Early Speechlanguage Development in Females with Rett Syndrome: Focusing on the Preserved Speech Variant

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE

Early speech–language development in females with Rett syndrome: focusing on the preserved speech variant

1 Institute of Physiology (IN:spired; Developmental Physiology and Developmental Neuroscience), Centre for Physiological Medicine, Medical University of Graz, Graz, Austria. 2 Tuscany Rett Centre Versilia Hospital, Lido di Camaiore, Camaiore, Italy. 3 Duckworth Consultancy Ltd, Forensic Speech Analysis, South Brent, UK. 4 ENT University Hospital Graz, Department of Phoniatrics, Medical University of Graz, Graz, Austria. 5 Department of Linguistics, Karl-Franzens-University of Graz, Graz, Austria.

Correspondence to Dr Christa Einspieler at Institute of Physiology, Centre for Physiological Medicine, Medical University of Graz, Harrachgasse 21 ⁄ 5, 8010 Graz, Austria. E-mail: [email protected]

This article is commented on by Budden. To view this paper visit http://dx.doi.org/10.1111/j.1469-8749.2012.04246.x.

PUBLICATION DATA AIM Our aim was to contribute new ﬁndings related to the pre-regressional verbal develop- Accepted for publication 12th September 2011. ment of females with a variant of Rett syndrome (RTT) as the loss of spoken language is one Published online. of the key clinical features of RTT, and it would be of particular interest to study the early speech–language development of females who are considered to have preserved some ABBREVIATIONS speech–language abilities. PSV Preserved speech variant METHOD We analysed 461 minutes of audio–video recordings containing play situations and the RTT Rett syndrome daily routines of six females (aged 7 to 24 months; mean birthweight 3057g, SD 195g) with the preserved speech variant (PSV) of RTT. All videos were recorded by parents and analysed retrospectively after the diagnosis PSV was made. RESULTS From the age of 7 months onwards, we observed two types of vocalizations, appearing intermittently: (1) apparently normal sequences; and (2) atypical (i.e. inhalatory, pressed, or high-pitched crying-like) vocalizations. Some participants failed to reach the milestone of canonical babbling. We observed a limited phonological and lexical complexity and a restricted compositional variability. Volubility was reduced during the whole period under observation. Hand stereotypies with simultaneous atypical vocalizations appeared only during the second year of life. INTERPRETATION The intermittent character of normal versus abnormal verbal behaviours might contribute to an early identiﬁcation of children with a possible genetic mutation, and provides evidence that speech–language functions are abnormal from the very beginning.

Rett syndrome (RTT, MIM 312750), a profoundly disabling or deceleration of head growth; epilepsy and hyperventilation neurodevelopmental disorder that predominantly occurs in are rare.3–5 Furthermore, individuals with PSV show a postre- females, is mainly caused by mutations in the gene MECP2 for gressional improvement in hand use; language abilities may be the methyl-CpG-binding protein 2 (Xq28).1 It is assumed that regained or preserved. Lexicon size and syntactic complexity MeCP2, a regulator of neuronal activity-dependent synaptic are reported to increase slowly, but are usually accompanied maturation, plays a central role in postnatal brain develop- by features such as echolalia, peculiar prosody, or limited ment. Disruption of MeCP2 affects a wide range of neurode- pragmatic functions.3–5 velopmental functions such as cognitive processes, purposeful Our own studies have contributed to the delineation of early hand use, and communicative abilities.2 The pathogenesis of signs of classic RTT and PSV before the onset of regression, RTT is characterized by a four-stage trajectory, the second of focusing on abnormalities of the early spontaneous motor rep- which is the regression period, in which the clinical signs ertoire and behavioural peculiarities such as the early onset of become more prominent.1 The trajectory can be observed in hand stereotypies.6–8 As part of an interdisciplinary approach, females with classic RTT as well as in other variants of RTT, we searched for further early developmental deviations and of which the so-called preserved speech variant (PSV) or Zap- thereby focused on another key clinical feature in RTT, the pella variant (Z-RTT) has a more benign overall pathogenesis, speech–language domain. In classic RTT and its variants, the including better manual and speech–language abilities.1,3,4 partial or complete loss of acquired spoken language is one of Females with PSV have the same staging and a number of the main inclusion criteria.1 In fact, many females with RTT the same symptoms as in classic RTT (e.g. the characteristic begin to talk, but in the regression stage the majority of them hand stereotypies) but usually show no general growth failure undergo a profound deterioration of communicative skills or

