Three different profiles: Early socio-communicative capacities in typical Rett syndrome,the preserved speech variant and normal development

Background and aims: This is the first study aiming to compare pre-diagnostic socio-communicative development of a female with typical Rett syndrome (RTT), a female with the preserved speech variant of RTT (PSV) and a control toddler.

Methods: We analysed 1275?min of family videos at the participants’ age between 9 and 24 months and used the Inventory of Potential Communicative Acts (IPCA) to delineate their repertoires of communicative forms and functions.

Results: The results revealed different profiles for the three different conditions. The repertoire of communicative gestures and (pre)linguistic vocalizations was most comprehensive in the control toddler, followed by the female with PSV and the female with RTT.

Conclusion: These findings contribute to the growing knowledge about early developmental abnormalities in RTT. In order to define distinctive profiles for typical and atypical RTT and evaluate their specificity, a larger body of evidence is needed.     

Comparing social reciprocity in preserved speech variant and typical Rett syndrome during the early years of life

This study compared early markers of social reciprocity in children with typical Rett syndrome (RTT) and in those with the preserved speech variant (PSV) of RTT. Retrospective video analysis of 10 toddlers with typical RTT and five with PSV investigated participants’ orientation to their name being called between the ages of 5 and 24 months, prior to their diagnosis. From analysis of the recordings two distinct profiles were apparent. Although response rate was higher in girls with typical RTT than PSV at 5 to 8 months this noticeably reversed from 9 to 12 months onwards. By two years of age there was a markedly higher rate and range of responses from girls with PSV. This study contributes to the delineation of different profiles for the variants of RTT.     

Case Report: Retracing Atypical Development: A Preserved Speech Variant of Rett Syndrome

The subject of the present study is the development of a girl with the preserved speech variant of Rett disorder. Our data are based on detailed retrospective and prospective video analyses. Despite achieving developmental milestones, movement quality was already abnormal during the girl's first half year of life. In addition, early hand stereotypies, idiosyncratic vocalizations, asymmetric eye opening, and abnormal facial expressions are early signs proving that this variant of the Rett complex, too, manifests itself within the first months of life.     

Profiling early socio-communicative development in five young girls with the preserved speech variant of Rett syndrome

Rett syndrome (RTT) is a developmental disorder characterized by regression of purposeful hand skills and spoken language, although some affected children retain some ability to speech. We assessed the communicative abilities of five young girls, who were later diagnosed with the preserved speech variant of RTT, during the pre-regression period (aged 12-24 months). Videotapes, obtained by parents during routine family situations and celebrations, were analyzed to identify communicative forms and functions used by these toddlers. Non-verbal communicative forms dominated over verbal-communicative forms for six of the eight identified communication functions. Although the girls used various non-verbal forms to make requests, for example, none of the individuals were observed to make choices or request information. Early peculiarities in the speech-language domain during the first year of life became more prominent and evident during the second year of life as general differences between typical development and atypical development become more obvious in RTT. These findings highlight the importance of assessing socio-communicative forms and functions at early age in children with RTT. The results suggest that speech-language functions did not appear to play a major role in the children's communicative attempts. We conclude that, even among children with the preserved speech variant, socio-communicative deficits are present before regression and persist after this period.     

Early socio-communicative forms and functions in typical Rett syndrome

Rett syndrome (RTT) is a severe neurological disorder characterized by a developmental regression in motor and speech-language domains. There is, however, limited research on socio-communicative development of affected children before the onset of regression. We analyzed audio–video recordings made by parents of six 9- to 12-month old girls later diagnosed with typical RTT, applying the Inventory of Potential Communicative Acts (IPCA) to identify early communicative forms and functions. Each girl used at least one communicative form (e.g., body movement, eye gaze, or vocalizations) to gain attention and answer, but none were observed to make choices or request information. Varying numbers of children were observed to perform other communicative functions according to the IPCA including social convention, rejecting or requesting an object. Non-verbal forms (e.g., reaching, moving closer, eye contact, smiling) were more common than non-linguistic verbal forms (e.g., unspecified vocalizations, pleasure vocalizations, crying). (Pre-)linguistic verbal forms (e.g., canonical or variegated babbling, proto-words) were not used for communicative purposes. These data suggest that atypical developmental patterns in the socio-communicative domain are evident prior to regression in young individuals later diagnosed with RTT.     

Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms

A total of 45 different mutations of methyl-CpG-binding protein 2 gene (MECP2) were identified in 145 of 219 Japanese patients with typical or atypical Rett syndrome (RTT) (66.2%). A missense mutation, T158M was the most common mutation of MECP2, identified in 22 (19.1%) patients, followed by four nonsense mutations, R168X (14.8%), R270X (13.0%), R255X (9.6%), and R294X (6.1%) in 115 patients with classical RTT. Two missense mutations, R133C (33.3%) and R306C (23.3%), and a nonsense mutation, R294X (13.3%), were common in 30 patients with atypical RTT, including the preserved speech variant (PSV). Frameshift mutations due to nucleotide deletion or insertion were identified in 22 patients with MECP2 mutations, and one of them had a 3.6 kb deletion encompassing exons 3 and 4. Three patients with classical RTT had a splicing anomaly. The wide spectrum of phenotypic variability in patients with RTT has been considered to be correlated with the mutation type and location in MECP2, and X-inactivation. However, most patients showed a random X-inactivation pattern evaluated by an androgen receptor gene polymorphism in this study, suggesting that a skewed X-inactivation might not be a main modification factor on clinical phenotypes of RTT. In addition, three new missense mutations, P176R, A378V and T479M, were identified in patients with RTT, but also in healthy Japanese, indicating that these mutations are non-pathogenic in Japanese. Information about rare polymorphic variations is very important for the molecular diagnosis of RTT, although rare polymorphic variants might differ among ethnic groups.     

Mutation analysis of the methyl-CpG-binding protein 2 gene (MECP2) in Rett patients with preserved speech

Genomic DNAs from 35 Japanese sporadic patients with Rett syndrome (RTT) were screened for DNA mutations in the entire coding region and exon–intron boundaries of methyl-CpG-binding protein 2 (MECP2). We detected mutations in 30 (85.7%) of 35 patients. Among these 35 RTT patients, five patients (14%) had the preserved speech variant of this disease. Four respective mutations (R133C, R306C, R294X, 2 base pair (bp) deletion) were found in these five patients. Two patients had the same missense mutation, R133C. The patients with the R133C mutation and one with frameshift mutation presented the relatively mild clinical presentation, and the R133C mutation was not found in any other patient without preserved speech. We confirmed that the preserved speech variant is one of the clinical phenotypes of RTT and is also caused by MECP2 mutation. We speculated that the clinical phenotype of patients with the R133C missense mutation might be mild.     

Contributing to the early detection of Rett syndrome: the potential role of auditory Gestalt perception

To assess whether there are qualitatively deviant characteristics in the early vocalizations of children with Rett syndrome, we had 400 native Austrian-German speakers listen to audio recordings of vocalizations from typically developing girls and girls with Rett syndrome. The audio recordings were rated as (a) inconspicuous, (b) conspicuous or (c) not able to decide between (a) and (b). The results showed that participants were accurate in differentiating the vocalizations of typically developing children compared to children with Rett syndrome. However, the accuracy for rating verbal behaviors was dependent on the type of vocalization with greater accuracy for canonical babbling compared to cooing vocalizations. The results suggest a potential role for the use of rating child vocalizations for early detection of Rett syndrome. This is important because clinical criteria related to speech and language development remain important for early identification of Rett syndrome.     

