli and Edythe L. Broad Asperger Research Center, University of California, Santa Barbara, CA USA
6University of Bari, Bari, Italy
In the present study we assessed the forms and functions of prelinguistic communicative behaviors for 120 children and adults with Rett syndrome using the Inventory of Potential Communicative Acts (IPCA) (Sigafoos et al. Communication Disorders Quarterly 21:77–86, 2000a). Informants completed the IPCA and the results were analysed to provide a systematic inventory and objective description of the communicative forms and functions present in each individual's repertoire. Results show that respondents reported a wide variety of communicative forms and functions. By far most girls used prelinguistic communicative behaviors of which eye contact/gazing was the most common form. The most often endorsed communicative functions were social convention, commenting, answering, requesting and choice-making. Problematic topographies (e.g., self-injury, screaming, non-compliance) were being used for communicative purposes in 10 to 41% of the sample. Exploratory analyses revealed that several communicative forms and functions were related to living environment, presence/absence of epilepsy, and age. That is, higher percentages of girls who showed some forms/functions were found in those who lived at home, who had no epilepsy and who were relatively young.
Rett syndrome is a X-linked neurodevelopmental disorder affecting predominantly females in early childhood. The prevalence is estimated at 1.09 per 10,000 females by the age of 12 years (Laurvick et al. 2006). It is considered to be the second most common cause, after Down syndrome, of severe intellectual disability in females. In up to 90% of individuals with Rett syndrome, mutations in the MECP2 (methyl-cpG-binding protein 2) gene can be found (Smeets et al. 2003).
Rett syndrome is characterized by a progressive decline in motor and adaptive (i.e., cognitive, communicative) functioning starting when the child is between 5 and 18 months old. The condition results in profound cognitive impairment, stereotyped hand movements, breathing abnormalities (e.g., hyperventilation), seizures, scoliosis, and motor disorders (e.g., spasticity) as a result of which the child may require the use of a wheelchair (Matson et al. 2008b). The decline follows four stages: (a) stage 1: stagnation, (b) stage 2: regression, (c) stage 3: stationary, and (d) stage 4: motor deterioration (Budden et al. 1990; Lavas et al. 2006). Eventually, the child's behavioral repertoire and responsiveness to environmental stimulation is severely limited (Sigafoos et al. 2009).
Regression and severe deficits in communicative skills are one of the major criteria for Rett syndrome. Early studies (see Budden et al. 1990; Coleman et al. 1988) reported that young children with Rett syndrome often show a range of prelinguistic behaviors that may be used for communicative purposes, but that their speech and language development was restricted to only a few single words at most. Loss of speech and language abilities most often occurred after reaching stage 1, and some children showed some form of nonverbal prelinguistic communication at later stages.
Other researchers have provided a more detailed picture of communicative forms and functions in children with Rett syndrome. For example, Woodyatt and Ozanne (1992) assessed communicative behaviors in six girls (2–13 years old) with Rett syndrome. All children had lost the ability to communicate through speech after their initial regression and showed inconsistent social-communicative responses. Their expressive language skills were all assessed as being mainly at the preintentional level, but some communicative functions were inferred from the fact that some children engaged in various prelinguistic behaviors that appeared to serve a potential communicative function, including vocalizations, facial expressions, touching, and gazing. However, a confirmed communicative function could be identified in only two children who showed prelinguistic behaviors mainly for requesting objects and for gaining social interactions. All children showed limited imitation skills and older children did not show better communication skills than younger ones.
These results suggest that some children with Rett syndrome may retain some communicative ability expressed through the use of prelinguistic behavior. If so, it would seem important to develop useful assessments to identify prelinguistic behaviors that the child may use for communication. Once identified, intervention could be targeted to strengthen the child's prelinguistic communication skills.
For the purpose of assessing the potential communicative forms and functions of existing prelinguistic behaviors in individuals with severe disabilities, Sigafoos et al. (2000a) developed the Inventory of Potential Communicative Acts (IPCA; see Method). Results of studies involving the IPCA have indicated that even when children present with extremely limited communicative and behavioral repertoires (e.g., eye gazing, body movements), they may nonetheless retain some prelinguistic acts that are interpreted by parents and teachers as communicative. Thus these retained prelinguistic acts could be seen as having some communicative functions.
The possible communicative functions that prelinguistic behaviors might serve for the child include (a) greeting, (b) conversation, (c) requesting an object, and (d) protesting and rejecting. However, these conclusions are based mainly on informant-supplied responses to the IPCA. Results from naturalistic observations to confirm these informant supplied responses remain inconclusive with respect to whether individuals' behaviors were in fact communicative (Dahlgren-Sandberg et al. 2000; Hetzroni and Rubin 2006). For example Dahlgren-Sandberg et al. assessed communicative functions in eight young women with Rett syndrome. Six of them showed some type of social interaction abilities while eye pointing was observed in only few individuals. Expressions of communicative intent (i.e. function) were rare. Also, Hetzroni and Rubin found that in eight girls with Rett syndrome (stage 4), eye gazing was the most common type of communicative behavior. As with the studies by Sigafoos et al. (2000a, b) and Dahlgren-Sandberg et al., the results of Hetzroni and Rubin suggest that is often difficult to assess the communicative function of prelinguistic behaviors in individuals with severe disabilities. However, it is unclear if this difficultly also extends to older individuals with Rett syndrome. One might suspect that over time, it may become easier to identify the communicative functions of a person's prelinguistic behaviors as these behaviors may become more situationally-specific over time and/or informants may improve in their ability to interpret the person's communicative intent over time.