ª The Authors. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press DOI: 10.1111/j.1469-8749.2012.04123.x 1 even lose them entirely before eventually entering a period of What this paper adds 2,9 partial amelioration. In this late stage, various prelinguistic • Speech–language functions are not preserved but follow an atypical develop- behavioural patterns such as specific body movements, reach- mental trait. ing, and facial expressions have been reported to fulfil a com- • Communicative development is affected from the first vocalizations onwards. municative function, eye gazing being the most common • The article provides evidence of a (specific) intermittent character of normal 10–14 versus abnormal vocal behaviours. form. The developmental pathway (especially the first 2y • The findings of this study support previous findings of early developmental of life) of such idiosyncratic communicative behavioural peculiarities, which contradicts the hypothesis of an uneventful first year of life. patterns resembles a black box, which requires further study. The early verbal development of females with PSV might prove nally observed between the ages of 7 and 24 months; four of crucial for the further understanding of speech–language acqui- them came from Italian-speaking families and two were sition in the context of the whole RTT complex, since early German. All females were singletons born as a result of vocalizations in infancy constitute precursors to speech.15,16 uneventful pregnancies and deliveries; the mean birthweight The typical sound repertoire of the infant develops systemat- was 3057g (SD 195g) and birth lengths, occipitofrontal cir- ically and reflects a maturing speech capacity long before the cumferences, and Apgar scores were in the normal range. first words are uttered.15,16 From pre-canonical sounds such as Genetic testing revealed the following MECP2 mutations: quasi-vowels and cooing to the most salient early vocalizations, C468G in one, c.1163del44 in one, R133C in three, and a that is canonical babbling like ⁄ baba ⁄ , ⁄ dada ⁄ (well-formed syl- large intragenic deletion (c.378–43_964delinsGA) in one (the lables, reduplicated sequences), a stage model for vocal devel- motor development of this child is dealt with elsewhere8). All opment (phonation stage, primitive articulation stage, infants met the clinical criteria for PSV.1,4 expansion stage, canonical stage) has been achieved by international consensus. According to this consensus, vegetative Recordings before the onset of regression sounds (sneezing, coughing, etc.) and fixed vocal signals Audio–video recordings of play situations and daily routines (crying, laughing, etc.) have to be treated separately from prot- had been made by the females’ parents, who had not been aware ophones.15,17 Protophones (cooing, canonical babbling, etc.) at that time that their daughters had RTT. Therefore, our doc- are sounds that are specific precursors to speech. They are usu- umentation of normal or abnormal patterns and of the respec- ally followed by proto-words – which have a consistent pho- tive age of their first appearance rested only upon our video netic character – around the first birthday; their use is often database. contextual and not necessarily conventional (e.g. reduction of The footage comprised a total of 461 minutes recorded in phonological complexity: ⁄ efant ⁄ vs. ⁄ elefant ⁄ ). 316 different clips; the recording times for the four predefined The reason why there is only little systematic knowledge of age intervals were as follows: months 7 and 8, median=29 min- prediagnostic speech–language development in females with utes (min.=26min, max.=30min); months 9 and 10, classicRTToritsvariantsisthatthediagnosisofRTTis median=17 minutes (min.=10min, max.=24min); months 11 often unclear until at least toddler age. Our knowledge of and 12, median=11 minutes (min.=1min, max.=15min); months prelinguistic and early linguistic development is therefore 13 to 24, median=41 minutes (min.=17min, max.=73min). mainly based on retrospective studies that include parental questionnaires. This method has been applied in the docu- Assessment of speech–language (dis)abilities mentation of various developmental phenomena such as We meticulously analysed the quality and rate of occurrence autism or developmental language delay, but faces certain lim- of age-specific vocalizations (i.e. protophones, proto-words, itations such as the memory bias of parents with affected and first words). In addition, we calculated the volubility children.18–20 The use of family videos, by contrast, provides a (i.e. utterances per minute) of typical and atypical age-related unique and reliable opportunity to trace back the development vocalizations to document the frequency of occurrence. even to early infancy and focus on a wide variety of aspects.6 When assessing the second year of life, we also focused on Examination of longitudinally collected video footage of six the realization of single words and word combinations. The females with PSV made it possible for us to retrace the trajec- complexity of vocalizations refers to combinations of certain tory of the females’ verbal development and shed light on their (proto-)vowels [V] and (proto-)consonants [C] such as CV-, preregression speech–language abilities, which is one of the CVC- or CCVC-clusters. The complexity ratio refers to the key clinical features in the context of RTT, and to determine number of single (proto-)vowels and (proto-)consonants or whether particular communicative functions follow a typical number of more complex clusters divided through the total developmental trait and may be considered preserved or number of vocalizations. The mental lexicon was assessed by whether the first prelinguistic and communicative milestones means of spontaneous speech analyses and additional parental are already acquired inadequately by females with this variant reports (diaries and interviews). Vegetative sounds (sneezing, of RTT. coughing, etc.) were excluded from the analyses. Fixed vocal signals such as crying and laughing were noted if abnormal METHOD (e.g. high-pitched crying or inadequate laughing). We addi- Participants tionally transcribed all qualitatively deviant (e.g. inspiratory) The focus of the present study was the age-related speech and vocalizations.21 Furthermore, we paid particular attention to language abilities of six females with PSV who were longitudi-

