A brief history of MECP2 duplication syndrome: 20-years of clinical understanding

Ta, Daniel; Downs, Jenny; Baynam, Gareth; Wilson, Andrew; Richmond, Peter; Leonard, Helen

doi:10.1186/s13023-022-02278-w

Cited by 34 publications

(35 citation statements)

References 144 publications

(700 reference statements)

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“…Here we apply a bi-stable visual perception paradigm to study the mouse model of MECP2 duplication syndrome (Collins et al, 2004; Ramocki et al, 2010), a syndromic ASD caused by genomic duplication of methyl-CpG-binding protein 2 (Ramocki et al, 2010) that exhibits 100% penetrance in males. In humans MECP2 duplication syndrome shows all core features of idiopathic autism (Ta et al, 2022; Peters et al, 2013). MECP2 duplication mice carry a number of core autism features including repetitive stereotyped behaviors, altered vocalizations, increased anxiety, motor savant phenotype and over-reliable visual responses (Collins et al, 2004; Samaco et al, 2012; Jiang et al, 2013; Sztainberg et al, 2015; Zhang et al, 2017; Zhou et al, 2019; Ash et al, 2017, 2021, 2022).…”

Section: Introductionmentioning

confidence: 99%

Tug-of-peace: Visual Rivalry and Atypical Visual Motion Processing in MECP2 duplication Syndrome of Autism

Bogatova

Smirnakis

Palagina

2022

Preprint

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Extracting common patterns of neural circuit computations in autism spectrum and pinning them as a cause of specific core traits of autism is the first step towards identifying cell- and circuit-level targets for effective clinical intervention. Studies in human subjects with autism have identified functional links and common anatomical substrates between core restricted behavioral repertoire, cognitive rigidity, and over-stability of visual percepts during visual rivalry. To be able to study these processes with single-cell precision and exhaustive neuronal population coverage, we developed the visual bi-stable perception task for mice. Our task is based on plaid patterns consisting of two transparent gratings drifting at an angle of 120 degrees relative to each other. This results in spontaneous reversals of the perception between local component motion (motion of the plaid perceived as two separate moving grating components) and integrated global pattern motion (motion of the plaid perceived as a fused moving texture). This robust paradigm does not depend on the explicit report of the mouse, as the direction of the optokinetic nystagmus (OKN, rapid eye movements driven by either pattern or component motion) is used to infer the dominant percept. Using this paradigm, we found that the rate of perceptual reversals between global and local motion interpretations of the stimulus is reduced in MECP2 duplication mouse model of autism. Moreover, the stability of local motion percepts is greatly increased in MECP2 duplication mice at the expense of global motion percepts. Thus, our model reproduces a subclass of core features in human autism (reduced rate of visual rivalry and atypical perception of visual motion). This further offers a well-controlled approach for dissecting neuronal circuits underlying these core features if combined with mesoscale 2-photon imaging and optogenetic manipulation of neuronal circuits.

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Section: Introductionmentioning

confidence: 99%

Tug-of-peace: Visual Rivalry and Atypical Visual Motion Processing in MECP2 duplication Syndrome of Autism

Bogatova

Smirnakis

Palagina

2022

Preprint

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“… 40 , 41 Individuals with MDS typically have severe developmental delay, early infantile hypotonia with progressive acquired spasticity, feeding difficulties, and recurrent respiratory infections. 41 , 42 While developmental delay and hypotonia are commonly observed in neurodevelopmental disorders, the predisposition to infection distinguishes MDS. Infections range from otitis media to pneumonia, pyelonephritis, and sepsis.…”