There are several studies that have assessed communicative abilities in large samples of individuals with Rett syndrome and which have included both children and adults. For example, Cass et al. (2003) assessed communicative abilities in 87 children and adults with Rett syndrome who were referred to a tertiary multidisciplinary clinic. Two-thirds of the sample (66%) used eye pointing for communicative purposes and about half (51%) were able to make choices. Few (7%) used words with any communicative intent. Analyses revealed that communication abilities were not related to age or to epilepsy and breathing difficulties, though there was a significant positive correlation between communication ability and mobility and self-help skills, and a negative correlation between communication ability and oral motor dysfunction.
Results from another study (Lavas et al. 2006), involving 125 children and adults (age range 2.5–55 years) with Rett syndrome, showed that most children (69%) used one or more words during early childhood, but stopped speaking by 3 years. Forty individuals (32%) used some type of communication aid (e.g., pictures, yes/no board). However, an interesting finding was that only 4% of them used graphical means to express their will. Most individuals (90%) could express their will by eye pointing while half of the sample (55%) used vocal means (e.g., sounds, laughter, screaming) for that purpose.
While the aforementioned studies have assessed communicative behaviors in individuals with Rett syndrome, several shortcomings should be mentioned: (a) sample size was small and selected (e.g., Dahlgren-Sandberg et al. 2000; Hetzroni and Rubin 2006), (b) detailed information on communicative form (e.g., Budden et al. 1990; Coleman et al. 1988) and communicative function (e.g., Lavas et al. 2006) was lacking, and/or (c) associations between communicative form/function and other variables, such as living circumstances were not explored (e.g., Lavas et al. 2006).
The aim of the present study was to (a) assess a comprehensive range of communicative forms and functions in a large sample (n=120) of females with Rett syndrome, and (b) explore associations between form/function and other variables such as syndrome stage, presence of epilepsy/breathing difficulties, age and living setting. For this purpose, we used the Inventory of Potential Communicative Acts (see Method).
Participants and Setting
The IPCA questionnaire (see below) was sent to 190 parents who were members of the Dutch Rett Syndrome Parent Association and who had a child with Rett syndrome. In an accompanying letter, parents were asked to complete the IPCA jointly. If their child lived in a residential facility, they were asked to complete the IPCA together with a staff member who knew the child well. Parents were sent a reminder after 5 weeks. We received 120 completed IPCAs, constituting a response rate of 63%.
Participants were 120 females, and their mean age in years was 21.1 (SD=11.97; range: 5–55). Rett syndrome was confirmed (MECP2 mutation) in 89 (74%) of the cases. Of the participants, 50% had classic or typical Rett syndrome, 24% had atypical Rett syndrome while syndrome type was unknown in 26% of the participants.
Most participants (65%) lived at home with his or her parents, 35% lived in a residential facility, and/or 8% lived in a community based group home. Of the sample, 72 females (60%) had epilepsy, of which 29 (40%) were seizure-free as a result of anticonvulsive medication. Most participants (76%) had breathing difficulties/disturbances of whom 35 (38%) showed shallow breathing, 29 (32%) had hyperventilation, 70 (76%) had breath holding spells, 30 (33%) showed forced expulsion of air. Most participants (i.e., n=90; 75%) were wheelchair bound and scoliosis was present in 73 females (61%).
Inventory of Potential Communicative Acts
The IPCA is a tool for the assessment of form and function of communicative behavior in people with severe communication impairments. It seeks to identify potential communicative acts or communicative forms that may be used by an individual for any of 10 communicative functions. A potential communicative act is defined as any behavior that the informant has identified as being used by the participant for communicative purposes (Sigafoos et al. 2000a, b). The IPCA is based on an extensive review of the literature and analyses of communicative forms and functions expressed by individuals with developmental disabilities and communication impairment (see e.g. Sigafoos et al. 2000a, b; Keen et al. 2002).
In the IPCA, ten categories of communicative function are delineated and accompanying questions are used to identify the forms of behavior that the child uses to accomplish each of these ten communication function. These categories (and example questions) are (a) social convention (e.g. 'How does your child greet you?'), (b) attention to self (e.g. 'How does your child request your attention?'), (c) reject/protest (e.g. 'What does your child do if a routine is disrupted?'), (d) request an object (e.g. 'How does your child let you know that s/he wants something?'), (e) request an action (e.g. 'How does your child let you know that s/he wants help with dressing?'), (f) request information (e.g. 'How does your child let you know that s/he needs clarification if s/he does not understand?'), (g) comment (e.g. 'How does your child let you know that s/he is happy?'), (h) choice making (e.g. 'How does your child choose between two objects?'), (i) answer (e.g., 'How does your child react when someone talks to him/her?'), and (j) imitation (e.g. 'How does your child imitate something that you say or do?').
