Fragile X Syndrome

Introduction

Fragile X Syndrome (FXS) is an X-linked disorder primarily characterized by mild to moderate mental retardation, cognitive and behavioral issues, and a characteristic body habitus. It is the second most common form of genetic mental retardation, second only to Down’s syndrome, and the most common type of familial mental retardation. In the US population, FXS has a frequency of around 1 in 4000 to 1 in 6000 in males and one-half this prevalence in females; the carrier rate of the fragile X gene is thought to be 1 in 750 males and 1 in 250 females.

Genetics

FXS is caused by an unstable trinucleotide repeat of the series CGG at the FMR1 (familial mental retardation) gene region on the long arm of the X chromosome, which leads to decreased or absent levels of fragile X mental retardation protein (FMRP). Normal unaffected individuals have between 5 to 50 CGG triplet repeats in the FMR1 promoter region. Unaffected but “pre-mutated” patients (carriers) may have 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.

FXS an X-linked disorder with an unusual inheritance pattern. Males are primarily affected, though occasional females may also develop Fragile X syndrome; however, only those individuals who inherit the gene from their mothers will be affected. There is also a wide phenotypic range from mild to very severe mental retardation; generally, males are more severely affected than females. These phenotypic variations can result from mosaicism for the size of the affected gene, the degree of methylation of the gene, and/or lyonization in females. The number of affected family members usually increases with successive generations.

Clinical Features

In affected males, FXS is mostly prominently associated with:

Neurocognitive abnormalities:

1. Mental retardation: Affected males’ IQs average 30-50; carrier females have IQs in the 70s

2. Developmental delay in childhood

3. Autism spectrum behavior: poor eye contact and stereotypic movements

4. Attention deficit-hyperactivity disorder: associated with poor attention and increased activity

5. Speech and language problems, particularly mathematics abilities, visuospatial abilities, attention and executive function, and visual-motor coordination

6. Decline in cognitive level and adaptive behavior skills after early childhood: prepubertal boys, and in particular preschool boys with FXS, generally have higher IQs than adolescents and adults.

Anatomic abnormalities:

1. Overall large body size

2. Macrocephaly: associated with underlying structural abnormalities in the brain

3. Macro-orchidism: volume >25mL after puberty with normal testicular function

4. Characteristic facies: Long and narrow face, with prominent forehead and chin

5. Large ears

Individuals with premutations (CGG 50 to 200 trinucleotide repeats) do not display the characteristic phenotype of FXS, but may present with premature ovarian failure, tremor-ataxia later in life, and neurocognitive defects.

Diagnosis

Initially, Fragile X syndrome was diagnosed by karyotyping cells in a folate-deficient medium to look for the fragile site on the X chromosome (thus leading to the disease’s name). Unfortunately, this method was not reliable and could not 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 cure available for FXS, but treatments can be tailored to suit the particular needs of a given FXS patient. Individuals diagnosed with FXS should be provided with special educational services to meet their specific cognitive disabilities. As early diagnosis is important for beginning such educational interventions in an optimally effective time frame, 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 FXS. Additionally, women with a child or a family history of Fragile X should be evaluated for carrier status and may undergo pre-implantation or prenatal genetic testing.

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.

6. Borghgraef M, Fryns JP, Dielkens A, Pyck K, Van den Berghe H. Fragile (X) syndrome: a study of the psychological profile in 23 prepubertal patients. Clin Genet. 1987;32(3):179-86.