Chapter 17 – Fragile X-Associated Disorders

Fragile X-associated disorders include fragile X syndrome (FXS) caused by the full mutation (> 200 CGG repeats that are usually methylated) on the front end of the Fragile X Mental Retardation 1 gene (FMR1) and premutation disorders (55–200 CGG repeats) including depression, anxiety, fragile X-associated primary ovarian insufficiency (FXPOI; cessation of menses before age 40) and fragile X-associated tremor/ataxia syndrome (FXTAS). Premutation carriers are common in the general population with approximately 1 in 130–250 females and 1 in 250–810 males, whereas those with the full mutation and FXS occur in approximately 1 in 4000 to 1 in 5000. Males with FXS usually have intellectual disability (ID) and behavior problems including autism spectrum disorder (ASD) in 60%, attention deficit hyperactivity disorder (ADHD) in 80%, anxiety in 80%, and aggression in 40%. Females are less affected and only 30% have ID because they have a second, normal X chromosome and the FMR1 gene occurs at the Xq27.3 region. FXS is the most common identified genetic cause of autism or inherited ID. Fragile X DNA testing should be carried out in anyone diagnosed with ID or ASD. The full mutation is always inherited from the mother who may be a premutation carrier or have a full mutation. Males with the premutation will pass on only the premutation to all of their daughters, and their sons will receive the Y chromosome so they will not be affected by the fragile X mutation. Premutation carriers usually have normal intellectual abilities because FMR1 is not methylated and the level of FMRP is usually normal except in the upper range of the premutation with > 120 CGG repeats when FMRP may be mildly deficient. However, the level of FMR1 messenger RNA (mRNA) is increased in carriers ranging from 2–8 times normal leading to toxic effects in the neuron. Psychiatric problems are common in carriers including anxiety, which can start in childhood and present as shyness or social anxiety, and persist in adulthood and often worsen with aging because of the onset of neurological problems associated with FXTAS. Depression is also common in adulthood and is often associated with alcohol abuse particularly in males. FXPOI occurs in approximately 20% of carriers and can also be associated with psychiatric problems related to early estrogen deficiency with the early onset of menopause. Female carriers often experience hypertension, hypothyroidism and/or fibromyalgia in mid adult life. FXTAS occurs overall in 40% of males and up to 16% of females with an average age of onset at 62 years. FXTAS symptoms include a cerebellar intention tremor, which typically occurs first followed by ataxia, neuropathy pain, autonomic dysfunction, and cognitive decline. Approximately 50% of males with FXTAS develop dementia. Memory problems and executive function deficits are common typically when individuals present with tremor and/or ataxia. Approximately 30% have parkinsonian symptoms including resting tremor so patients are often misdiagnosed with Parkinson disease or benign tremor. Current research is focused on the mechanisms of RNA toxicity that occur in the premutation range and targeted treatments that can reverse the neurobiological abnormalities that occur in FXS and in premutation disorders.