The IPCA was developed through initial field testing with 30 children with developmental disabilities and severe communication impairments (Sigafoos et al. 2000a). The results of that field testing indicated that the IPCA was appropriate for gathering descriptive information on the existing pre-linguistic communicative behaviors of children with developmental disabilities and severe communication impairments (Sigafoos et al. 2000a, b). Field testing also indicated good agreement between parents and teacher informants, suggesting the IPCA has adequate inter-informant agreement for the purpose of identifying the existing pre-linguistic communicative behaviors of children with developmental disabilities and severe communication impairments (Sigafoos et al. 2000a). The IPCA has also been shown to have adequate predictive validity for identifying intervention targets in programs aimed at replacing pre-linguistic communication acts with more formal communication skills (Keen et al. 2002; Tait et al. 2004).
The IPCA was translated into Dutch and completed by parents and caretakers who knew the participant for at least 6 months. For the purpose of this study, several additional questions were added (e.g., type and stage of Rett syndrome, age, epilepsy, breathing difficulties, scoliosis, and living setting). Parent and caregiver informants were asked to describe the communicative behaviors (i.e. forms) that s/he had observed in the individual with Rett syndrome for each of the above ten categories. In the IPCA, a wide variety of examples of communicative behaviors or forms are given as examples from which the informant may choose. These are nonsymbolic (e.g., eye gazing, pointing, facial expressions, bodily movements, vocalizations, challenging behavior) and symbolic communicative behaviors (e.g., use of pictures, and pointing to a picture on a communication board). Informants were encouraged to mention other communicative behaviors that were not included in the list of examples of communicative acts.
Each returned IPCA was summarized and entered into tables for analysis. The first analysis was percentage of individuals with Rett syndrome who showed each communicative form for each of the ten communicative functions. This was calculated for the overall sample based on the communicative behaviors that were mentioned by respondents. Following this, comparisons were made of the percentage of individuals that showed each communicative form and function by syndrome stage, presence of epilepsy/breathing difficulties, age, and living environment. These comparisons were made using chi-square analyses.
Percentages of females with Rett syndrome who showed communicative forms for each of the ten communicative functions are shown in Table 1. Most of the communicative behaviors are pre-linguistic or non-symbolic. A variety of communicative forms were used of which the most common types were eye contact/gazing and laughing/smiling. Only 15 to 16% of the females used some type of symbolic communication (i.e. speech/words) for the purpose of requesting. In our sample, other symbolic communication forms, such as manual signs or voice output devices, were not mentioned by respondents. The most often endorsed communicative functions were social convention, commenting, answering, requesting and choice-making. Problematic topographies (e.g., self-injury, screaming, non-compliance) were being used for communicative purposes in 10 to 41% of the sample. Such topographies were mainly used for the purpose of commenting, and requesting an object, attention and/or action. Finally, only a small number of females (13%) showed stereotyped hand movements and this behavior was shown for the purpose of commenting.
Percentages of females with Rett syndrome showing communicative forms for each of the ten communicative functions
Tables 2, 3 and 4 show percentages of females with Rett syndrome that showed communicative forms and functions as related to other variables. Outcomes were compared for females living at home and those living in a residential facility (Table 2), females with and without epilepsy (Table 3), and females in different age groups (Table 4).
Percentage of females with Rett syndrome who are living at home and in a residential facility and who show functions and forms of communicative behaviors, chi-square and p-values
Percentage of females with Rett syndrome with and without epilepsy who show forms and functions of communicative behavior, chi-square and p-values
Percentage of children (4–12 years), youth (13–21 years) and adults (22–54 years)with Rett syndrome who show functions and forms of communicative behaviors, chi-square and p-values
Results in Table 2 show that there were significant differences between females with Rett syndrome who lived at home and those living in a facility in 'eye contact/gaze' for the purpose of rejecting and protesting and requesting an object. Other significant differences were for 'laughing/smiling' (for choice-making and answering), and 'vocalizations' (for request an action). In general, several communicative forms and functions were most often found in females who lived at home than in those living in a facility except for 'closing eyes' which was more often found in females living in a facility.
The presence or absence of epilepsy was related to communicative forms in that more females without epilepsy used 'approaching of another person' for the purposes of social convention and drawing attention to oneself than females with epilepsy. Females without epilepsy for example were more often 'looking happy' for the purpose of answering than those with epilepsy. Generally, communicative forms and functions were more common in females without epilepsy than in those with epilepsy.
