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FMR1-Related Disorders.

Authors

Saul RA1, Tarleton JC2.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
1998 Jun 16 [updated 2012 Apr 26].

Author information

1
Greenwood Genetic Center, Greenwood, South Carolina
2
Fullerton Genetics Center, Asheville, North Carolina

Excerpt

CLINICAL CHARACTERISTICS:

FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related primary ovarian insufficiency (POI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Because FMR1 pathogenic variants are complex alterations involving non-classic gene-disrupting alterations (trinucleotide repeat expansion) and abnormal gene methylation, affected individuals occasionally have an atypical presentation with an IQ above 70, the traditional demarcation denoting intellectual disability (previously referred to as mental retardation). Males with an FMR1 full mutation accompanied by aberrant methylation may have a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears), connective tissue findings (joint laxity), and large testes after puberty. Behavioral abnormalities, sometimes including autism spectrum disorder, are common. FXTAS occurs in males (and some females) who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor. FMR1-related POI (age at cessation of menses <40 years) occurs in approximately 20% of females who have an FMR1 premutation.

DIAGNOSIS/TESTING:

The diagnosis of FMR1-related disorders rests on the detection of an alteration in FMR1. More than 99% of individuals with fragile X syndrome have a loss-of-function variant of FMR1 caused by an increased number of CGG trinucleotide repeats (typically >200) accompanied by aberrant methylation of FMR1. Other pathogenic variants within FMR1 that cause fragile X syndrome include deletions and single-nucleotide variants. All individuals with FXTAS and FMR1-related POI have FMR1 premutation trinucleotide repeats ranging from 55 to approximately 200. Both increased trinucleotide repeats and methylation changes in FMR1 can be detected by molecular genetic testing.

MANAGEMENT:

Treatment of manifestations: Fragile X syndrome: early developmental intervention, special education (individual attention, small class size, and avoiding sudden change and excessive stimulation), and vocational training; individualized pharmacologic management of behavioral issues that significantly affect social interaction; routine treatment of medical problems. FXTAS: supportive care for gait disturbance and/or cognitive deficits. POI: reproductive endocrine evaluation for treatment and counseling for reproductive options. Agents/circumstances to avoid: Folic acid in individuals with poorly controlled seizures.

GENETIC COUNSELING:

All mothers of individuals with an FMR1 full mutation (expansion >200 CGG trinucleotide repeats and abnormal methylation) are carriers of an FMR1 pathogenic variant. Mothers and their female relatives who are premutation carriers are at increased risk for FXTAS and POI; those with a full mutation may have findings of fragile X syndrome. All are at increased risk of having offspring with fragile X syndrome, FXTAS, and POI. Males with premutations are at increased risk for FXTAS. Males with FXTAS will transmit their FMR1 premutation expansion to none of their sons and to all of their daughters, who will be premutation carriers. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the diagnosis of an FMR1-related disorder has been confirmed in a family member.

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