Fragile X syndrome is characterized by neurodevelopmental dysfunction including intellectual disability and behavioral problems, facial dysmorphism, and connective tissue findings. Clinical features may be subtle in childhood while developmental delays typically present at a young age. Manifestations in affected females tend to be milder than those seen in males.
Fragile X-associated late-onset tremor-ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder that typically presents after age 50 and affects men more commonly than women.
Fragile X-associated premature ovarian insufficiency (FXPOI) can present as decreased ovarian reserve, decreased fertility, elevated follicle-stimulating hormone (FSH) levels, or premature ovarian failure (POF).
Fragile X syndrome, FXTAS, and FXPOI are caused by triplet repeat expansions in the FMR1 gene on the X chromosome.
Greater than 99% of fragile X syndrome is associated with repeat sizes of greater than 200 (full mutation). Less than 1% is associated with other mutations that silence the FMR1 gene.
FXTAS and FXPOI are associated with repeat sizes of 55 to 200 (premutation)
Females with a pre or full mutation have a 50% of passing an expansion mutation to their offspring.
Expansion of a premutation to a full mutation only occurs during female meiosis and depends on premutation size in carrier females.
Fragile X syndrome affects approximately 1/4000 males and 1/8000 females. The carrier frequency for FMR1 premutations in females in the United Statesis estimated to be 1/382.
Fragile X syndrome is the most common single gene cause of intellectual disability and autism. Therefore, it should be considered at the top of the differential diagnosis for males and females affected with either of the two.
Intellectual disability is seen as a part of many genetic syndromes, however, the presence of clinical features consistent with other conditions may help to rule out other diagnoses.
Genetic conditions that warrant consideration when a diagnosis of fragile X syndrome cannot be established include fragile XE syndrome, Sotos syndrome, and other chromosomal abnormalities.
Diagnostic Criteria and Clinical Characteristics
The clinical findings seen in individuals with fragile X syndrome are summarized in Table 159-1. Features tend to be milder in affected females than males, with 50% of females with a full mutation having normal intellect. Intellectual disability in males includes a spectrum of mild to severe with most falling in the moderate range with an IQ of 70 or lower. The facial features and connective tissue findings vary significantly and are often subtle or absent in young children. Macroorchidism, a hallmark feature of fragile X syndrome (not listed in Table 159-1), is not evident in boys until after puberty.
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A definitive diagnosis of fragile X syndrome is made when an individual with any of the above clinical findings is found to have a silencing mutation in the FMR1 gene.
FXTAS is an adult-onset progressive neurologic condition that typically presents after age 50. Men with FMR1 premutations are at significantly higher risk than female carriers. Diagnostic criteria for FXTAS include both clinical and neuroimaging findings.
Major criteria—intension tremor and cerebellar ataxia on clinical examination and white matter lesions of the middle cerebellar peduncles or brain stem on magnetic resonance imaging (MRI)
Minor criteria—short-term memory deficits, defects in executive function, parkinsonism, white matter lesions in the cerebral white matter, generalized atrophy on MRI
Definite diagnosis of FXTAS is made in an individual with an FMR1 premutation and one major clinical and one major imaging finding. A probable diagnosis of FXTAS requires the presence of two major clinical signs of one major imaging finding with one minor clinical sign. Additional neurologic findings associated with FXTAS can include cognitive decline, dementia, peripheral neuropathy, and muscle weakness. The majority of individuals with an FMR1 premutation are of normal intelligence although learning disabilities in children and mental health issues in females with premutations have been reported.