There were several significant differences in communicative forms/functions between age groups (see Table 4). For example, results suggest a linear trend across age groups in the percentage of females with Rett syndrome in terms of communicative forms for the purpose of attracting attention to self, requesting objects, and choice-making.
Overall, results of the exploratory comparative analyses revealed that several communicative forms and functions were significantly related to living environment, presence/absence of epilepsy, and age. That is, higher percentages of females who showed some forms/functions were found in those who lived at home, who had no epilepsy and who were relatively young.
Communicative forms and functions were explored in a large sample of females with Rett syndrome. Respondents reported a wide variety of forms and functions in this group. By far most females used prelinguistic communicative behaviors of which eye contact/gazing was the most common form. Females with Rett syndrome only rarely use symbolic forms for communication. These results are largely in agreement with those of other studies in this area (see e.g. Cass et al. 2003).
Comparative analyses revealed that some prelinguistic forms and functions of communicative acts for females with Rett syndrome were related to living environment, presence/absence of epilepsy, and age. In general, it may be concluded that communicative forms and functions were more prevalent in females who lived at home, in those without epilepsy and in those that were relatively young. These results should however be viewed with caution as our study was mainly descriptive and there may be interaction effects between these variables that might explain differences between subsamples. Our finding that communicative abilities were related to age and epilepsy are not in agreement with results from the study by Cass et al. (2003). Furthermore, our finding that very few females used symbolic communication skills (e.g. words) is not in agreement with findings from a study by Lavas et al. (2006) who found that more than one third of their sample used some type of symbolic communication (e.g. communication aids such as picture boards). However, it appeared that in the Lavas et al.'s study participants did not use these aids for communicative purposes.
It appears that communicative forms and functions are more developed in females with Rett syndrome who live at home as compared to those who live in a residential facility (see Table 2). Similar findings were reported by Didden et al. (2009) who investigated communicative forms and functions using the IPCA in 79 individuals with Angelman syndrome. One reason for this outcome is that in home environments communicative behaviors (e.g. eye contact/gaze, approaching) are more often elicited and reinforced than in residential facilities. The level of adult attention is much higher in home settings than in residential facilities. Prelinguistic behaviors that are spontaneously used by females with Rett syndrome may be extinguished if these behaviors (forms) are not elicited and reinforced by caregivers in residential settings.
It is suggested that intervention should focus on developing further the joint attention behaviors, intentional communications and communicative functions spontaneously used by individuals with disorders in the Rett syndrome complex (Dahlgren-Sandberg et al. 2000). Two intervention studies by Sigafoos and his colleagues (i.e., Sigafoos et al. 1995, 1996) in a case series showed that children with Rett syndrome may be taught to express choices via eye gazing and reaching and requesting via a "want" symbol. Results of these studies suggest that children with Rett syndrome may display intentional alternative communicative behaviors and that such behaviors may be taught using instructional procedures (see Duker et al. 2004; Sigafoos et al. 2009).
Several limitation of the study should be mentioned. A limitation of the present study is that we did not compare outcomes to those of one or more control groups thereby limiting the generality of our findings. Comparative studies in which a sample of individuals with Rett syndrome are included have been rarely conducted. For example, Matson et al. (2008a) compared communicative skills of a small group (n=6) of adult females with Rett syndrome to adults with autism and controls. The groups were matched according to age, gender and level of intellectual disability. They found no significant differences between groups in communication abilities. A second limitation is that the validity of our conclusions is unknown. We do not know if the communicative behaviors are indeed communicative as mentioned by parents/caregivers. Especially in individuals with Rett syndrome it is difficult to assess communicative forms and functions of (prelinguistic) behaviors (see e.g., Dahlgren-Sandberg et al. 2000). However, Sigafoos et al. (2000b) have shown that outcomes of the IPCA were in agreement with those of naturalistic observations in a small number of girls with Rett syndrome suggesting that communicative forms and functions may be identified in these individuals. Finally, due to the relatively small sample size, we were not able to analyse interaction effects. That is, associations between communicative forms/functions and other variables may be influenced by their interactions with 'third' variables.
We thank the parents and caregivers of individuals with Rett syndrome for their participation.
Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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The association between behaviour and genotype in Rett Syndrome using the Australian Rett Syndrome Database
Laila Robertson,1 Sonĵa E Hall,2 Peter Jacoby,1 Carolyn Ellaway,3,4 Nick de Klerk,1 and Helen Leonard1
1 Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia
2 School of Population Health, University of Western Australia
3 Western Sydney Genetics Program, The Children's Hospital at Westmead
4 Department of Paediatrics and Child Health, University of Sydney
Author for Correspondence: Ms Laila Robertson, Telethon Institute for Child Health Research, PO Box 855, West Perth, WA, AUSTRALIA 6872, Ph: +61 9489 7928, Fax: +61 9489 7700, Email: email@example.com
This study compared the behaviour profile of cases in the Australian Rett Syndrome Database (ARSD) with those in a British study using the Rett Syndrome Behaviour Questionnaire (RSBQ) then examined behavioural patterns as measured by the RSBQ by genetic status. There were 145 Australian cases meeting the criteria for the first arm of the study and 135 for the second arm. Comparison of the scores obtained from the British and Australian cohorts indicated that the RSBQ was a satisfactory measure for describing behaviours in Rett syndrome (RS). Overall, there were some differences amongst the behaviour patterns of cases with the well-known common mutations. Fear/anxiety was more commonly reported in those with R133C and R306C. Those with the R294X mutation were more likely to have mood difficulties and body rocking but less likely to have hand behaviours and to display repetitive face movements. In contrast, hand behaviours were more commonly reported in those with R270X or R255X. We found the RSBQ is an appropriate instrument for measuring behaviour in girls with RS. Some behaviours differ according to genetic mutation but there is both inter and intra mutation variation in behaviour and there is a need for larger studies involving international collaboration to improve statistical power.