2 Developmental Medicine & Child Neurology 2012 the appearance of hand stereotypies combined with (abnor- Table I: The presence (d), absence (s), and (age of first appearance) of mal) vocalizations. babbling, and (proto-)words and (proto-)word combinations before the As our analyses were based on spontaneous speech samples, onset of regression in six females with preserved speech variant all vocalizations and verbal utterances were phonetically transcribed in chronological order. The transcriptions can be best Well-formed described as phonetic approximations of utterances, according syllables ⁄ Lexical to the International Phonetic Alphabet (IPA), a transcription canonical diversity Complexity ⁄ babbling-like (number of (proto-)word convention that aims to ensure consistency. An utterance was Participant MECP2 vocalizations proto-words) combinations defined as a unit of speech, indicated by intonation or pause. no. mutation (mo) (mo) (mo) Each transcript and coding (by PBM) was rechecked by a sec- 1 c.378–43_964 d (7) d [11] (12) d (21) ond transcriber (KDB) against the audio–video files in order delinsGA to ensure accuracy and consistency. In case of disagreement, 2R133Cd (20) d [1] (20) s the utterances in question were discussed within the team 3C468Gss[0] s 4R133Css[0] s (PBM, KDB, CE) until agreement was achieved. Utterances 5 c.1163del44 d (12) d [5] (17) s unintelligible to all transcribers were not included. The final 6R133Cd (12) d [6] (16) s transcriptions formed the basis for phonological clustering, lexical grouping, and the analyses. The behavioural analysis reotypies (such as repetitive uni- or bilateral hand pronation was partly carried out by means of the Noldus Observer-XT with simultaneous wrist dorsiflexion) occurred during the first device (Version 9.0, Noldus Information Technology, http:// year of life but were not yet accompanied by atypical vocaliza- www.noldus.com). Three independent scorers (PBM, KDB, tions (Table II). CE) achieved a high interscorer agreement (Fleiss’ j=0.92). Phonetic analyses (MD, RV) were performed by means of From the first words to the onset of regression Praat (http://www.fon.hum.uva.nl/praat/); they included dura- During the second year of life, the first (proto-)words were tion measurements and a spectral analysis for the determina- uttered by participants 1, 2, 5, and 6 (Table I). Those four par- tion of breathy voice characteristics. ticipants exhibited a limited lexical complexity and a restricted The study was approved by the local research ethics compositional variability (i.e. nouns or predicates) with a med- committee. All parents gave their informed consent to this ian active vocabulary of three (proto-)words (range 0–11; longitudinal research and to the publication of the results. Table I). Participant 1 was the only child to utter word combinations before the onset of regression. Statistical analysis Since our sample was limited to six cases, the reporting of the data is purely descriptive. Table II: The presence (d) and absence (s) of various abnormal signs RESULTS within the first 24 months of life in six females with preserved speech As the focus of the analyses described above lay on universals variant of early verbal development (e.g. babbling) as well as on quan- Months Months Months Months titative measurements of (pre)linguistic entities (e.g. vocabu- Characteristics 7and8 9and10 11 and 12 13 to 24 lary size), we decided to provide a joint description for both German- and Italian-acquiring females. Atypical vocalizations ddd ddd ddd dddddd s Early vocalizations Inspiratory vocalizations ddd dd ddd ssssss From 7 months of age onwards, we observed two qualities of s s vocalizations that appeared intermittently: (1) apparently normal vocalization sequences including well-formed syllables Pressed vocalizations ddd dd ddd dddddd or canonical babbling (Table I, left column) within a limited with strained voice quality s s repertoire of proto-CV clusters (C=consonant, V=vowel; e.g. [ma] or [ba]); and (2) atypical vocalizations of (a) inhalatory, High-pitched ddd ddd ddd dddddd (b) pressed, or (c) high-pitched crying-like character crying-like vocalizations s (Tables II and III). The predominant early vocalizations were either single proto-vowels or single proto-consonants, Atypical vocalizations dddd whereas more complex structures such as babbling (CV-, and simultaneously ssss sss sss ss VC-, or more complex clusters) were rare (Table IV). Signifi- occurring hand stereotypies cant atypical features were extremely short inhaling sequences Hand stereotypies dddd dd ddd ddddd (min. = 43ms), proto-consonant and proto-vowel alternations s s produced on ingressive airstream and breathy voice characteristics. Inspiratory vocalizations eventually disappeared around No recording available, or the recording did not allow proper the time of the children’s first birthday (Table III). Hand ste- assessment.

