Nashville, TN

Synonyms: Martin–Bell syndrome, Marker X syndrome[1].

Definition: Fragile X syndrome is now a well established clinical entity which is the prototype of a series of inherited neurodevelopmental disorders caused by abnormal expansion of repeated trinucleotide sequences embedded in various genes[2]. This produces a single gene mutation on the X chromosomes[3], which abolish expression of an X-linked gene, FMR1, resulting in pathogenesis of the disease[4]. It is a common X-linked hereditary disease characterized by mental deficiency or retardation, mild connective tissue dysplasia and macroorchidism, caused by the absence or deficit of the FMR1 protein1^,[5],[6], and results from a dynamic mutation in a gene on the long arm of the X chromosome[7]. Fragile X is the most common cause of mental retardation after Down syndrome, and also the most common cause of inherited (familial) mental retardation wordwide.7^,[8],[9] the name “fragile X syndrome” refers to a cytogenic marker on the X chromosome at Xq27.3, a “fragile site” in which the chromatin fails to condense properly during mitosis[10].

History: Martin and Bell, in 1943, published the first documents of sex linked forms of mental retardation. In 1969, Lubs showed the presence of a fragile site on the long arm of the X chromosome in affected males and some carrier females in one family. Turner et al. and Cantu et al. were the first ones to describe macroorchidism without endocrinologic abnormalities. Sutherland demonstrated that expression of the fragile site with association between X linked mental retardation, macroorchidism, and the marker X chromosome was dependent on the nature of the cell culture medium1.

The gene which is responsible for fragile X syndrome was discovered in 1991. As a result, diagnosis of the disorder has improved and its molecular genetics are now understood[11].

Incidence: The disorder appears to be common. Among populations of mentally handicapped individuals, fragile X positive studies have been documented in up to 5.9% of males and up to .3% of females1. This X linked disorder affects 10:10.000 males and 5:10.000 females. The female carrier rate in the general population is estimated to be 1:6009. Other authors report incidences of 2.5:10.000 males and 1.25:10.000 females10^,11. Fragile X syndrome occurs in all racial and ethnic groups, and it is a condition of mayor epidemiological importance among mentally handicapped males.[12]

Etiology: The fragile X syndrome is caused by a dynamic mutation that occurs in the 5’ untranslated region of the first exon of a gene called “fragile X mental retardation 1” (FMR1), in the distal long arm of the X chromosome. The mutation consists of an abnormal massive expansion or stretch of a triplet repeat, which increases in length as it is transmitted from generation to generation. Under normal conditions a maximum of repeats of the CGG triplet is 54. Once the repeat exceeds a threshold length of 54 no fragile X protein is produced and disease results11^,[13]. Normal individuals have from 6 – 54 repeats. Both male and female premutation carriers have 54 – 200 repeats, while affected individuals (with the mutation) usually have more than 200 repeats1^,[14]. Expansion of premutation to full mutation occurs only in female meiotic transmission, and correlates with the size of the premutation1. No spontaneous expansions directly from a normal allele to a full mutation (without going through premutation) have been observed11.

Pathogenesis: The X chromosome, in its distal long arm, contains a normal allele or gene, which is called the “fragile X gene” or “FMR1” or “fragile X mental retardation 1”. Under normal conditions this gene, or allele, or regulatory coding region, by a process of transcription, produces the protein product “FMRP” (FMR1 encodes FMRP). This is a protein that binds RNAs (FMRP is an RNA binding protein) and regulates their expression after interacting with two autosomal homologues, the FXR1 and FXR2. FMRP is part of a ribonucleoprotein particle associated to actively translating polyribosomes, and which can shuttle between the nucleus and the cytoplasm. The properties of FMRP suggest that it is involved in nuclear export, cytoplasmic transport, and/or translational control of target mRNAs. FMRP seems to play a role in regulation of protein synthesis at postsynaptic sites of dendrites, and in maturation of dendritic spines. In other words, local protein synthesis (of FMRP in the FMR1 gene) within a neuron is determinant for proper synthesis of other proteins, synaptogenesis (synapse maturation process) and the development of cognitive abilities.