Rett syndrome (RS) is a neurodevelopmental disorder that affects 1 in 10 000 females (Leonard et al. 1997) and rarely occurs in males. Although studies have shown that some female cases may not have a period of normal early development (Leonard and Bower 1998; Leonard et al. in press; Nomura et al. 1984), this disorder is almost impossible to identify at birth, and there are usually no specific differentiating features until the onset of regression at 6-18 months of age. Clinical criteria (The Rett Syndrome Diagnostic Criteria Work Group 1988) and a four-stage progression model (Hagberg and Witt Engerstrom 1986) were developed to assist medical practitioners with the diagnosis of RS, but the stage to stage transition is not always clearly defined. There is considerable variability with respect to age of onset (Charman et al. 2002; Coleman et al. 1988; Goutieres and Aicardi 1986; Kerr et al. 1987), nature of the regression (Fiumara et al. 2002; Zappella 1992), clinical outcomes (Colvin et al. 2003), and expression of behaviours (Coleman et al. 1988; Mount et al. 2002a; Mount et al. 2001; 2002b; 2003; Sansom et al. 1993).
Genetic testing now plays an important role in RS diagnosis. In 1999, mutations within the MECP2 gene encoding X-linked methyl–CpG-binding protein 2 (MeCP2) were identified as the major cause of RS. While over 200 pathogenic mutations have been identified (Christodoulou and Grimm 2003), there are eight C>T transition mutations (T158M, R168X, R255X, R270X, R306C, R294X, R133C and R106W) accounting for 69% of mutation positive cases (Christodoulou and Grimm 2003). Variation in individual behaviours and the pattern of regression may be related to genotypic differences within RS (Mount et al. 2002a). There is evidence of a relationship between genotype and clinical severity, with some mutations having either a milder or a more severe clinical course (Colvin et al. 2003; Colvin et al. 2004; Fukuda et al. 2005; Huppke et al. 2002; Leonard et al. 2003; Schanen et al. 2004; Smeets et al. 2003).
Behavioural manifestations commonly seen in RS include pathognomonic hand stereotypies and breathing abnormalities (The Rett Syndrome Diagnostic Criteria Work Group, 1988). The diagnostic criteria for RS were recently revised and now include impaired sleep pattern from infancy and bruxism (Hagberg et al. 2002). Inappropriate vocalisation, night laughing and mouth grimacing, thought to be common in this disorder, are often associated with other causes of intellectual disability but should not be disregarded in RS research. Inappropriate vocalisation may restrict the ability of those families to interact with the community and sleep disturbances, and can be difficult to manage and burdensome for parents (Hunter 2002).
As more information becomes available about the genetic causes of intellectual disability (Poplawski 2003), there has been greater recognition of the association of syndrome specific behavioural symptomatology with genetic disorders (Dykens and Hodapp 2001). In an attempt to better delineate the behaviour profile of RS, Mount et al (2002) used the Developmental Behaviour Checklist (Einfeld and Tonge 1995) to compare the behaviour of girls with RS with a group of females with the same level of intellectual disability. They found that although girls with RS had a consistently higher score in the autistic related domain, there were qualitative differences between the behaviours seen in the two groups that could not be differentiated by the Developmental Behaviour Checklist (Mount et al. 2003). By reviewing published literature and consulting with parents and physicians about the behaviours found in RS in comparison with other intellectual disabilities, they devised the Rett Syndrome Behaviour Questionnaire (RSBQ). It contains 42 items designed to measure behaviour frequency and severity. The items are rated from 0-2 (Mount et al. 2002a) with a score of zero indicating the behaviour is not true for an individual; 1 meaning the behaviour is somewhat or sometimes true in the individual and 2 meaning that the behaviour is often or very true in the individual. The behaviours were organised, using factor analysis, into 8 domains: General Mood, Breathing Problems, Hand Behaviours, Repetitive Face Movements, Body Rocking and Expressionless Face, Night-time Behaviours, Fear/Anxiety, and Walking/Standing. The authors trialed the RSBQ on a cohort of females, identified through the UK Rett Syndrome Association and compared them with a group of girls of similar intellectual disability identified through local special needs schools.
