Group CBT in Adolescents With Fragile X Syndrome and in Adolescents With Autism Spectrum Disorder

Effectiveness of Cooperative Group Therapy in Adolescents With Fragile X Syndrome (FXS) and in Adolescents With Autism Spectrum Disorder (ASD)

Fragile X Syndrome (FXS) is a rare genetic syndrome, caused by a mutation in the FMR1 gene located on the X chromosome. It is considered the leading hereditary cause of intellectual disability (ID) and the primary cause of Autism Spectrum Disorder (ASD) due to a single gene-mutation. Many individuals with FXS exhibit symptoms overlapping with those of ASD, including difficulties in social-communication skills, challenges in peer relationships, restricted and repetitive behaviors/interests and deficits in adaptive functioning. Both in ASD and FXS, individuals with greater deficits in executive functions, socio-pragmatic, and socio-relational skills also demonstrate lower adaptive functioning and, consequently, reduced autonomy/independence throughout the life course and greater severity of the disorder.

Among empirically validated treatments recommended by National and International Guidelines for the treatment of ASD, cognitive-behavioral and psychosocial interventions have been shown to improve some aspects of ASD, such as core symptoms, emotional-behavioral disturbances, adaptive skills, and quality of life. Currently, it appears that cognitive-behavioral therapies, which include psychoeducation programs, are particularly appropriate for ASD, with greater efficacy for group interventions compared to individual ones. Regarding FXS, despite the well-established knowledge of the cognitive-behavioral phenotype and the clear need for scientifically validated programs, research on intervention strategies remains quite limited.

Considering the similarities between ASD and FXS and the need for standardized interventions, the present research project aims to conduct an RCT to evaluate the feasibility of Cooperative Group Therapy (CGT) in two different groups of adolescents with ASD and FXS. The decision to target the intervention to adolescents is due to the few clinical studies on this age group, which is a crucial target since, in FXS, there is often a plateau or reversal of intellectual and adaptive development after the age of 10, and in adolescents with ASD, the development and complexity of social, pragmatic skills, and executive functions are crucial for good adaptive functioning and a basic quality of life. Te main hypothesis is that CGT could contribute to the reduction of severity illness and in the enhancement of socio-communicative skills.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder affecting approximately 1% of the global population, characterized by early onset, difficulties in communication and reciprocal social interaction, and associated with unusually restricted and repetitive behaviors and interests.

Fragile X Syndrome (FXS) is a rare genetic syndrome affecting about 1 in 4.,000 males and 1 in 8.,000 females, caused by a mutation in the FMR1 gene located on the X chromosome. It is considered the leading hereditary cause of intellectual disability (ID) and the primary cause of ASD due to a mutation in a single gene.

Research shows that many individuals with FXS exhibit symptoms overlapping with those of ASD, including difficulties in social-communication skills, challenges in peer relationships, restricted and repetitive behaviors/interests, and deficits in adaptive functioning. In both syndromes, individuals with greater deficits in executive functions, socio-pragmatic, and socio-relational skills also demonstrate lower adaptive functioning and, consequently, reduced autonomy/independence throughout the life course and greater severity of the disorder.

Among empirically validated treatments recommended by National and International Guidelines for the Treatment of Autism, cognitive-behavioral and psychosocial interventions have been shown to improve some aspects of ASD, such as core symptoms, emotional-behavioral disturbances, adaptive skills, and quality of life. Currently, it appears that cognitive-behavioral therapies, which include psychoeducation programs, are particularly appropriate for ASD, with greater efficacy for group interventions compared to individual ones. However, a very recent meta-analysis of Conrad and colleagues (2021) highlighted that there are currently only 30 RCTs (Randomized Clinical Trials) on ASD and that most of these studies have been conducted in a limited geographical area, with few studies in Europe. Regarding FXS, despite the well-established knowledge of the cognitive-behavioral phenotype and the clear need for scientifically validated programs, research on intervention strategies remains quite limited. In a 2011 systematic review, Moskowitz and Carr analyzed 31 studies investigating the effectiveness of behavioral treatment in FXS and pointed out that most of them were conducted with limited methodological rigor. Indeed, their review revealed that the examined interventions employed various behavioral strategies, often using a single patient per technique, making it difficult to draw conclusions about individual techniques. The lack of empirically validated cognitive-behavioral intervention models remains a significant issue for all clinicians working with individuals with FXS and ASD. Consequently, parents continue to rely on intervention methods whose clinical effectiveness has not been tested, monitored, or replicated through studies with valid methodological rigor. As a result, there is an undeniable need to develop new interventions: a) conducted with methodological rigor (RCTs), b) applicable across different age groups, and c) structured, empirically measurable, and replicable.