Memory impairment in children with language impairment

Aim The aim of this study was to assess whether any memory impairment co‐occuring with language impairment is global, affecting both verbal and visual domains, or domain specific. Method Visual and verbal memory, learning, and processing speed were assessed in children aged 6 years to 16 years 11 months (mean 9y 9m, SD 2y 6mo) with current, resolved, and no language impairment using the Wide Range Assessment of Memory and Learning (WRAML), a standardized memory and learning test for children, and the Children’s Test of Non‐Word Repetition (CNRep), a test of phonological short‐term memory. Fifty‐one children (38 males, 13 females) with current speech and language impairment from 49 families were compared with 13 siblings (11 males, 2 females) with a past history of language impairment and 26 (15 males, 11 females) who had never had language impairment. Results Children with current language impairment showed impairment in all verbal memory measures compared with children who had never had language impairment, and these impairments were still evident in children with a past history of learning impairment. Visual memory and learning were not impaired compared with children who had never had language impairment. The severity of verbal memory impairment correlated with the degree of language impairment. Interpretation We concluded that in language impairment there is domain specificity of memory impairment affecting verbal processing.     

Mutation spectrum and genotype-phenotype correlation of MECP2 in patients with Rett syndrome

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder characterized by regression in cognition and adaptability with autistic behavior, stereotypical hand movements, epilepsy and ataxia. Over 120 different mutations in the methyl-CpG binding protein 2 gene (MECP2) have been reported in patients with RTT, but a genotype-phenotype correlation has not been established. We have studied MECP2 mutations in 142 Japanese sporadic patients diagnosed clinically as having RTT. Forty different mutations in MECP2 have been detected in 103 female patients. Common mutations were four missense mutations (T158M,P152R, R133C and R306C) observed in 34 cases and four nonsense mutations (R168X, R255X, R270X and R294X) detected in 38 cases. Among these, R133C, R306C, and R294X were associated with atypical RTT including the preserved speech variant type, T158M and R168X with typical clinical features of RTT, and P152R, R255X, and R270X with severe developmental delay. These results suggest a genotype-phenotype correlation RTT. However, a large scale study of adult RTT patients is required to determine more precisely the influence of MECP2 mutation types on the natural history and clinical phenotypes of RTT.     

A 77-year-old woman and a preserved speech variant among the Danish Rett patients with mutations in MECP2

Two cases with Rett syndrome (RTT) are presented. One of these is a 77-year-old woman. The occurrence of elderly women with diagnosed RTT is sparse; this may be due to the fact that the clinical traits of RTT often are atypical in adult women and the information about early childhood limited. The finding of mutations in the MECP2 gene in many patients with RTT has provided us with a tool for verification of suspected cases. The patient presented here was clinically diagnosed with RTT at the age of 66 years and now the presence of one of the common missense mutations in MECP2 has been demonstrated. Additionally, skewed X-chromosome inactivation was found. It is likely that this woman is the one of the oldest living patients with RTT. The other case is a 30-year-old woman with preserved speech and the MECP2 missense mutation R133C. Possibly this mutation gives rise to a relatively mild phenotype. A survey of the 44 mutations in the Danish patient group is given.     

PERINATAL RISK FACTORS AND FIRST-YEAR VOCALIZATIONS: INFLUENCE ON PRESCHOOL LANGUAGE AND MOTOR PERFORMANCE

Spontaneous vocalizations of nine children with neonatal risk factors were systematically tape-recorded during the first year of life, as were those of 20 randomly chosen children without such risk factors. All the children were also given a battery of tests measuring language, speech, intelligence and motor function at six years. Cumulated tape-recordings for the periods six to 11 months and six to 14 months showed the infants with risk factors to have a significant reduction in various reduplicated syllables and consonants during the first year compared to those without risk factors. At six years, six of the nine at-risk children had an abnormal language test, as did two of the 20 without neonatal risk factors. Children with abnormal language tests performed significantly more poorly on various motor tasks; they also had had significantly fewer reduplications and consonants during infant vocalizations than the children with normal language tests. Perinatal risk factors may delay the production of prelinguistic sounds, and analysis of vocalizations might help to identify children who are at risk for later language disorders.     