The Australian Rett Syndrome Database (ARSD), which commenced in 1992, is an on-going population-based registry of Australian RS cases born since 1976. Cases are recruited from a variety of sources and ascertainment is considered almost complete (Leonard et al. 1997). Families and clinicians provide data on enrolment and follow up questionnaires, administered to parents and carers every two years (Colvin et al. 2003), seek information on various aspects of RS, including measures of current behaviour using the RSBQ and functional ability using a questionnaire version of the WeeFIM (the Functional Independence Measure for Children)(Ottenbacher et al. 1999). Genetic testing was initiated for the cohort in 2000 (Weaving et al. 2003).
We have only encounterd one instance of the RSBQ's research application (Charman et al. 2005) since the UK group published their initial work (Mount et al. 2002a). Our present study aimed to compare RSBQ scores in the ARSD with the UK cohort and to use the RSBQ scores to investigate behavioural differences associated with mutation effects in the Australian cohort.
Materials and Methods
This analysis is based on data on 246 verified female cases of RS included in the ARSD in 2003. A follow-up questionnaire had been completed on 187 of these in 2002, and on a further 14 only in 2000; therefore, current behaviour had been reported on a total of 201 (82%) at one of the follow-up times. The majority (179/201) had undergone molecular testing and of these 135 had a mutation identified in the MECP2 gene. This cohort of 135 subjects was used to investigate the association between mutation type and behaviour profile. To compare the Mount cohort and the ARSD with respect to frequency and severity of current behaviour we included the 145 cases who were aged less than 19 years and had had one follow-up questionnaire completed, irrespective of their mutation status.
Each domain of the RSBQ is calculated as the total score for all questions in that domain (Mount et al. 2002a). As we used an earlier version of the RSBQ (personal communication Rebecca Mount) one question Makes repetitive face movements involving fingers around the tongue was missing and the analysis had to be adjusted to account for this.
Mutation testing was performed in molecular genetics laboratories in Perth and Sydney using previously reported methods (Weaving et al. 2003). Commonly occurring mutations were coded individually. Mutations were deemed common when their frequency was greater than six, thus only the following seven mutations: T158M, R168X, R294X, R270X, R133C, R306C and R255X were coded as discrete entities. C-terminal deletions were coded as a separate group and the remaining mutations including R106W were allocated to the category "other mutations".
Analysis of variance (ANOVA) was used to estimate the marginal mean RSBQ domain scores and 95% confidence intervals for each mutation type in the ASRD cohort. For comparing the proportions of individuals exhibiting behaviour in each question item between the ARSD registry and the Mount cohort, cross-tabulations were performed and chi-square statistics calculated. For investigating differences in severity of behaviour between the ARSD registry and the Mount cohort, one-sample t-tests were used to compare individual ARSD domain scores with mean domain scores from the Mount cohort. Individual domain scores from the Mount cohort were unavailable. Because of the large sample size (n=145), t-tests applied to mean scores do not violate distributional assumptions. Multiple Discriminant Analysis was used in determining to what extent individual mutations could be identified by discriminant function values comprising linear combinations of RSBQ domain scores. SPSS V11.0 was used to perform all the analyses.
The age of females in the genetic analysis ranged from 2.8 to 27.4 years (mean=14.1; SD=6.2). Those older than 19 years were excluded from comparison with the Mount cohort.
Behaviours identified in the RSBQ were reported to occur at similar frequencies in the ARSD population and the Mount cohort in 38 of 42 (90%) questions (Table 1). In three items (Q14, 24 & 26, Table 1) the behaviour was reported to occur significantly more commonly in the ARSD population, and in one item (Q2, Table 1) significantly less commonly. Comparison of the two cohorts at the domain level, gave an indication of the difference in severity of behaviour between the two cohorts (Table 2). A higher domain score relates to more severe or frequent behaviour in the cohort. For the domains of hand behaviour, body rocking/expressionless face and face movement, the ARSD cohort had a higher domain score, suggesting this behaviour domain was more frequent or severe in the ARSD cohort than in the Mount cohort. There was no statistically significant meaningful difference between the two cohorts in the remaining five domains.
Proportion of cases for which behavioural items were stated as 'somewhat true' or 'always true'
ARSD cohort and UK group mean scores on the RSBQ
The distribution of mutations in the genetic cohort is shown in Figure 1. Ninety-three of the 135 females in this cohort had one of eight commonly recognised mutations. Thus, the common mutations made up 69% (66% excluding R106W) of all MECP2 mutations in this cohort. In 44 cases no MECP2 mutation was detected.
Frequency of common mutations in the ARSD
The mean total RSBQ score varied by mutation but not significantly (p=0.52). The overall mutation effect did not account for a significant variation in any of the domain scores. However, the individual mutations that appeared most often to be different from the other mutations were R294X, R306C and R270X.