Early Speech–Language Development in Rett syndrome Peter B Marschik et al. 3 Table III: Volubility (utterances per minute) of normal versus abnormal vocalizations in six females with preserved speech variant, from 7 to 24 months of age; median (range)

Characteristics (vocalizations) Months 7 and 8 (n=4) Months 9 and 10 (n=3) Months 11 and 12 (n=4) Months 13 to 24 (n=6)

Total 0.78 (0.07–2.01) 1.09 (0.42–1.75) 2.33 (1.58–4.39) 1.59 (0.32–5.84) Normal 0.17 (0.00–0.70) 0.25 (0.00–0.50) 0.41 (0.03–4.45) 0.65 (0.00–1.31) Atypical 0.65 (0.00–1.31) 0.84 (0.42–1.25) 2.05 (1.37–3.29) 0.77 (0.29–1.75) Inspiratory 0.20 (0.00–0.40) 0.05 (0.00–0.08) 0.04 (0.00–0.21) 0.00 (0.00–0.00) Pressed 0.24 (0.00–0.50) 0.21 (0.00–0.42) 2.27 (1.49–4.12) 0.27 (0.11–0.65) High-pitched crying-like 0.13 (0.00–0.17) 0.40 (0.21–0.58) 0.65 (0.00–1.10) 0.25 (0.09–0.64)