Recall that the normal number of CGG triplet repeats within the FMR1 varies from 6 to 54. Therefore, abnormal repeats of 54 to 199 produce an unstable allele or “premutation allele”, and abnormal repeat units of 200 or more, produce a “mutation” allele. When a stretch of CGG repeats takes place within the fragile X gene (FMR1), no protein (FMRP) is produced, resulting in the fragile X chromosome. More than 200 copies of the repeats leads to excessive methylation of cytosines in the promoter of FMR1, a form of DNA modification that prevents normal promoter function and prevents expression of the gene. This dynamic mutation in this particular gene of the long arm of the chromosome X causes “transcriptional inactivation” and prevents adequate replication and chromatin condensation during mitosis. The mutation spares the coding region of the FMR1 gene, which potentially would allow synthesis of a normal indispensable protein. As no FMRP is encoded by the FXR1, neurophysiological processes are altered. This loss of function of FMR1 is what causes the fragile X syndrome5^{,[15],2,[16],[17],4,[18],3,14,10,[19],[20]} .

Diagnosis: Prenatal ultrasound by itself is not a diagnostic tool of choice for the detection of fragile X syndrome since there are no typical or pathognomonic findings. The ocacional findings can also be seen in other syndromes as well as in normal individuals and can be misleading.

Although cytogenetic analysis is a useful modality for detecting affected males, DNA-based molecular analysis allows both identification of full mutation and premutation carriers and is the preferred laboratory adjunct to diagnosis1.

Diagnostic methods for prenatal and postnatal diagnosis include PCR amplification and Southern blotting, which are performed on DNA isolated from peripheral leukocytes. Recently, varying immunocytochemical tests have been described to identify fragile X patients, based on detection of FMR1 protein in cells by a monoclonal antibody5^,[21],[22].

Clinical findings: Clinical features include physical as well as cognitive and neurophysiological deficits.

Although fragile X syndrome follows an X-linked pattern of inheritance (which explains the predominance of affected males), females can also be affected. Most likely based on the phenomenon of X inactivation, the risk that the daughter of a premutation carrier female will be clinically affected is smaller (15-30%)1. Many inconsistencies exist between the genetic inheritance pattern of fragile X and traditional Mendelian inheritance tenets of most X-linked deseases9.

In males, an allele mutation with repeat size of 200 or greater, the termed “full mutation”, is always associated with the affected phenotype, whereas in females only half are affected. Individuals with alleles having repeat size in the range 55-199 are unaffected, but in females, the sequence is heritably unstable so that it is at high risk of expansion to a full mutation in her offspring. This allele is known as a “premutation” to contrast it with the full mutation found in the affected individuals11.

Common abnormalities:

• Mental retardation – Most affected males have moderate to severe learning disabilities with IQs under 50 whereas most females have borderline IQs of 70-8511. There is a wide range from mild to profound. Some cases are in the borderline normal range. Cluttered speech will be present in mildly retarded patients, short bursts of repetitive speech in more severely retarded males, and complete lack of speech in severely and profoundly retarded males. Approximately 50% of females are mentally retarded or have educational difficulties1^,14.
• Macroorchidism or enlarges testicles - Testicular size may be increased before puberty, but this increase becomes more obvious postpubertally1^,14.
• Macrocephalia with long face and facial atypia -  in early childhood1^,11,14.

?      Prognathism -  usually not noted until after puberty1.

?      Thickening of the nasal bridge extending down to the nasal tip1.

?      Large protruding ears with soft cartilage1.

?      Pale blue irides1.

?      Epicanthal folds1.

?      Dental crowding1.

• Autism - Can be present in 60%1, with hyperkinetic behavior, emotional instability, hand biting and other autistic features. Attention problems associated with hyperactivity are common. Other authors think that fragile X syndrome is not a common cause of autism although the number of individuals with the syndrome who meet criteria for autism is higher than can be accounted for by chance[23].
• Increased growth rate – growth rate is slightly increased in the early years1.

Occasional abnormalities:

• Premature ovarian failure – can be seen in approximately 21% of premutation carriers compared to only 1% of the normal population (relative risk of 21). In idiopathic and rare forms of familial premature ovarian failure, approximately 2% and 14%, respectively, carry the premutation1^,17.
• Nystagmus1
• Strabismus1
• Epilepsy1
• Myopia1
• Hypotonia1
• Hyperextensible fingers1
• Torticollis1
• Pectus excavatum1
• Kyphoscoliosis1
• Flat feet1
• Submucous cleft palate1
• Mitral valve prolapse1
• Aortic dilatation1

Differential diagnosis: Fragile X syndrome must be considered in the differential diagnosis of any child with developmental delay, mental retardation or learning disability12.

