To full tale the 2005 Annual Clini...

To full tale the 2005 Annual Clinical Focus forward medical genomics, AFP will be publishing a series of short reviews in succession genetic syndromes. This series was designed to increase awareness of these diseases thus that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the to come The first review in this series discusses fragile X syndrome

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Fragile X syndrome is caused from an expansion mutation in the Fragile X mental retardation 1 (FMR1) gene located upon the X chromosome. It characteristically leads to any degree of mental retardation. The phenotype is astute with minor dysmorphic features and developmental delay during childhood. Characteristic features during adolescence are an elongated face, prominent jaw, large ears, macro-orchidism, and a range of behavioral anomalies and cognitive deficits (Figure 1) lately recognized manifestations in premutation carriers include premature ovarian failure and tremor/ataxia. (1) Premature ovarian failure appears in up to 20 percent of women who are premutation carriers of the FMR1 gene (1) Fragile X-associated tremor/ ataxia syndrome (FXTAS) affects 30 percent of premutation carrier men between the ages of 50 and 60 years, and its prevalence increases with age. (1)

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Epidemiology

Fragile X syndrome the phenotype associated with abounding mutation, occurs in approximately the same in 4,000 men and single in kind in 6,000 to 8,000 women The premutation in the FMR1 gene offers in approximately one in 800 men and up to single in 100 to 200 women Premutation male carriers are susceptible to FXTAS after age 50 Premature ovarian failure may be finded in as many as undivided third of women with a premutation.

Clinical Presentation

Although fragile X syndrome flash on the minds in males and females, females generally current with milder symptoms. The first clinical clew in children often is delayed attainment of single in kind or more developmental milestones. (23) upon average, boys with fragile X syndrome sit without support at 10 month of age and walk and talk at 20 month (2) With hardly any exceptions, affected males have mental retardation, generally of moderate order About one third of affected females have mild to rigorous mental retardation. (2) There is a specific pattern of deficits in abstract reasoning, sequential processing, and mathematics. Clinical findings during early childhood may include macrocephaly and frontal bossing (unusually prominent forehead). After puberty, macroorchidism is at hand in affected men. Additional findings may include strabismus and mild connective tissue dysplasia, similar as mitral valve prolapse, hyperextensible joints, and pe planus. Behavior is characterized through attention deficits, hand flapping, hand biting, and gaze aversion. Family physicians are greatest in number likely to encounter the undiagnosed child before place of education age, when formal testing can confirm cognitive deficits. However, the average age of diagnosis publicly is eight years, reflecting the cleverness of features in young children. (4)

FXTAS is a neurodegenerative disorder with progressive intention tremor and cerebellar ataxia. (5) Affected someones present with parkinsonism, peripheral neuropathies, and dementia after age 50 years.

Premature ovarian failure may meet the eye as an isolated clinical finding in women with premutations. (16) Follicle-stimulating hormone (FSH) plains are elevated in these women level before the onset of premature ovarian failure. Approximately 1 percent of women in the general population have premature ovarian failure, moreover the prevalence in women with a premutation is 30 times higher. (6) Women who are infertile and have prematurely elevated FSH evens should be considered for carrier status testing of the FMR1 premutation. A family history of FXTAS or premature ovarian failure in a child with cognitive deficits is another indicator to initiate genetic testing for fragile X syndrome (Figure 2)

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Diagnosis

The diagnosis of fragile X syndrome is confirmed by dint of molecular genetic testing of the FMR1 gene Prenatal testing is available. FMR1 is characterized on a repetitive CGG trinucleotide succession which is repeated six to 50 times in unaffected human frames (Figure 2). A full mutation consists of more than 200 CGG repeats in the FMR1 gene plus hypermethylation, which leads to an inability to exhibit the FMR1 protein. Almost all males and more than common half of females with sated mutations have fragile X syndrome2 Premutation carriers, who have between 50 and 200 CGG repeats, are not cognitively affected on the other hand may have physical or psychiatric findings. In addition, they are susceptible to developing premature ovarian failure and FXTAS. Rarely, the fragile X phenotype come to passs in a premutation carrier if hypermethylation is not past nor future Conversely, the phenotype may be absent in a human frame with a full mutation without hypermethylation, confirming that fragile X syndrome accrues from the absence of FMR1 protein.