Fragile X is the second most common form of genetic mental retardation, second to Down’s syndrome, and the most common type of familial mental retardation. Fragile X has a frequency of around 1 in 1500 males and about 1 in 2000 to 4000 of the general population (females included). The carrier rate of the fragile X gene is thought to be around 1/163 to 1/1538. Generally, males are affected, but occasionally females can be affected as well. Fragile X syndrome is named for an unstable, or fragile site on the X chromosome that can be seen when the cells are karyotyped on folate deficient medium. It was subsequently discovered that the Fragile X gene is located on the distal long arm of the X chromosome at Xq27.3

Clinical Features

Fragile X syndrome in affected adult males is associated with:
 
 

1. Mental retardation-Males 30-50, females 70's

2. Large body size

3. Macro-orchidism

4. Long face

5. Prominent jaw

6. Large ears

7. Autistic behavior-poor eye contact, stereotypic movements

8. Attention deficit-hyperactivity disorder-often diagnosied because of poor attention and increased activity

9. Speech and language problems
 
 

Genetics

Fragile X is caused by an unstable trinucleotide repeat of the series CGG at the FMR1 gene (familial mental retardation) region on the long arm of the X chromosome. Normal unaffected individuals have between 5 to 50 ( average is about 29) CGG triplet repeats in the FMR1 promoter region. In unaffected but pre-mutated patients, there were found to be up to 200 repeats. Affected patients have >200 to thousands of CGG trinucleotide repeats. The number of CGG repeats, along with the degree of methylation of this gene determine the phenotype of the affected individual. The Fragile X phenotype results from a loss of function of a protein, and not from the production of an abnormal protein in this gene region.

Fragile X syndrome is an X-linked disorder with an unusual inheritance pattern. Males are affected primarily, but some females are known to have Fragile X syndrome. Also, there is a wide phenotypic range from mild to very severe mental retardation, generally, males are more severely affected than females. Phenotypic variations can result from mosaicism for the size of the affected gene, the degree of methylation of the gene, and lyonization in females. Interestingly, the number of affected family members usually increases with successive generations. Also, it is notable that only individuals who inherited the Fragile X gene from their mothers were affected.

Diagnosis

Initially, Fragile X syndrome was diagnosed by a cytogenetic technique of karyotyping cells in a folate deficient medium to look for the fragile site on the X chromosome. Unfortunately, this method was not reliable and did not help to identify carriers of the gene. Currently, the fragile X gene can be examined directly using Southern blot analysis and endonuclease restriction digestion. Amniocentesis is preferred over chorionic villus sampling for prenatal diagnosis of fragile X syndrome.

Treatment

There is no specific treatment for fragile X syndrome. Patients should be provided with special educational services to meet their specific disabilities. Parents who have a child with mental retardation, developmental delay of unknown etiology, or autistic symptoms should have their child seen by a geneticist and evaluated for Fragile X. Additionally, women with a child or a family history of Fragile X should be evaluated for carrier status.

References:

1. Wenstrom, K. D. Fragile X and Other Trinucleotide Repeat Diseases. Obstetrics and Gynecology Clinics. 2002; 1367-1376.

2. Goez. Textbook of Clinical Neurology. W.B. Saunders. 1999, 1st Ed. pp. 317-318.

3. Behrman. Nelson Textbook of Pediatrics. W.B. Saunders. 2000. 16th Ed. pp. 781-783.

4. Eliez, S., Reiss, A. Genetics of Childhood Disorders: XI. Fragile X Syndrome. Journal of the American Academy of Child and Adolescent Psychiatry, 2000; 201-203.

5. Index of Suspicion Case 3 Pediatrics in Review October 2004 25;364-369