opmental disorder, while at the same time it reveals early Table IV: Age-related complexity ratio of vocalizations abnormality in functional brain development. Our finding of abnormal vocalizations, especially inspira- Months Months Months Months 7and8 9and10 11 and 12 13 to 24 tory ones, indicates early signs of poor control of respiratory Characteristics (n=4) (n=3) (n=4) (n=6) rhythm and involuntary movements that affect the orofacial muscles and consequently contribute to articulation difficulties Single proto-vowels 0.92 0.78 0.84 0.57 5,10,21 or proto-consonants in individuals with RTT. Functional neuroimaging has CV- or VC-clusters 0.05 0.15 0.16 0.29 suggested that Broca’s area might be involved in governing CVC-, or VCV-, or more 0.03 0.07 0.00 0.14 the production of repetitive sound patterns, which is a crucial complex clusters stage in the developing control of vocal behaviour.24 The C, consonants; V, vowels. functional development goes hand in hand with the morpho- logical specification of Brodmann areas 44 and 45, i.e. postna- Yet still the predominant type of verbal production was to be tal processes whose gradual completion takes at least found in single proto-vowels or proto-consonants; again, vocal- 2years.25 Hence, a MECP2 mutation might have an early izations of complex consonant-vowel clusters (e.g. CCVC, effect on the specification process of the fronto-opercular CVCV structures) were rare (Table IV). We further observed cerebral cortex (Broca region), affecting language acquisition increasing verbal perseverations (echolalia) and – yet again – even before regression. episodes of high-pitched crying. For example, perseveration of Usually canonical babbling, which is the controlled produc- more than 20 consecutive unconventional vocalizations with- tion of well-formed syllables, appears according to a strict time out conventional meaning or communicative intention such as plan, that is by no later than 10 months of age.15,16 Children ⁄ tise ⁄ or ⁄ oti ⁄ was followed by a high-pitched cry, which in turn with Down syndrome, Williams syndrome, cerebral palsy, or was followed by another stereotypic verbal event. profound hearing impairment, however, enter this stage of Anecdotally, we observed that, during the second year of verbal development with a significant delay.16,26–28 Aretro- life, two of the females whistled from time to time, on both spective study based on questionnaires found similar results in ingressive and egressive airstream. individuals with RTT.29 Onset of canonical babbling was also delayed in three of our participants. Two other females in our DISCUSSION sample did not reach this milestone of language development Since the introduction of clinical criteria for RTT, a number until 24 months of age (Table I). It is known from their clini- of scientists, clinicians, and parents have assumed that the early cal histories that their speech–language abilities developed development of females with RTT might actually be less after their second birthday, but it remains unclear whether inconspicuous than initially believed.6–8,21,22 The subtlety of they ever went through a stage of canonical babbling. Only peculiarities makes it difficult to detect the disorder in its clas- one female (participant 1) entered the stage of canonical bab- sic form, and this is even more true in milder variants before bling during her 7th month of age, and she was the only one the onset of regression.21,23 Females with PSV have been to produce word combinations before the onset of regression. believed to develop typically up to 36 months of age, although This is all the more significant as the sound repertoire of the Zappella et al.3 have speculated about mild abnormalities in human infant is believed to develop systematically, reflecting, social interaction already during the preregression period. as it were, the maturation process of speech capacity long Our study is the first to include a longitudinal assessment of before the first words are uttered.15 the early repertoire of speech–language representations in Even in those four participants (1, 2, 5, 6) who, according to females with PSV on the basis of comprehensive audio-video the given data set, went through a period of canonical bab- analyses. As expected, the results provide evidence of early bling, the phoneme inventory and combinations thereof abnormalities in vocal development from the first speech-like remained limited throughout the first 2 years of life, as did the vocalizations onwards. On the one hand, the intermittent mental lexicon. Again, this is in line with the findings reported character of typical and atypical age-specific patterns of verbal by Tams-Little and Holdgrafer,29 who furthermore stated that behaviour hampers early detection of this severe neurodevel- the lack of communicative gestures that mark the transition

