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At a glance

Most common form of X-linked mental retardation. Symptoms most often are limited to mild to moderate intellectual disability. Affects males more often and more severely than females. The clinical presentation is delayed development of speech and language by age 2. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles (macroorchidism) after puberty. In a third of people behavioral features include autism-like signs such as problems with social interactions and delayed speech. Hyperactivity is common and seizures occur in about 10%.


FRAXA Syndrome; Martin Bell Syndrome; X-linked Mental Retardation Macroorchidism Syndrome.


The incidence for boys is estimated to be 1:1,000 to 5,000 live births, making it the most common chromosomal cause of mental retardation second only to trisomy 21. The clinical picture can vary significantly. Fragile X Syndrome occurs in about 1 in 4,000 males and 1 in 8,000 females.

Genetic inheritance

Inheritance is X-gonosomal dominant. Fragile X Syndrome is typically due to an expansion of the CGG triplet repeat within the Fragile X mental retardation 1 (FMR1) gene on the X chromosome. The genetic defect has been mapped to Xq27.3. Advanced maternal age seems to be a risk factor for this disorder.


The clinical picture may be suggestive of the disease, although the dysmorphic features are rather subtle. The diagnosis can be confirmed using molecular genetic testing (Southern blot) and relies on the detection of an altered fragile X mental retardation-1 (FMR1) gene. In almost all patients, the mutation is caused by a significantly increased number of CGG (C = cytosine, G = guanosine) trinucleotide repetitions, which is also associated with abnormal methylation of the FMR1 gene. The absence of or mutation in the fragile mental retardation protein (FMRP) is responsible for the Fragile X Syndrome. FMRP is an RNA binding protein that shuttles between the nucleus and the cytoplasm. It seems that FMRP is located at synapses, where it is involved in signal transduction and encoding of cytoskeletal proteins. It also appears that lack of FMRP affects synaptic plasticity. Prenatal diagnostic is possible.

Clinical aspects

This progressive X-linked mental retardation affects boys (moderate mental retardation) more often and more severely than girls (mild mental retardation). The main neurologic symptoms include delayed language skills, delayed motor development, autism or autistic-like behavior, behavioral problems (attention deficit hyperactivity disorder, oppositional defiant disorder, enuresis, encopresis), and poor sensory skills. Anatomical features may include macrocephaly, a long face with prognathism (which in fact is often just a prominent symphysis of the mandibula rather than real prognathism), strabismus, prominent large ears, high arched palate, and a high-pitched voice. The external male genitalia show pronounced growth during puberty, which results in macroorchidism. ...

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