Prognosis: Fragile X syndrome can be a devastating condition, as many boys are severely retarded and require multiple services[24]. Life span is usually normal1.

Prevention: No information is available from randomized trials to indicate whether routine pre-conceptual or antenatal screening for fragile X carrier status confers any benefit over testing women thought to be at increased risk7. Prevention is achieved by reducing birth prevalence through methods such as pre-conceptional and antenatal screening11

Treatment: The treatment of fragile X syndrome is limited[25]and involves behavioral management techniques, appropriate school placement, community support for the family, and careful medical follow-up including psychopharmacology24.

Intensive research and investigation is actually being done and the possible treatment in the future will be pharmacological regimens to reactivate the gene function so that the FMR1 will encode FMRP2.

Refrences

[1] Jones K.  Smith’s Recognizable Patterns of Human Malformation. Saunders. 5^th Edition. 1997

[2] Chiurazzi P, Neri G. Pharmacological reactivation of inactive genes: the fragile X experience. Brain Res Bull  2001 Oct-Nov 1;56(3-4):383-7

[3] Mazzocco MM. Advances in research on the fragile X syndrome. Ment Retard Dev Disabil Res Rev  2000;6(2):96-106

[4] Inoue SB, Siomi MC, Siomi H. Molecular mechanisms of fragile X syndrome. J Med Invest  2000 Aug;47(3-4):101-7

[5] Oostra BA, Willemsen R. Diagnostic tests for fragile X syndrome. Expert Rev Mol Diagn  2001 Jul;1(2):226-32

[6] Welch JL, Williams JK.  Fragile X syndrome. Neonatal Netw  1999 Sep;18(6):15-22

[7]Kornman L, Chambers H, Nisbet D, Liebelt J. Pre-conception and antenatal screening for the fragile site on the X-chromosome. Cochrane Database Syst Rev  2002;(1):CD001806

[8] Oostra BA, Chiurazzi P. The fragile X gene and its function. Clin Genet  001 Dec;60(6):399-408

[9] Donnenfeld AE. Fragile X syndrome. Indian J Pediatr  1998 Jul-Aug;65(4):513-8

[10] Nussbaum RL, McInnes R, Willard HF. Genetics In Medicine. Sixth Ed. W.B. Saunders Company, Philadelphia Pennsylvania. Pg 242. 2001

[11] Murray J, Cuckle H, Taylor G, Hewison J. Screening for fragile X syndrome. Health Technol Assess  1997;1(4):i-iv, 1-71

[12] Pimentel MM. Fragile X syndrome . Int J Mol Med  1999 Jun;3(6):639-45

[13] Kooy RF, Willemsen R, Oostra BA.  Fragile X syndrome at the turn of the century. Mol Med Today  2000 May;6(5):193-8

[14] de Vries BB, Halley DJ, Oostra BA, Niermeijer MF. The fragile X syndrome. J Med Genet  1998 Jul;35(7):579-89

[15] Kaytor MD, Orr HT.  RNA targets of the fragile X protein. Cell  2001 Nov 30;107(5):555-7

[16] Irwin SA, Galvez R, Greenough WT.  Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb Cortex  2000 Oct;10(10):1038-44

[17] Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet  2000 Fall;97(3):189-94

[18] Irwin SA, Galvez R, Greenough WT. Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb Cortex  2000 Oct;10(10):1038-44

[19] Gantois I, Kooy RF. Targeting fragile X. Genome Biol  2002;3(5):reviews1014

[20] Jin P, Warren ST. Understanding the molecular basis of fragile X syndrome. Hum Mol Genet  2000 Apr 12;9(6):901-8

[21] Willemsen R, Oostra BA. FMRP detection assay for the diagnosis of the fragile X syndrome. Am J Med Genet  2000 Fall;97(3):183-8

[22] Hammond LS, Macias MM, Tarleton JC, Shashidhar Pai G.  Fragile X syndrome and deletions in FMR1: new case and review of the literature.  Am J Med Genet  1997 Nov 12;72(4):430-4

[23] Feinstein C, Reiss AL. Autism: the point of view from fragile X studies. J Autism Dev Disord  1998 Oct;28(5):393-405

[24] Phillips JP, Wilson GA. Fragile X syndrome. Indian J Pediatr  1998 Mar-Apr;65(2):181-91

[25] Murray J, Cuckle H.  Cystic fibrosis and fragile X syndrome: the arguments for antenatal screening. Comb Chem High Throughput Screen  2001 May;4(3):265-72