Fragile X syndrome
Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities, ataxia (after 50years of age) and cognitive impairment.
1. Males are more severely affected by this disorder than females.
2. Fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females.
3. Fragile X syndrome is inherited in an X-linked dominant pattern.
4. Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency (4-5%).
5. Family history with mental retardation especially in males.
6. Females with Premature ovarian insufficiency POI (very scant or highly delayed period interval or no period prior to 40 years of age), with or without diminished ovarian reserve, (high FSH> 10-15 miu/ml, Low Anti Mullerian Hormone AMH < 1.5 ng/ml, Low Antral Follicular Count AFC follicles between 2-9mm,in both ovaries combined, of < 7 in number) should be offered testing, using the PCR DNA blood test If this is positive, the patient can be offered preimplantation genetic testing, prenatal diagnosis or Oocyte donation), thus preventing the conception of affected children.
Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental retardation 1 FMR1 gene locus Xq27.3,. This causes methylation of the gene and the FMR1 protein production falls resulting in decrease in synaptic plasticity and maturation.
Fragile X syndrome is inherited in an X-linked dominant pattern.
CGG repeat < 45 : Normal
CGG 45-55: Intermediate
CGG55-200: Premutation CGG>200: Full mutation
Full Mutation :
1. Men : More affected than females. Men have intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. language delay, sensory hyper arousal and anxiety.
2. Girls are less affected than boys, only 25% have intellectual disability. Women with FM and FXS are going to present a wider range of phenotypic characteristics than men, depending on the activation ratio of the affected X chromosome AR in peripheral blood (AR = percentage or ratio of cells with the normal allele present on active X chromosome, so that higher AR correspond to higher FMRP levels produced by the normal FMR1 allele). The severity of the phenotype in women can vary from typical physical characteristics and mental impairment to the absence of physical phenotype together with a mild learning disability. Seventy per cent of the women with the FM present some degree of cognitive impairment.
Permutation
Premutation carriers usually have a normal IQ with mild or no physical features;
1. 40% of male carriers develop FXTAS. Tremor/Ataxia Syndrome is a late onset progressive neurodegenerative disorder, characterized by neurological deficits that include progressive intention tremor, cerebellar ataxia, parkinsonism, neuropathy and autonomic dysfunction.
20% of women develop FXPOI or FXTAS, although fragile X-associated primary ovarian insufficiency, which indicate the cessation of the menses before 40 years old, affects women by producing a series of complications in their fertility and reproduction, because it causes menstrual cycle irregularities, infertility and ovary hormonal deficiency.
Diagnosis
The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. The FMR1 DNA test can be administered with two different lab procedures:
1. The Southern blot analysis test determines if the gene has a full mutation, its approximate size, whether the gene has been “methylated,” and if there is mosaicism of the gene (a mixture of different cell types).
2. The polymerase chain reaction (PCR) analysis can determine the actual number of CGG repeats (a pattern of DNA) that are present in the Fragile X gene. For various technical reasons, PCR has not been the test of choice to diagnose a full mutation, but is quite accurate in determining premutation and normal gene repeat numbers. However, PCR is less expensive and quicker than Southern blot, and recent advances in technology have increased its ability to identify Fragile X full mutations. PCR may thus be the only test used in the near future.
Screening
There are three general circumstances in which Fragile X testing should be considered:
1. Clinical symptoms that suggest Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS), or Fragile X-associated primary ovarian insufficiency (FXPOI).
2. A family history of FXS, FXTAS, intellectual or learning disabilities or autism of unknown cause, or infertility.
3. Family or personal history of a Fragile X genetics and inheritance (i.e., carrier).
Specific indications for testing include:
1. Any male or female with intellectual disabilities, developmental delay, speech and language delay, autism, or learning disabilities of unknown cause.
2. Any female with infertility, elevated FSH (follicle-stimulating hormone) levels, premature ovarian failure, primary ovarian insufficiency, or irregular menses.
3. Any adult over 50 with features of FXTAS, including intention tremors, ataxia, memory loss, cognitive decline, or personality change, especially in combination with a positive family history of Fragile X.
4. Any preconception or pregnant woman who expresses interest in or requests Fragile X carrier testing.
Treatment
During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children World Fragile X day 22 nd July.