In 2020, Valeri and colleagues conducted the first European RCT to assess the clinical effectiveness of Cooperative Parent-Mediated Therapy (CPMT) in preschool children with Autism, showing that CPMT is effective in improving socio-communication skills, core ASD symptoms, and in reducing parental stress related to dysfunctional parent-child interactions.

Subsequently, in 2021, Alfieri and colleagues conducted a study to verify the efficacy of CPMT in treating socio-communicative deficits in children with FXS and Williams Syndrome, demonstrating that the use of a parent-mediated intervention, theoretically founded and utilizing ECEN strategies (Evolutive and Naturalistic Behavioral Interventions), results in significant improvement in socio-communicative-relational skills even in these populations.

Additionally, Montanaro and coll. in 2020 performed a study to examine the efficacy of Corp-osa-Mente (CoM), a combined neuropsychological and cognitive behavioral group therapy (nCBT) tailored on young adults and targeting the different clinical manifestations of FXS through a unified approach. Results indicated an improvement in participants' psychopathological symptoms, cognitive abilities, and general adaptive behavior. However the study faced different methodological issues, such as the absence of standardized measures. Therefore, additional methodologically rigorous studies were required to substantiate these initially promising findings.

Based on these encouraging results in children and adults with FXS, the present research project aims to conduct an RCT to evaluate the clinical efficacy and feasibility of Cooperative Group Therapy (CGT) in two different groups of adolescents with ASD and FXS. The decision to target the intervention to adolescents is due to the few clinical studies on this age group, which is a crucial target since, in FXS, there is often a plateau or reversal of intellectual and adaptive development after the age of 10, and in adolescents with ASD, the development and complexity of social, pragmatic skills, and executive functions are crucial for good adaptive functioning and a decent quality of life. Specifically, the primary goal is the reduction of the mean score on the Global Clinical Impression - Severity Scale (CGI-S), which measures the severity of the disorder, after treatment compared to baseline. Pre- and post-treatment evaluations of cognitive and adaptive profiles will also be conducted, and standardized questionnaires will be administered, with results used as secondary endpoints (e.g., Social Responsiveness Scale, SRS; Behavior Rating Inventory of Executive Functioning, BRIEF; Vineland Adaptive Behavior Scales -II, VABS-II; Multidimensional Anxiety Scale for Children-II, MASC II; Child Behavior Checklist, CBCL; Conners' Parent Rating Scale, CPRS; Quality of Life Scale, QoLS; Parenting Stress Index, PSI).

FXS group:

Inclusion Criteria

• Clinical diagnosis of FXS confirmed by genetic testing.
• Age between 13 and 19 years.
• Language skills compatible with group intervention (verbal language at sentence level).
• Impairment in adaptive functioning measured by VABS II < 70.
• Informed consent for participation and data processing provided by parents. Exclusion Criteria
• Severe visual or hearing impairments.
• Diagnosis of epilepsy or a history of seizures requiring medication.
• Participation in other non-pharmacological treatments.
• Changes in pharmacological therapy within the last 3 months.
• Presence of medical problems or behaviors that could interfere with group activities, as measured by the Autism Behavior Checklist (ABC) (ABC Irritability Scale < 18).
• IQ < 40 measured by the Leiter third edition (Leiter 3)
• Severe adaptive functioning, measured by VABS II < 20.

ASD group:

Inclusion Criteria

• Clinical diagnosis of Autism Spectrum Disorder (ASD) confirmed by ADOS-2 and ADI-R interviews.
• Age between 13 and 19 years.
• Language skills compatible with group intervention (verbal language at sentence level).
• Impairment in adaptive functioning measured by VABS II < 70.
• Informed consent for participation and data processing provided by parents.

Exclusion Criteria

• Severe visual or hearing impairments.
• Identification of specific genetic abnormalities or presence of known genetic syndromes associated with ASD (e.g., TSC, FXS, 22q11, 16p11.2, Rett Syndrome).
• Diagnosis of epilepsy or a history of seizures requiring medication.
• Participation in other non-pharmacological treatments.
• Changes in pharmacological therapy within the last 3 months.
• Presence of medical problems or behaviors that could interfere with group activities, as measured by the Autism Behavior Checklist (ABC) (ABC Irritability Scale < 18).
• IQ < 40 measured by the Leiter third edition (Leiter 3)
• Severe adaptive functioning, measured by VABS II < 20.