Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders that manifests during early childhood. ASD is characterized by impairment in social communication and interaction skills, often associated with restricted and repetitive behaviors (American Psychiatric Association, 2013). Approximately 45% of individuals with ASD may also exhibit intellectual disability (ID) (Lai, Lombardo, & Baron-Cohen, 2014). Diagnosis is based on a clinical assessment of symptoms using standardized questionnaires and scaling tools (American Psychiatric Association, 2013). The prevalence of ASD has been exponentially increasing in recent years and there is no sign that this trend may be slowing down. Specifically, in 2022, the worldwide prevalence of ASD in children was 1%, while the median prevalence was only 0.62% in 2012 (World Health Organization, 2013, Zeidan et al., 2022).

Several factors arising from genetic, neurobiological, and environmental origins are thought to contribute to ASD (Corrales and Herbert, 2011, Karimi et al., 2017, Sandin et al., 2012). However, the exact etiology remains unknown and currently there is no effective treatment. Moreover, the lack of specific biomarkers impairs our ability to monitor the severity and progression of ASD. Given the diversity in ASD etiology and the high degree of clinical variation, it is crucial to identify homogeneous patient subgroups sharing similar molecular and clinical features (Genovese & Butler, 2020). Indeed, disease subtyping can help uncover a distinct endotype: an underlying pathobiological mechanism that accounts for these differences.

Fragile X syndrome (FXS) is the most prevalent monogenic cause of ASD affecting 1 in 2 500–4000 males and 1 in 7000–8000 females (Hagerman et al., 2017). The lower occurrence of FXS in females can be attributed to the X-linked nature of the disorder. In females, if one X chromosome carries the FXS mutation, the presence of a healthy copy of the gene on the other X chromosome allows them to compensate for the genetic defect. This means that females who carry the mutation are more likely to have milder symptoms or may even be unaffected by the disorder altogether (Pretto et al., 2014). Up to 50% of FXS-affected individuals meet the diagnostic criteria for ASD (Demark, Feldman, & Holden, 2003), while 90% of them exhibit autistic characteristics (Bailey, Hatton, Mesibov, Ament, & Skinner, 2000). Moreover, individuals with FXS display moderate to severe ID along with other comorbidities including macroorchidism, connective tissue anomalies, craniofacial anomalies, and aberrant behavior such as anxiety, hyperactivity, and attention deficit (Ciaccio et al., 2017, Hagerman et al., 2017). FXS is caused by a deficiency of expression of the Fragile X Messenger Ribonucleoprotein (FMRP) encoded by the FMR1 gene, located on the X-chromosome (Pieretti et al., 1991, Verkerk et al., 1991). FMRP is a ubiquitous protein, highly expressed in the brain that binds and regulates up to of 25–30% of presynaptic and postsynaptic mRNAs (Corbin et al., 1997, Darnell and Klann, 2013, Dionne and Corbin, 2021, Dionne et al., 2021, Greenblatt and Spradling, 2018). FMRP deficiency leads to an imbalance between neuronal excitation and inhibition, a common feature reported in several cases of neurodevelopmental disorders, including ASD (Bhakar et al., 2012, Kelleher and Bear, 2008, Pal and Bhattacharya, 2019). Despite being a genetically well-characterized syndrome, affected individuals present a wide range of cognitive dysfunction and aberrant behaviors. Residual levels of FMRP expression explain in part the heterogeneity in the FXS phenotype (Kim et al., 2019, Lessard et al., 2012). Some treatments have been proposed to manage some of the most prominent comorbidities harbored by FXS patients (Protic et al., 2022). Behavioral interventions, such as occupational, physical and speech-language therapies, have been proven successful in improving sensory processing, motor skills and social communication respectively (Kaufmann et al., 2017, Lieb-Lundell, 2016, Martin et al., 2013). Pharmacological treatments targeted against some of the core cellular deficits of FXS are also under investigation in various clinical trials (Berry-Kravis et al., 2021, Berry-Kravis et al., 2022, Proteau-Lemieux et al., 2021). Despite this, there is still no cure for FXS. Thus, a deeper characterization of FXS physiopathology is necessary to support the development of efficient treatments that modifies its natural progression.

Despite the significant phenotypic heterogeneity found in FXS and across the autism spectrum, there appears to be a shared prevalence of disrupted lipid metabolism, particularly cholesterol metabolism across some of these conditions. We will first provide an overview of the metabolism of peripheral and brain cholesterol and then describe lipid abnormalities reported so far in these conditions. Overall, the present review aims to resume the role of lipid metabolism in neurodevelopmental disorders and highlight potential avenues for future research and therapeutic development.