Atypical presentations and specific genotypes are associated with a delay in diagnosis in females with Rett syndrome

Fehr, Stephanie; Downs, Jenny; Bebbington, Ami; Leonard, Helen

doi:10.1002/ajmg.a.33640

Cited by 33 publications

(50 citation statements)

References 36 publications

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“…[6][7][8]21,22 The subtlety of peculiarities makes it difficult to detect the disorder in its classic form, and this is even more true in milder variants before the onset of regression. 21,23 Females with PSV have been believed to develop typically up to 36 months of age, although Zappella et al 3 have speculated about mild abnormalities in social interaction already during the preregression period.…”

Section: Discussionmentioning

confidence: 99%

“…This description might contribute to the debate on whether or not females with a R133C mutation (1) have a milder phenotype, (2) are diagnosed later, and (3) exhibit better speech-language abilities. 2,4,9,23 Aside from the intermittent character of rapidly alternating normal versus abnormal vocalizations, a certain developmental trend could be observed. The inspiratory vocalizations disappeared around the females' first birthday, while atypical vocalizations with simultaneously occurring hand stereotypies emerged only around this age (Table II).…”

Section: Discussionmentioning

confidence: 99%

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

Marschik

Pini

Bartl-Pokorny

et al. 2012

Develop Med Child Neuro

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ABBREVIATIONSPSV Preserved speech variant RTT Rett syndrome AIM Our aim was to contribute new findings related to the pre-regressional verbal development of females with a variant of Rett syndrome (RTT) as the loss of spoken language is one 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 speech-language abilities.METHOD We analysed 461 minutes of audio-video recordings containing play situations and the 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. INTERPRETATIONThe 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 neurodevelopmental disorder that predominantly occurs in females, is mainly caused by mutations in the gene MECP2 for the methyl-CpG-binding protein 2 (Xq28).1 It is assumed that MeCP2, a regulator of neuronal activity-dependent synaptic maturation, plays a central role in postnatal brain development. Disruption of MeCP2 affects a wide range of neurodevelopmental functions such as cognitive processes, purposeful hand use, and communicative abilities.2 The pathogenesis of RTT is characterized by a four-stage trajectory, the second of which is the regression period, in which the clinical signs become more prominent.1 The trajectory can be observed in females with classic RTT as well as in other variants of RTT, of which the so-called preserved speech variant (PSV) or Zappella variant (Z-RTT) has a more benign overall pathogenesis, including better manual and speech-language abilities. 1,3,4 Females with PSV have the same staging and a number of the same symptoms as in classic RTT (e.g. the characteristic hand stereotypies) but usually show no general growth failure or deceleration of head growth; epilepsy and hyperventilation are rare.3-5 Furthermore, individuals with PSV show a postregressional improvement in hand use; language abilities may be regained or preserved. Lexicon size and syntactic complexity are reported to increase slowly, but are usually accompanied by features such as e...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Marschik

Pini

Bartl-Pokorny

et al. 2012

Develop Med Child Neuro

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“…Seventeen years later, Bengt Hagberg and colleagues attributed Dr Rett's name to the condition they had also seen in their patients. 2 The disorder affected girls whose initial apparently normal development was followed, between seven and eighteen months (now known to extend later), 3 by loss of previously achieved abilities, in particular hand use and speech.…”

Section: Introductionmentioning

confidence: 99%

Clinical and biological progress over 50 years in Rett syndrome

2016

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It is fifty years since Andreas Rett first described Rett syndrome, a disorder now known to be caused by a mutation in the MECP2 gene. A compelling blend of astute clinical observations, clinical and laboratory research has already built our understanding of Rett syndrome and its biological underpinnings. We document the contributions of the early pioneers and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, the lessons from both cell and animal models and how they may inform future clinical trials. With a focus on the core criteria, we examine the relationships that have been demonstrated between genotype and clinical severity. We review what is known about the many comorbidities that occur in this disorder and how genotype may also modify their presentation. We acknowledge the important drivers that are accelerating this research program including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we conclude by highlighting the major milestones since 1966 and what they mean for the day-to-day lives of those with Rett syndrome and their families. Key pointsThere has been an explosion of knowledge about Rett syndrome in relation to its genetic basis, clinical characteristics and their relationships during the fifty years since the disorder was first described by Andreas Rett.Whilst initially the diagnosis of Rett syndrome was based only on clinical criteria, identifying its genetic cause has had a major positive impact on how clinicians diagnose the disorder but also provides new challenges as we enter the era of next generation sequencing.

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“…9–11,13,15–18,20,37,38 Such studies have also begun to delineate different profiles in early development according to both RTT variant and mutation type. 2,3,39–43 …”

Section: Resultsmentioning

confidence: 99%

Early development in Rett syndrome – the benefits and difficulties of a birth cohort approach

Marschik

Lemcke

Einspieler

et al. 2017

Developmental Neurorehabilitation

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Purposes: Typically, early (pre-diagnostic) development in individuals later diagnosed with Rett syndrome (RTT) has been investigated retrospectively using parent reports, medical records and analysis of home videos. In recent years, prospective research designs have been increasingly applied to the investigation of early development in individuals with late phenotypical onset disorders, for example, autism spectrum disorder. Methods: In this study, data collected by the Danish National Birth Cohort lent itself to prospective exploration of the early development of RTT, in particular early motor-, speech-language, and socio-communicative behaviors, mood, and sleep. Results and Conclusions: Despite limitations, this quasi prospective methodology proved promising. In order to add substantially to the body of knowledge, however, specific questions relating to peculiarites in early development could usefully be added to future cohort studies. As this involves considerable work, it may be more realistic to consider a set of indicators which point to a number of developmental disorders rather than to one.

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Atypical presentations and specific genotypes are associated with a delay in diagnosis in females with Rett syndrome

Cited by 33 publications

References 36 publications

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

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

Clinical and biological progress over 50 years in Rett syndrome

Early development in Rett syndrome – the benefits and difficulties of a birth cohort approach

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