4 Developmental Medicine & Child Neurology 2012 from preintentional to intentional communication might be a position of the mental lexicon. Thus, the strength of video potential predictor of RTT. Moreover, our patients’ volubility analysis lies in the descriptiveness of observable behaviour never reached normal values, which, according to reports, are which, in the case of RTT, clearly deviates from the typical at least three times higher.15,16 age-specific developmental patterns.6–8,30 As our sample consists of three participants with a R133C Even though the present study is based on a small number mutation, we should mention that although two of them of cases and may therefore be restricted in its general validity, passed the milestones of babbling and first words, they did so it should contribute to our understanding of how MECP2 with a marked delay and with qualitative deficiencies (Table I). influences brain and communicative development. As it is This description might contribute to the debate on whether or often difficult to reliably detect a disorder early in develop- not females with a R133C mutation (1) have a milder pheno- ment, prelinguistic communicative behaviours (i.e. in particu- type, (2) are diagnosed later, and (3) exhibit better speech–lan- lar the intermittent and rapidly alternating character of guage abilities.2,4,9,23 expected and unexpected behaviours) may provide a diagnostic Aside from the intermittent character of rapidly alternating marker that will facilitate early identification. Development is normal versus abnormal vocalizations, a certain developmental profoundly affected from the first vocalizations onwards, and trend could be observed. The inspiratory vocalizations disap- so we claim once again that the speech–language abilities of peared around the females’ first birthday, while atypical vocal- individuals with PSV are not preserved but follow an atypical izations with simultaneously occurring hand stereotypies pathway.21 It is clear, though, that these findings need further emerged only around this age (Table II). Some participants evidence in order to provide a better understanding of the jig- showed pressed vocalizations and high-pitched crying-like saw puzzle of developmental genetic disorders and to contrib- vocalizations from the age of 7 months onwards, while in the ute to an early identification of children with a possible rest of the sample such peculiarities appeared only during the genetic mutation. second year of life. Although a systematic and objective video analysis is a valu- ACKNOWLEDGEMENTS able and effective instrument for the identification of physio- We should like to thank the participants and their families for their logical, behavioural, and cognitive functional features and cooperation, effort, and kindness; Professors Angus Clarke and Franco details that are hard to capture otherwise, it nonetheless has Laccone for sharing their expertise in genetics; Professor Sylvia Moos- certain limitations. One of its most obvious insufficiencies is mu¨ller for acoustical analyses; Professor Gerhard Friedrich for discuss- the potential absence of features in a given data set: video anal- ing phoniatric issues; Dr Andreas Oberle for providing clinical data on ysis allows us to describe observable phenomena and point out one case; Mag Alexander Avian for statistical consulting; and Miha peculiarities, but we must never conclude that the absence of a Tavcar (scriptophil) for copy-editing the article. The study was sup- sign or typical feature is definite.30 Lexical diversity, for exam- ported by the Austrian Science Fund (FWF; P19581-B02), Koerner ple, can be documented by means of annotating observable Fond, Country of Styria; Dipartimento Diritto alla Salute, Tuscany; lexical items, and yet it will not let us capture the entire com- and the Lanyar Foundation (P325, P337).