An examination of the crowding hypothesis in epileptic patients who have undergone the carotid amytal test

Epileptic patients who had undergone the carotid amytal test were assessed on a variety of measures of verbal and non-verbal ability. All patients had left hemisphere dysfunction of early onset. Patients with atypical speech patterns performed as well as patients with left hemisphere speech on most, though not all, measures of language function. Transfer of language to the right hemisphere, however, occurred at a heavy cost. Patients with atypical speech patterns performed more poorly than their left hemisphere speech counterparts on a wide variety of non-verbal tests. These results are discussed in terms of the "crowding" hypothesis.     

Nothing to Say,Something to Sing: Primary Progressive Dynamic Aphasia

We describe a 76-year-old man (ADY) with dynamic aphasia in the setting of a degenerative frontal lobe dementia: primary progressive dynamic aphasia. He displayed a striking paucity of propositional speech despite intact speech production, and preserved singing and prosody. Vocal expression in the verbal and musical domains was investigated in a series of neuropsychological experiments based on novel language and musical tasks that were designed to establish the nature and specificity of the verbal output deficit. The features of the language disorder indicated that the speech output pathway was disrupted at the early stage of generation of a new pre-verbal message. In contrast, tests of musical output demonstrated that the generation of new musical ideas was unimpaired. The domain-specificity of dynamic aphasia may result from the disruption of specific cognitive processes necessary for the creation of verbal messages, as well as selective damage of brain regions involved in language production.     

Nothing to say,something to sing: primary progressive dynamic aphasia

We describe a 76-year-old man (ADY) with dynamic aphasia in the setting of a degenerative frontal lobe dementia: primary progressive dynamic aphasia. He displayed a striking paucity of propositional speech despite intact speech production, and preserved singing and prosody. Vocal expression in the verbal and musical domains was investigated in a series of neuropsychological experiments based on novel language and musical tasks that were designed to establish the nature and specificity of the verbal output deficit. The features of the language disorder indicated that the speech output pathway was disrupted at the early stage of generation of a new pre-verbal message. In contrast, tests of musical output demonstrated that the generation of new musical ideas was unimpaired. The domain-specificity of dynamic aphasia may result from the disruption of specific cognitive processes necessary for the creation of verbal messages, as well as selective damage of brain regions involved in language production.     

Immature Vocalizations Simplify the Speech of Tseltal Mayan and U.S. Caregivers

What is the function of immature vocalizing in early learning environments? Previous work on infants in the United States indicates that prelinguistic vocalizations elicit caregiver speech which is simplified in its linguistic structure. However, there is substantial cross-cultural variation in the extent to which children's vocalizations elicit responses from caregivers. In the current study, we ask whether children's vocalizations elicit similar changes in their immediate caregivers’ speech structure across two cultural sites with differing perspectives on how to interact with infants and young children. Here, we compare Tseltal Mayan and U.S. caregivers’ verbal responses to their children's vocalizations. Similar to findings from U.S. dyads, we found that children from the Tseltal community regulate the statistical structure of caregivers’ speech simply by vocalizing. Following the interaction burst hypothesis, where clusters of child-adult contingent response alternations facilitate learning from limited input, we reveal a stable source of information that may facilitate language learning within ongoing interaction.     

