Behavioural biomarkers of typical Rett syndrome: moving towards early identification

Wien Med Wochenschr Behavioural biomarkers of typical Rett syndrome: moving towards early identification Christa Einspieler 0 1 2 Michael Freilinger 0 1 2 Peter B. Marschik 0 1 2 0 P. B. Marschik Center for Neurodevelopmental Disorders, Department of Women's and Children's Health (KIND), Karolinska Institutet , Stockholm , Sweden 1 M. Freilinger Department of Paediatrics and Adolescent Medicine, Medical University of Vienna , Vienna , Austria 2 Prof. Dr. C. Einspieler ( ) · P. B. Marschik Research Unit iDN, interdisciplinary Developmental Neuroscience, Institute of Physiology, Center for Physiological Medicine, Medical University of Graz , Harrachgasse 21/5, 8010 Graz , Austria Frühe Auffälligkeiten in Motorik, Sprache und Kommunikation bei Rett-Syndrom Schlüsselwörter Säugling · Bewegung · Verbales Verhalten · Sprechen · Phonation Infant; Movement; Verbal behavior; Speech; Phonation - Summary The dynamic course of Rett syndrome (RTT) is still said to begin with a period of apparently normal development although there is mounting evidence that individuals with RTT show behavioural peculiarities and abnormalities during their infancy. Their spontaneous general movements are abnormal from birth onwards. Normal cooing vocalisation and canonical babbling (if at all required) are interspersed with abnormalities such as proto-vowel and proto-consonant alternations produced on ingressive airstream, breathy voice characteristics, and pressed or high-pitched vocalisations. The gestural repertoire is limited. Certain developmental motor and speech-language milestones are not at all acquired or show a significant delay. Besides abnormal blinking, repetitive and/or long lasting tongue protrusion, and bizarre smiling, there are already the first body and/or hand stereotypies during the first year of life. We are currently on a promising way to define a specific set of behavioural biomarkers pinpointing RTT. Zusammenfassung Die vorherrschende Lehrbuchmeinung über die Pathogenese des Rett-Syndroms (RTT) ist immer noch so, dass die frühe Entwicklung annähernd normal verläuft, obwohl Ergebnisse aus Elterninterviews, -fragebögen, aber auch aus Videoanalysen belegen, dass Patientinnen mit RTT bereits im Säuglingsalter auffällig sind. Ihre Spontanbewegungen („general movements“) sind nicht altersadäquat und qualitativ abnormal; ihre frühen Vokalisationen (z. B. das Gurren und das kanonische Lallen) sind zumindest intermittierend auffällig mit alternierenden Protovokalen und Protokonsonanten bei einwärts strömender Luft, hauchiger, gepresster oder hoher Stimme; das Repertoire an kommunikativen Gesten ist limitiert; bestimmte motorische, soziokommunikative und sprachliche Meilensteine werden nicht oder nur mit großer Verzögerung erworben. Neben einseitigem Blinzeln, wiederholter und lang anhaltender Zungenprotrusion sowie bizarrem Lächeln kommt es bereits im ersten Lebensjahr zum Auftreten von Stereotypien des Körpers oder der Hände. Mit diesen Befunden nähern wir uns derzeit der Definierung eines spezifischen Spektrums an frühen Auffälligkeiten, die typisch für das RTT sein könnten. Mutations in the X-linked gene encoding Methyl-CpGbinding protein 2 (MeCP2) account for 95–97 % of cases of Rett syndrome (RTT, MIM312750), a genetic disorder affecting neurodevelopment, predominantly Behavioural biomarkers of typical Rett syndrome: moving towards early identification 333 Table 1 Prominent signs and peculiarities in infants later diagnosed with typical Rett syndrome Poor repertoire general movements (birth–2 months after term) Absent or abnormal fidgety movements (3–5 months after term) Significant delayed in or no achievement of sitting alone, pulling to stand or walking alone Touching objects with extended fingers rather than manipulating them Asymmetric opening of the eye lid after a blink Frozen, bizarre, inadequate smile Repetitive or long-lasting tongue protrusion Delay and/or abnormalitiesa in cooing vocalisation and canonical babbling aProto-vowel or proto-consonant alternations produced on ingressive airstream, breathy voice characteristics and pressed or high-pitched vocalisations. in females [1, 2]. Among the key features of typical RTT are (a) stereotyped hand movements coinciding with a regression in purposeful hand use, and (b) a regression in expressive language [2–4]. The dynamic course of RTT is said to involve a period of apparently normal early development followed by a profound neurological regression and subsequent stabilization or partial recovery [2–4]. This view, however, contrasts with mounting evidence of behavioural peculiarities and abnormalities observable already during the first months of life (e. g. [5, 8]). RTT is usually diagnosed around 3 years of age [9], and being a rare disease, there are hardly any possibilities except retrospective data analyses to track down the pathways of various developmental domains before the assumed loss of previously acquired functions. Retrospective analyses (...truncated)