Diagnosis and treatment of vitamin B12 deficiency in children.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism spectrum disorder (ASD), affecting approximately 1 in 4,000 males and 1 in 4,000–8,000 females (). FXS results from a CGG trinucleotide repeat expansion exceeding 200 repeats in the 5’-untranslated region of the FMR1 gene on Xq27.3, leading to promoter hypermethylation, transcriptional silencing, and loss of Fragile X Messenger Ribonucleoprotein (FMRP) (; ). FMRP is an RNA-binding protein that regulates mRNA translation at the synapse and plays a critical role in synaptic plasticity and neuronal development (). Its absence results in a broad neurodevelopmental phenotype encompassing intellectual and developmental disability, behavioral abnormalities including anxiety, aggression, hyperarousal, and seizures (). Current FXS management is entirely symptomatic. Behavioral and educational interventions, including occupational therapy, speech-language therapy, applied behavior analysis, and special education, form the foundation of care (). This is supplemented by pharmacologic management of associated symptoms such as anxiety, attention difficulties, and irritability using agents including selective serotonin reuptake inhibitors, clonidine, stimulants, and antipsychotics, among others (; ; ). Despite the widespread use of these interventions, most caregivers report that current symptomatic treatments provide limited functional improvement in the core features of FXS, underscoring the urgent need for therapies that target the underlying etiology (). Despite decades of research and multiple failed targeted treatment trials, no disease-modifying therapy addressing the underlying genetic etiology of FXS has been approved (). The unmet need for curative treatment is widely recognized within the FXS community and represents a central priority for affected families, clinicians, and researchers alike. Gene therapy offers a direct approach to addressing the root cause of FXS by restoring FMRP expression. As defined by the U.S. Food and Drug Administration (FDA), gene therapy encompasses methods of modifying a person’s genes to treat or cure disease (). Adeno-associated virus (AAV)-mediated delivery of FMR1 has demonstrated promising results in preclinical models, restoring FMRP expression and improving behavioral outcomes in FXS animal models (; ; ). AAV-based gene therapy strategies are already in active clinical development for related neurodevelopmental disorders, including Rett syndrome and Angelman syndrome, providing a translational precedent for FXS (; ). Given this emerging clinical landscape, AAV-mediated gene therapy for FXS is a realistic near-term prospect, making community preparedness an urgent priority.