Cases with R294X were more likely to have mood difficulties (Figure 2.1), body rocking (results not shown) and night-time behaviours (Figure 2.2) but less likely to have hand behaviours (Figure 2.3) and to display repetitive face movements (results not shown). They also had a higher score for the walking or standing domain (results not shown). Similarly, those with R133C were more likely to have mood difficulties (Figure 2.1) and night-time behaviours (Figure 2.2) and less likely to have hand behaviours reported (Figure 2.3). They were also reported to experience more fear or anxiety (results not shown). The pattern with R306C was similar to R133C with respect to the mood difficulties (Figure 2.1) and fear or anxiety (results not shown) but not in relation to hand behaviours (Figure 2.3). These cases were also more likely to have body rocking and repetitive face movements reported (results not shown). Those with T158M were less likely to have mood disturbances (Figure 2.1) reported than the three previous mutations described whilst hand behaviours (Figure 2.3) were relatively commonly reported.
Figure 2.1:Estimated marginal mean scores and 95% Confidence Interval for General Mood Score between common mutations
Cases with R270X had the lowest score for the walking/standing domain (results not shown). They had more hand behaviours (Figure 2.3) and repetitive face movements as well as night-time behaviours (results not shown). Cases with R255X also had more hand behaviours reported (Figure 2.3). On the other hand cases with R168X were most likely to have repetitive face movements and less likely to have hand behaviours (Figure 2.3) or fear or anxiety reported. In contrast, the cases with C-terminal deletions were reported to have more severe hand behaviours (Figure 2.3) and body rocking but less repetitive face movements.
Discriminant analysis classified 26.7% of individuals into the correct mutation category based on combinations of RSBQ domain scores. This success rate fell to only 9.9% when cross-validation was used. The discriminant model performed best in identifying C-terminal deletion cases with 25.0% of these individuals correctly classified using cross-validation. Overall, the discriminant model was not significant (Wilks' Lambda Chi-Square (56df) = 49.7; p=0.71).
We established that behaviours described by Mount et al (2002), in an opportunistic sample of 143 girls identified through the UK Rett syndrome parent association, were similar to those of the Australian population-based Rett syndrome cohort. When behaviours were grouped at the domain level, we found that the ARSD cohort differed significantly in 3/8 behaviours with higher scores, in the ARSD cohort in each case.
These differences in behaviour could be related to study design. Our study surveyed families of cases in the only ongoing population-based RS cohort where the process for diagnostic verification uses information from both clinicians and families and in most cases molecular data (Colvin et al. 2003; Leonard and Bower 1998; Leonard et al. 1997). On the other hand the Mount study (2002a) had less rigorous inclusion criteria, which could have resulted in a case group diluted by subjects without a clinically verified diagnosis of RS. The fact that in three of the eight domains behaviour occurred more frequently in the ARSD cohort than in the Mount cohort supports this hypothesis. Moreover, our questionnaire response fraction was considerably higher than in the UK sample (82% compared with 50%). It is, therefore, possible that the behaviour represented in our study may be more reflective of RS than the Mount study.
The main aim of this study was to determine whether the RSBQ could be helpful in capturing the behavioural phenotype associated with genetic variation in RS. Despite the small sample size, we consider that there was evidence of a pattern suggesting that cases with mutations R294X, R133C and R306C were more likely to exhibit behaviours relating either to mood, fear and anxiety or body rocking. Conversely, with one exception (R306C), these cases were less likely to exhibit hand behaviours. On the other hand, the cases with R270X and R255X mutations, both located in the nuclear localisation signal (NLS) region within the transcription repression domain (TRD), were more likely to manifest hand behaviours.
The RSBQ has eight behavioural domains (Mount et al. 2002a) representing behaviours both commonly recognised in RS as well as those identified much less frequently in the literature (Mount et al. 2001). The features reported in the general mood domain are not typically reported in RS other than during the regression period, following which there is said to be a period during which subjects are said to "wake up" and become more communicative. Two early studies did report screaming fits in 53/63 (Coleman et al. 1988) and 7/22 subjects (Naidu 1990). Our study and the UK study (Mount et al. 2002a) show that a substantial proportion of individuals have behavioural and mood difficulties which persist beyond regression.
The breathing problems domain, consisting principally of episodic hyperventilation and apnoeas during wakefulness, relates to one of the supportive criteria noted early in the history of RS. Recent research has comprehensively described the spectrum of breathing abnormalities and their relationship to autonomic dysfunction (Julu et al. 2001); however, information on clinical management is still lacking.
The hand behaviours domain included hand stereotypies and loss of purposeful hand function, which are hallmark features of the RS and necessary for diagnosis of the syndrome (Hagberg et al. 2002). Yet, research characterising the nature, course and mechanism of the hand stereotypies is limited (Mount et al. 2002a). The "repetitive face movements" which often include the tongue could also be considered to be part of the spectrum of stereotypical movements in RS or they could also be a manifestation of extrapyramidal features described early in RS research (Fitzgerald et al. 1990).