REFERENCES

1. Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: speech variant of Rett syndrome. J Autism Dev Disord 2009; 16. Nathani S, Oller DK, Neal AR. On the robustness of vocal revised diagnostic criteria and nomenclature. Ann Neurol 39: 958–61. development: an examination of infants with moderate-to- 2010; 68: 944–50. 9. Uchino J, Suzuki M, Hoshino K, Nomura Y, Segawa M. severe hearing loss and additional risk factors. J Speech Lang 2. Kerr AM, Archer HL, Evans JC, Gibbon F. People with Development of language in Rett syndrome. Brain Dev Hear Res 2007; 50: 1425–44. mutation positive Rett disorder who converse. J Intellect 2001; 23: 233–5. 17. Oller DK. Development of vocalizations in infancy. In: Wi- Disabil Res 2006; 50: 386–94. 10. Budden S, Meek M, Henighan C. Communication and oral- nitz H, editor. Human Communication and its Disorder: A 3. Zappella M, Gillberg C, Ehlers S. The preserved speech vari- motor function in Rett syndrome. Dev Med Child Neurol Review, vol. IV. Timonium: York Press, 1995: 1–30. ant: a subgroup of the Rett complex: a clinical report of 30 1990; 32: 51–5. 18. Luyster R, Lopez K, Lord C. Characterizing communicative cases. J Autism Dev Disord 1998; 28: 519–26. 11. Woodyatt G, Ozanne A. Communication abilities and Rett development in children referred for autism spectrum 4. Renieri A, Mari F, Mencarelli MA, et al. Diagnostic criteria syndrome. J Autism Dev Disord 1992; 22: 155–73. disorders using the MacArthur–Bates Communicative for the Zappella variant of Rett syndrome (the preserved 12. Cass H, Reilly S, Owen L, et al. Findings from a multidisci- Development Inventory (CDI). J Child Lang 2007; 34: 623– speech variant). Brain Dev 2009; 31: 208–16. plinary clinical case series of females with Rett syndrome. 54. 5. Zappella M, Meloni I, Longo I, Hayek G, Renieri A. Dev Med Child Neurol 2003; 45: 325–37. 19. Marschik PB, Einspieler C, Garzarolli B, Prechtl HF. Events Preserved speech variants of the Rett syndrome: 13. Didden R, Korzilius H, Smeets E, et al. Communication in at early development: are they associated with early word molecular and clinical analysis. Am J Med Genet 2001; individuals with Rett syndrome: an assessment of forms and production and neurodevelopmental abilities at the preschool 15: 14–22. functions. J Dev Phys Disabil 2010; 22: 105–18. age? Early Hum Dev 2007; 83: 107–14. 6. Einspieler C, Kerr AM, Prechtl HF. Is the early development 14. Sigafoos J, Kagohara D, van der Meer L, et al. Commu- 20. Einspieler C, Widder J, Holzer A, Kenner T. The predictive of females with Rett disorder really normal? Pediatr Res nication assessment for individuals with Rett syndrome: a value of behavioural risk factors for sudden infant death. 2005; 57: 696–700. systematic review. Res Autism Spectr Disord 2011; 5: 692– Early Hum Dev 1988; 18: 101–9. 7. Einspieler C, Kerr AM, Prechtl HF. Abnormal general 700. 21. Marschik PB, Einspieler C, Prechtl HF, Oberle A, Laccone movements in females with Rett disorder: the ﬁrst four 15. Oller DK, Eilers RE, Neal AR, Schwartz HK. Precursors to F. Relabelling the preserved speech variant of Rett syndrome months of life. Brain Dev 2005; 27: 8–13. speech in infancy: the prediction of speech and language dis- [Letter]. Dev Med Child Neurol 2010; 52: 218. 8. Marschik PB, Einspieler C, Oberle A, Laccone F, Prechtl orders. J Commun Disord 1999; 32: 223–45. 22. Leonard H, Bower C. Is the female with Rett syndrome HF. Case report: retracing atypical development: a preserved normal at birth? Dev Med Child Neurol 1998; 40: 115–21.

Early Speech–Language Development in Rett syndrome Peter B Marschik et al. 5 23. Fehr S, Downs J, Bebbington A, Leonard H. Atypical pre- 26. Lynch MP, Oller DK, Steffens ML, Levine SL, Basinger 29. Tams-Little S, Holdgrafer G. Early communication develop- sentations and speciﬁc genotypes are associated with a delay DL, Umbel V. Onset of speech-like vocalizations in infants ment in children with Rett syndrome. Brain Dev 1996; 18: in diagnosis in females with Rett syndrome. Am J Med Genet with Down syndrome. Am J Ment Retard 1995; 100: 68–86. 376–8. A 2010; 152A: 1535–42. 27. Masataka N. Why early linguistic milestones are delayed in 30. Marschik PB, Einspieler C. Methodological note: video 24. Willems RM, Hagoort P. Neural evidence for the interplay children with Williams syndrome: late onset of hand banging analysis of the early development of Rett syndrome—one between language, gesture, and action: a review. Brain Lang as a possible rate-limited constraint on the emergence of method for many disciplines. Dev Neurorehabil 2011; 14: 2007; 101: 278–89. canonical babbling. Dev Sci 2001; 4: 158–64. 355–7. 25. Judas M, Cepanec M. Adult structure and development of 28. Levin K. Babbling in infants with cerebral palsy. Clin Linguist the human fronto-opercular cerebral cortex (Broca’s region). Phon 1999; 13: 249–67. Clin Linguist Phon 2007; 21: 975–89.

6 Developmental Medicine & Child Neurology 2012