Genetic mutations: FRAGILE X SYNDROME

Genetic mutations: FRAGILE X SYNDROME

Concept

The fragile X syndrome (FXS) is the most common inherited genetic syndrome causing mental retardation and one of the best characterized forms of autism spectrum. It mainly affects men who have a characteristic phenotype and transmitted mainly by women. Its name is due to a narrowing of the distal end of chromosome X (Xq27.3) that appeared in the karyotype of affected individuals, and "fragile site" was called. In 1991, the gene responsible for this syndrome was identified, a fact which replaced the cytogenetic analysis as a diagnostic method.

Prevalence

The prevalence of FXS has been revised downward. Initial estimates of speaking of 1: 1250 affected males in the general population, has been passed to a prevalence of between 1: 4,000 and 1: 6,000. The figure for females is approximately half (1: 8000-1: 12,000). The prevalence of carriers in the population is about 1: 250 women, the relationship to the male carriers is 3: 1.

 

Genetic causes fragile x syndrome (fxs)

The genetic cause of FXS is a mutation or change in the normal sequence of DNA in the FMR1 gene, resulting in inactivation of the same and thus, lack of protein synthesis (FMRP) synthesizing.

The most common mutation involves elongation (expansion) of a small part of the sequence formed by repeating the nucleobases cytosine-guanine-guanine, which is called abbreviated CGG. This CGG triplet repeat is at the beginning of the gene, in an area that has no information for the protein it encodes, but rather had to do with his activity, in particular, that more or less copies of the FMRP protein is synthesized . This repetitive sequence typically contains between 6 and 55 CGG triplet repeats, the most frequent of 30 repetitions. But in Fragile X expansion in the number of CGG triplet repeats of this it occurs to be more than 200.

 Clinical feature:

The main clinical feature of FXS is mental retardation in affected males is moderate while in women it is slight. Other features that are usually present in most affected males are elongated face with prominent chin and broad forehead, large ears and detached, hypermobility (with increased mobility especially in small joints) and large testicles (macroorchidism) after puberty.

Other common physical findings are: large head (macrocephaly), abnormalities in the mouth, high palate and crowded teeth in the jaws, flat feet, hands with fingers flared at its distal end, heart murmur, strabismus (eye muscle hypotonic) , recurrent otitis, overweight or obesity, epilepsy and generalized hypotonic. In individuals with FXS clinical findings vary with age, in the case of joint laxity decreases with age, or the size of the testicles that usually normal until puberty.
in the first years of life, it delays in acquiring psychomotor functions, especially the language, which is subsequently manifests repetitive.
In the preschool may not be obvious physical traits that occur in later life. With age also become more evident ophthalmic, orthopedic, heart and skin problems. For women affected (full mutation) clinical findings are especially facial, but appear less frequently and are milder than in the case of men.
Recently it described two late onset subphenotypes related SXF. One appears especially in men with premutation (PM) between 50 and 60 years, is a multisystem neurological disorder with ataxia and intention tremor, why it was called Tremor-Ataxia Syndrome associated SXF (FXTAS, Fragile X-associated Tremor / Ataxia Syndrome).

Most frequent clinical manifestations:

Physical

• Long face with high forehead and prominent chin

• Large and protruding headphones Fields

• Joint hypermobility

• Large Testicles (macroorchidism) after puberty

• Squint

• Flat Feet

• Heart murmur (mitral valve prolapse)

• Thin skin

Intelligence and behavior

  • Intellectual Disability (mild to moderate)

• delayed onset of language

• Attention Deficit Hyperactivity Disorder

• Avoidance look

• Pseudoautista behavior.

Treatment

 The cause of the clinical manifestations of FXS is the lack of expression of the FMRP protein. At present, studies are underway for a possible molecular therapy to compensate somehow the lack of this protein. Treatment should be based on a multidisciplinary action, including diagnosis and early intervention newborn, drug treatment of the clinical manifestations, the psycho-pedagogical support, speech therapy and occupational therapy.
Gene therapy, acting on the genetic defect or deficiency of the protein FMRP, it would be a chance to improve or reverse some clinical manifestations of the syndrome. This is the future and that the different research teams are based.
There is no cure, but there are drugs that effectively, treat many of the symptoms described.

Bibliography:

William Glover, Feliciano Ramos .etal. (2006). FRAGILE X SYNDROME. Madrid, Spain: GIRMOGEN.
MP Ribate Molina, J Foot Juste, FJ Ramos Fuentes. (2010). Fragile X Syndrome. 19.11.15, Spanish Association of Pediatrics Website: http://www.aeped.es/sites/default/files/documentos/sindrome_de_x_fragil.pdf