Examinando por Autor "Pulido, Rafael"

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    Cognitive and adaptive functioning of CTNNB1 syndrome patients: a comparison with autism spectrum disorder and cerebral palsy
    (John Wiley and Sons Inc, 2025-03-27) Pallarès Sastre, Mercè; Amayra Caro, Imanol; Pulido, Rafael; Nunes Xavier, Caroline Elisabeth; Bañuelos Rodriguez, Sonia; Cavaliere, Fabio; García Martín, Maitane
    Background: The CTNNB1 syndrome is a neurodevelopmental disorder considered an ultra-rare disease, first discovered in 2012. Given its comorbidity of symptoms with more prevalent diseases, such as ASD or CP, many CTNNB1 syndrome patients had previously received those diagnosis. Therefore, the aim of this study is to establish differences on the cognitive and adaptive functioning of the CTNNB1 syndrome compared with ASD and CP. Methods: A total of 55 paediatric patients—25 CTNNB1 syndrome, 17 ASD and 13 PC—were assessed with an extensive protocol for neuropsychological domains through in-person assessments and online meetings for the parent-reported questionnaire. Results: No cognitive differences were found among verbal tasks between groups, even though CTNNB1 syndrome patients obtained significantly lower scores in visuospatial and logical tasks. Regarding adaptive functioning, ASD patients outperformed the CTNNB1 syndrome group in most domains, whereas CP patients did not differ as much, obtaining only lower scores in gross motor ability. Externalizing problems were more prevalent in the CTNNB1 syndrome group compared with the control groups. Also, correlations indicated improvement of cognitive and adaptive functioning over the years for the CTNNB1 syndrome patients. Conclusions: This is the first study to compare the cognitive and adaptive functioning of CTNNB1 syndrome patients with control diseases and detect significant difference. Although intellectual disability is one of the main manifestations of the CTNNB1 syndrome, patients performed better on verbal cognitive tasks than in visuospatial and logical thinking exercises, while adaptive functioning performances did not differ from control groups.
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    Genotype-phenotype characterization and functional reconstitution of pathogenic β-catenin variants from CTNNB1 syndrome patients
    (PLOS, 2025-10-13) Nunes Xavier, Caroline Elisabeth; Pallarès Sastre, Mercè; Rodríguez Ramos, Ana; Bañuelos Rodriguez, Sonia; Cortajarena, Irune; Cavaliere, Fabio; Ruiz Espinoza, Cynthia Liz; Llano Rivas, Isabel; García Martín, Maitane; Amayra Caro, Imanol; Pulido, Rafael
    Germline variants in the CTNNB1 gene, encoding β-catenin protein, cause severe neurodevelopmental alterations manifested early in the infancy, and define the CTNNB1 syndrome. Patients with CTNNB1 syndrome display heterogeneous clinical manifestations, and most of them carry CTNNB1 pathogenic nonsense or frameshift variants that generate premature termination codons (PTC). We have previously described the neuropsychological manifestations of a group of CTNNB1 syndrome patients harboring novel β-catenin variants. Here, we have analysed the molecular and functional characterization of these β-catenin variants, performed genotype-phenotype analyses, and tested for β-catenin functional reconstitution. We describe a complex variety of N-terminal and C-terminal truncated β-catenin proteoforms generated by PTC. Protein stability of truncated proteoforms was variable, as indicated by their expression levels and biophysical analysis, and high protein stability correlated with better patient performance in visuospatial tests. Transcriptional activity was abrogated in most of the β-catenin variants, although some specific truncations, as well as a three-residues in-frame deletion variant, retained partial transcriptional activity. Reconstitution of full-length β-catenin expression and function was achieved in specific β-catenin PTC variants by induction of translational readthrough with aminoglycosides and protein synthesis stimulators. Inhibition of β-catenin degradation by MG-132 proteasome inhibitor also resulted in partial rescue of β-catenin transcriptional activity. Our results suggest the existence of intricate patterns of truncated β-catenin proteoforms in CTNNB1 syndrome patients, which may correlate with clinical manifestations, and provide insights to increase the function of β-catenin in patients carrying CTNNB1 pathogenic variants.
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    Novel CTNNB1 gene variants in spanish CTNNB1 syndrome patients: clinical and psychological manifestations
    (Springer, 2026-09) Pallarès Sastre, Mercè ; Amayra Caro, Imanol ; Pulido, Rafael; Nunes Xavier, Caroline Elisabeth; Bañuelos Rodriguez, Sonia ; Cavaliere, Fabio ; García Martín, Maitane
    CTNNB1 Syndrome is a neurodevelopmental disorder caused by de novo pathogenic variants characterized by global cognitive impairment, microcephaly, speech and motor delay, abnormal muscle tone, ophthalmologic impairments, behaviour problems and autistic spectrum disorder (ASD) symptoms. The aim of this study is to carry out a thorough clinical and psychological characterization of Spanish CTNNB1 syndrome patients. We used standard clinical assessment instruments and an ad hoc questionnaire to measure motor functioning, neurodevelopmental milestones, sleep problems, daily life activities, behavioural problems, communication and speech impairments, eating disorders and autistic features in 25 participants with CTNNB1 syndrome (15 females, 10 males; mean age 7.1 ± 4.1). Main clinical manifestations reported were microcephaly, motor impairment, sight problems, sleep disturbances and sensorial problems. Attainment of developmental milestones indicated motoric, language and daily living skills to be generally delayed. All participants had adaptative skills below their chronological age, even though verbal individuals had better functioning compared to nonverbal. Regarding behaviour impairments, CTNNB1 syndrome patients scored significantly high at internalizing and externalizing behavioural problems. Additionally, about 60% presented symptoms of ASD. Our findings have important implications for the psychotherapeutic and clinical approaches of CTNNB1 syndrome patients. We show the importance of early stimulation, given that an early attainment of developmental milestones is related to a current better function of many clinical variables. Moreover, previous underrated symptoms such as sleep problems, impaired adaptative skills and high rates of behavioural symptoms should be taken into consideration due to the harmful impact that have on every day life.