The Body rocking and expressionless face domain is somewhat heterogeneous in its inclusion of both eye gaze and expressionless face. Recently included in the supportive criteria for the atypical form (Hagberg et al. 2002) the eye gaze and use of 'eye pointing' to communicate are features which can help distinguish RS from other causes of severe intellectual disability. These behaviours are generally seen after the wake-up period before which RS may often be confused with autism (Percy et al. 1990; Percy et al. 1988). Rocking movements and expressionless face, which are less defined and overlap with features of autism, were recorded in 16% and 29% respectively of the reports including behavioural features reviewed by Mount (Mount et al. 2001).
The night-time behaviours domain included both laughing and the screaming, which are recognised features of RS (Hagberg et al. 2002) for which a pathophysiological mechanism has not been identified. Different methodologies have been used to examine sleep behaviour and have generally found night sleep to be disturbed, but compensated for, by an increase in day-time naps (Ellaway et al. 2001; Piazza et al. 1996). Research into the natural history of sleep disorders in RS over time is lacking.
Behaviours in the fear/anxiety domain such as "fear in unfamiliar situations" were reported in 46/63 cases in Coleman's study (Coleman et al. 1988) and anxiety in 81/107 cases in UK study (Sansom et al. 1993). It is difficult to surmise the underlying pathophysiology of these behaviours; however, they could be related to autonomic dysfunction.
The walking and stiff leg domain characterises the manifestation of the motor impairment and spasticity associated with this RS, which is recognised as necessary criteria (Hagberg B. et al. 2002). However, we found low functional ability (as measured by WeeFIM score) was associated with the absence of behaviours in the walking/standing domain, indicating cases with a higher score were more mobile (Robertson 2003). A higher score, such as in this example, will not necessarily be associated, as would be expected, with a more severe behavioural/functional outcome. Domain scores, when considered in relation to one another, can provide a behaviour profile that reflects the characteristics of cases with specific mutations.
One of the strengths of this study is that it is population-based (Colvin et al. 2003; Leonard and Bower 1998; Leonard et al. 1997) and therefore there should be minimal selection bias and the results should be generalisable. This study also has more cases than many other studies investigating the relationship between genotype and phenotype (Hoffbuhr et al. 2001; Huppke et al. 2002; Schanen et al. 2004). Nevertheless, the numbers of cases with individual mutations remain small. We only had 16 cases with a T158M mutation, the most commonly reported hot-spot mutation representing 12.1% of pathogenic mutations (Christodoulou and Grimm 2003). Thus, analytical power remains low and it is not surprising that the discriminant model was not statistically significant.
A number of scoring systems have already been developed and some further modified to quantify clinical severity (Amir and Zoghbi 2000; Hoffbuhr et al. 2001; Huppke et al. 2002; Leonard et al. 2003; Monros et al. 2001). Commenting that mildly affected girls could be more restless and aggressive; Huppke et al (2002) suggested that clinical severity may not necessarily reflect social severity in RS. This is consistent with the clinical observations of authors HL and CE. Nevertheless, our results support findings from previous analyses of the association between clinical variability and genetic characteristics. Three mutations having both a milder phenotype and more likely to be found in those surviving to adolescent/adulthood (Smeets et al. 2003) are the R133C (Leonard et al. 2003), R294X (Colvin et al. 2003) and R306C mutations (Fukuda et al. 2005; Kerr A. M. and Prescott in press; Schanen et al. 2004). We found cases with these mutations were more likely to exhibit behaviours relating to mood and body rocking and less likely to demonstrate hand behaviours. Cases with R306C and R133C showed more fear and anxiety. In contrast, cases with R270X appeared to show more hand behaviours and have a lower score on walking/standing, suggesting they were less mobile. This mutation has been found to have a more severe clinical phenotype (Colvin et al. 2004; Leonard et al. in press). Our interpretation of these findings is that individuals with R133C, R294X and R306C mutations have a milder phenotype and are functioning at a higher level so are more capable of externalising and demonstrating such behaviours than subjects with more severe mutations, such as the R270X mutation. It is possible that for family and carers, the burden of caring for subjects in the milder group is equally or more demanding than it is for those with more severe functionally incapacitating mutations.
In summary we have used the RSBQ to investigate the possibility of identifying variation in behavioural phenotypes associated with specific MECP2 mutations. We found that patterns of behaviour differ between groups of mutations previously shown to have either a mild or a severe phenotype but due to the rarity of RS the statistical power was limited. This work forms a useful basis for future international collaborative studies that could be carried out through InterRett, an international RS database where data collection is not limited to cases from one country (Moore et al. 2005).
The ARSD currently is funded by National Institute of Child Health and Human Development (1 R01 HD43100-01A1) and was previously funded by Financial Markets Foundation for Children and the Rett Syndrome Australian Research Fund. Helen Leonard is funded by NHMRC program grant 353514. We gratefully acknowledge Dr Rebecca Mount for the RSBQ, the families who participate in the ARSD, and the Australian Paediatric Surveillance Unit and the Rett Syndrome Association of Australia.
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