Fragile X Syndrome
Incidence
It is X-linked inheritance. The overall prevalence of retardation due to the fragile X syndrome is approximately 1 per 1250 males and 1 per 2000 females.
Clinical Characteristics
Approximately 20 percent of all X-linked mental retardation results from the fragile X syndrome itself. Therefore, the fragile X syndrome is one of the most common heritable causes of mental retardation worldwide. Somatic features generally appear in childhood and include increased head circumference, coarsening of facial features, hypotonia, and prominence of the ears, forehead, and jaw. A connective-tissue disorder may be suspected because of joint hyperextensibility, pectus excavatum, pes planus, mitral valve prolapse, and dilatation of the aortic root. Enlarged testes (macroorchidism) is uncommon prior to puberty (15 percent) but is present in nearly 90 percent of postpubertal males. Longevity appears to be normal without any single disease entity clearly identified as a major cause of death in males with the fragile X syndrome. Mental retardation is common but varies in severity in males with the fragile X syndrome, even within the same family. Over 90 percent of male patients have IQ scores in the range 20 to 60, with a mean between 30 and 45. Seizures occur in approximately 10 percent of patients. Certain behavioral abnormalities are frequently present in childhood and may aid in the diagnosis. These include attention deficit disorder or hyperactivity, poor eye contact, and stereotypic hand movements. In verbal patients, rapid speech with stuttering and perseveration is seen frequently. Patients are often pleasant or docile, but violent disruptive behavior occurs in a significant minority of patients and has required institutionalization in a number of cases. Many of the behavioral abnormalities wane as patients enter adulthood. Approximately 50 percent of females carrying the full mutation show mental impairment, with intellectual deficits ranging from learning disability with normal formal IQ testing to severe retardation; female carriers of the premutation are all clinically normal. No characteristic behaviors have been noted in mentally impaired female carriers of the fragile X syndrome. Facial features similar to those seen in affected males may be present in retarded female heterozygotes, and it has been suggested that the degree of somatic expression of the gene defect in females correlates with the severity of mental retardation. Neuropathological examination of fragile X syndrome males demonstrated nonspecific abnormalities in dendritic spine and synaptic structure in the cortex but was otherwise unrevealing. Thus, the pathogenesis of the abnormalities seen in this disorder remains obscure. A diagnosis of the fragile X syndrome is often suspected based on clinical phenotype and family history of X-linked mental retardation. The diagnosis of the fragile X syndrome should not be made on phenotypic grounds alone, but must be confirmed with direct analysis of the trinucleotide repeat expansion in FMR1. In normal individuals, the number of repeats of the trinucleotide (CGG)n ranges between ~2 and ~60; these different triplet lengths constitute alleles of a genetic polymorphism and are inherited stably in a Mendelian manner. In families with individuals affected with the fragile X syndrome, however, the length of the repeat is increased and the stability of the amplified fragment is very abnormal. Transmitting males and many unaffected female carriers have trinucleotide repeat lengths that range between 60 and 200 copies (\"premutation\"). Premutations are not associated with clinical disease, rarely cause cytogenetic expression of the fragile site, and appear to be stable in somatic tissues of the individual carrying the amplification. Premutations are of major importance genetically because they are unstable when inherited, especially through a female parent, and have a high risk of undergoing further expansion, to >200 copies and often to thousands of copies, leading to the clinical and cytogenetic manifestations of the fragile X syndrome. The fundamental molecular assay for the fragile X syndrome is the measurement of the length of the (CGG)n repeat in the FMR1 gene. No specifc treatment for the fragile X syndrome is available. Treatment is symptomatic. Speech and occupational therapy may help patients reach their own intellectual potential.
Precipitants
None
Provocation Tests
none
Diagnostic Procedures
DB-W. The diagnosis of the fragile X syndrome should not be made on phenotypic grounds alone, but must be confirmed with direct analysis of the trinucleotide repeat expansion in FMR1. In normal individuals, the number of repeats of the trinucleotide (CGG)n ranges between ~2 and ~60; these different triplet lengths constitute alleles of a genetic polymorphism and are inherited stably in a Mendelian manner. In families with individuals affected with the fragile X syndrome, however, the length of the repeat is increased and the stability of the amplified fragment is very abnormal. Transmitting males and many unaffected female carriers have trinucleotide repeat lengths that range between 60 and 200 copies (\"premutation\"). Premutations are not associated with clinical disease, rarely cause cytogenetic expression of the fragile site, and appear to be stable in somatic tissues of the individual carrying the amplification. Premutations are of major importance genetically because they are unstable when inherited, especially through a female parent, and have a high risk of undergoing further expansion, to >200 copies and often to thousands of copies, leading to the clinical and cytogenetic manifestations of the fragile X syndrome. The fundamental molecular assay for the fragile X syndrome is the measurement of the length of the (CGG)n repeat in the FMR1 gene.