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Most common form of X-linked mental retardation. Affects males more often and more severely than females. Only subtle dysmorphic features. Behavioral issues may be more pronounced.

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

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The incidence for boys is estimated to be 1:1000-5000 live births, making it the most common chromosomal cause of mental retardation second only to trisomy 21. The clinical picture can vary significantly.

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Inheritance is X-gonosomal dominant. The genetic defect has been mapped to Xq27.3. Advanced maternal age seems to be a risk factor for this disorder.

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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.

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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. Overall, muscle tone is low with generalized joint laxity (particularly of the fingers). Pectus excavatum, flat feet, shortening of the tubular bones of the hands, and hyperlordosis may be present. Heart defects (e.g., mitral valve prolapse), dilatation of the aortic root, and seizures have been described. Researchers found that the hippocampus often shows an age-related increase in size, whereas the superior temporal gyrus and the posterior cerebellar vermis are diminished in size. After age 50 years, patients show an increased rate of progressive parkinsonism, cognitive decline, and generalized brain atrophy.

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The cardiovascular findings may prompt the anesthetist to request an echocardiography. If pectus excavatum is present and significant, a chest radiograph should be obtained. Because these patients are mentally retarded and may have some additional behavior issues, preoperative sedation is most often helpful and therefore recommended.

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