Section: Rett Syndrome (Rtt)mentioning

confidence: 99%

Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage

Collins¹,

Neul²

2022

NDT

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Rett syndrome (RTT) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene Methyl-CpG-binding protein 2 ( MECP2 ), which encodes the MeCP2 protein. RTT is a MECP2 -related disorder, along with MECP2 duplication syndrome (MDS), caused by gain-of-function duplications of MECP2 . Nearly two decades of research have advanced our knowledge of MeCP2 function in health and disease. The following review will discuss MeCP2 protein function and its dysregulation in the MECP2 -related disorders RTT and MDS. This will include a discussion of the genetic underpinnings of these disorders, specifically how sporadic X-chromosome mutations arise and manifest in specific populations. We will then review current diagnostic guidelines and clinical manifestations of RTT and MDS. Next, we will delve into MeCP2 biology, describing the dual landscapes of methylated DNA and its reader MeCP2 across the neuronal genome as well as the function of MeCP2 as a transcriptional modulator. Following this, we will outline common MECP2 mutations and genotype–phenotype correlations in both diseases, with particular focus on mutations associated with relatively mild disease in RTT. We will also summarize decades of disease modeling and resulting molecular, synaptic, and behavioral phenotypes associated with RTT and MDS. Finally, we list several therapeutics in the development pipeline for RTT and MDS and available evidence of their safety and efficacy.

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“…In these individuals, the risk of fractures and microfractures is three to four times greater than in typical individuals [13,[16][17][18], particularly in the vertebrae and in the femur, thus causing considerable pain. Contractures of the ankle, knees, hip/trunk, elbows and wrist joints have also been reported [19][20][21][22][23][24]. Less common musculoskeletal problems are also present, such as juvenile idiopathic arthritis [25], osteopenia/osteoporosis [26,27], joint hypermobility [28][29][30][31], muscle atrophy [32], lordosis [33] and torticollis [34,35].…”

Section: Introductionmentioning

confidence: 99%

Pain in Rett syndrome: a pilot study and a single case study on the assessment of pain and the construction of a suitable measuring scale

Fabio

Chiarini

Canegallo

2022

Orphanet J Rare Dis

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Background Rett Syndrome (RTT) is a severe, neurodevelopmental disorder mainly caused by mutations in the MECP2 gene, affecting around 1 in 10,000 female births. Severe physical, language, and social impairments impose a wide range of limitations in the quality of life of the patients with RTT. Comorbidities of patients with RTT are varied and cause a lot of pain, but communicating this suffering is difficult for these patients due to their problems, such as apraxia that does not allow them to express pain in a timely manner, and their difficulties with expressive language that also do not permit them to communicate. Two studies, a pilot study and a single case study, investigate the manifestation of pain of patients with RTT and propose a suitable scale to measure it. Aims of this study The first aim was to describe pain situations of RTT by collecting information by parents; the second aim was to test and compare existing questionnaires for non-communicating disorders on pain such as Pain assessment in advanced demenzia (PAINAD), the Critical care pain observation tool (CPOT) and the Non-communicating Children’s Pain Checklist-Revised (NCCPC-R) to assess which of them is best related to the pain behavior of patients with RTT. The third aim was to identify the specific verbal and non-verbal behaviors that characterize pain in girls with Rett syndrome, discriminating them from non-pain behaviors. Method Nineteen participants, eighteen girls with RTT and one girl with RTT with 27 manifestations of pain were video-recorded both in pain and base-line conditions. Two independent observers codified the 90 video-recording (36 and 54) to describe their behavioral characteristics. Results The two studies showed that the most significant pain behaviors expressed by girls with respect to the baseline condition, at the facial level were a wrinkled forehead, wide eyes, grinding, banging teeth, complaining, making sounds, crying and screaming, and the most common manifestations of the body were tremors, forward and backward movement of the torso, tension in the upper limbs, increased movement of the lower limbs and a sprawling movement affecting the whole body. Conclusion The results of the two studies helped to create an easy-to-apply scale that healthcare professionals can use to assess pain in patients with Rett’s syndrome. This scale used PAINAD as its basic structure, with some changes in the items related to the behavior of patients with RTT.

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A brief history of MECP2 duplication syndrome: 20-years of clinical understanding

Cited by 34 publications

References 144 publications

Tug-of-peace: Visual Rivalry and Atypical Visual Motion Processing in MECP2 duplication Syndrome of Autism

Tug-of-peace: Visual Rivalry and Atypical Visual Motion Processing in MECP2 duplication Syndrome of Autism

Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage

Pain in Rett syndrome: a pilot study and a single case study on the assessment of pain and the construction of a suitable measuring scale

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