Fragile X syndrome and fragile X-associated disorders

Abstract

Fragile X syndrome (FXS) is caused by a full mutation on the FMR1 gene and a subsequent lack of FMRP, the protein product of FMR1. FMRP plays a key role in regulating the translation of many proteins involved in maintaining neuronal synaptic connections; its deficiency may result in a range of intellectual disabilities, social deficits, psychiatric problems, and dysmorphic physical features. A range of clinical involvement is also associated with the FMR1 premutation, including fragile X-associated tremor ataxia syndrome, fragile X-associated primary ovarian insufficiency, psychiatric problems, hypertension, migraines, and autoimmune problems. Over the past few years, there have been a number of advances in our knowledge of FXS and fragile X-associated disorders, and each of these advances offers significant clinical implications. Among these developments are a better understanding of the clinical impact of the phenomenon known as mosaicism, the revelation that various types of mutations can cause FXS, and improvements in treatment for FXS.

Keywords: FMR1 gene; copy number variants; point mutations; whole exome sequencing.

Figure 1.

This 7-year-old boy with fragile X syndrome demonstrates a broad forehead ( a) and a high arched palate ( b) . However, he does not have a long face or prominent ears. He is a high-functioning individual with mosaicism, and DNA testing displays a band at 300 CGG repeats that is methylated as well as bands between 100 and 790 repeats that are unmethylated; overall, 30% of his alleles are unmethylated. He presents with a sequential IQ of 71 and a simultaneous IQ of 83. He has done well with treatment; sertraline has improved his anxiety symptoms, and a long-acting methylphenidate preparation has improved his attention-deficit hyperactivity disorder symptoms.

Figure 2.. There is significant overlap between fragile X syndrome (FXS), autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD).

Approximately 60% of all patients with FXS also meet criteria for ASD, although FXS accounts for only 2% to 6% of all cases of ASD. Furthermore, nearly 80% of children with FXS and 50% of children with ASD have co-occurring ADHD ^, .