Frontal and temporal contributions to understanding the iconic co‐speech gestures that accompany speech

In everyday conversation, listeners often rely on a speaker's gestures to clarify any ambiguities in the verbal message. Using fMRI during naturalistic story comprehension, we examined which brain regions in the listener are sensitive to speakers' iconic gestures. We focused on iconic gestures that contribute information not found in the speaker's talk, compared with those that convey information redundant with the speaker's talk. We found that three regions—left inferior frontal gyrus triangular (IFGTr) and opercular (IFGOp) portions, and left posterior middle temporal gyrus (MTGp)—responded more strongly when gestures added information to nonspecific language, compared with when they conveyed the same information in more specific language; in other words, when gesture disambiguated speech as opposed to reinforced it. An increased BOLD response was not found in these regions when the nonspecific language was produced without gesture, suggesting that IFGTr, IFGOp, and MTGp are involved in integrating semantic information across gesture and speech. In addition, we found that activity in the posterior superior temporal sulcus (STSp), previously thought to be involved in gesture‐speech integration, was not sensitive to the gesture‐speech relation. Together, these findings clarify the neurobiology of gesture‐speech integration and contribute to an emerging picture of how listeners glean meaning from gestures that accompany speech. Hum Brain Mapp 35:900–917, 2014. © 2012 Wiley Periodicals, Inc.     

MECP2 gene analysis in classical Rett syndrome and in patients with Rett-like features

OBJECTIVE: To discuss the diagnostic criteria for Rett syndrome based on mutational screening of the methyl-CpG-binding protein 2 gene ( MECP2 ) in patients with classic Rett syndrome and patients with Rett-like features. METHODS: Thirty-nine patients with classical Rett syndrome, one with preserved speech variant (PSV), and 12 patients with developmental delay and some features of Rett syndrome were recruited for sequence analysis of the MECP2 gene coding region. The phenotype of the patients was correlated with the presence and type of the mutation as well as the X-chromosome inactivation (XCI) pattern. RESULTS: found in 100% of the patients with classical Rett syndrome originating from Finland. One novel mutation, P127L, was detected in a patient with PSV. No mutations were found in other cases. The XCI status was found to be random in 72% of the patients with classical Rett syndrome, including the patient with PSV and all patients with developmental delay informative for the analysis. CONCLUSIONS: An MECP2 mutation can be found in almost every patient with classical Rett syndrome. More patients need to be analyzed in order to clarify the mutation prevalence in patients with atypical Rett syndrome and in patients with mental retardation.     

Developmental Progression in Play Behavior of Children between Nine and Thirty Months: II: Spontaneous Play and Language Development

The relationship between play behavior displayed in a structured play situation and language development was studied cross-sectionally in 85 children at eight age--evels between nine and 30 months. There were no correlations between types of play behavior, in particular functional play (appropriate use of objects on the child's own body), representational play (appropriate use of objects on a doll or another person), or symbolic play (substitution of present objects for absent ones) and speech measures such as total number of words and of vocalizations, number of different words and different vocalizations, and number of sentences. Identification of objects upon verbal request was not related to any type of play behavior, but comprehension of verbal requests for functional or representational play was postively correlated with the display of functional or representational play. The children did not respond to verbal requests for functional or representational play unless these types of play behavior were part of their spontaneous play repertoire. Understanding of prepositions seemed to be related to spatial concepts expressed in play behavior, such as container play or arranging chairs around a table and setting the table.     

Congenital variant of Rett syndrome due to an intragenic large deletion in MECP2

Rett syndrome (RTT) is a neurodevelopmental disorder that is one of the most common causes of mental retardation in females. RTT diagnosis is based on distinct clinical criteria. We describe here a female patient with severe phenotype of congenital variant RTT. The patient originally presented with severe developmental delay prior to the age of 6 months and later exhibited characteristic features of RTT that included air swallowing, bruxism, and hand stereotypies. Results of an array-based comparative genomic hybridization analysis indicated there was a very small microdeletion in Xq28. Multiplex ligation-dependent probe amplification analysis further confirmed there were heterozygous deletions of intron 2, exon 3, intron 3, and part of exon 4 in MECP2. Findings in the present patient confirm the view that large MECP2 deletions are an important cause of severe congenital variant RTT. To ensure an accurate diagnosis of congenital variant RTT, a multiplex ligation-dependent probe amplification analysis of MECP2 should be performed in patients suspected of having this disorder.