Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Semiology of the premutation and gray zone in the fragile x syndrome childhood by Ferrando Lucas MªT( * ,1) Martorell Sampol L,( **), Póo Argüelles P(*) López Sala, A (*), Sans Fito A(*), Campistol Plana J(*) (*) Servei de Neurologia. (**) Servei de Genética. Hospital Sant Joan de Déu. Barcelona (1) Servicio de Pediatría. Consulta de Trastornos Cognitivos. Hospital Quirón Madrid Asociación Síndrome X frágil de Madrid Miembro de X fragile Europe ABSTRACT The Fragile X Syndrome f (FXS), the most frequent form of hereditary genetic disability is caused by the expansion of the trinucleotic CGG. Full mutation is defined by a number of repetitions superior to 200. In this situation the transcription is silenced and, consequently, the FMR protein is produced in a very small quantities or not produced at all. This protein is widely distributed in the human body and it is involved in two large groups of functions: 1)In the formation and proper operation of the connective tissue from wide semiology of general pathology that FXS children can present (infectious, cardiac, dermatological, osteoarthophaty, etc…) derives; and 2) In the nervous system, the protein is essential during odogenesis so that the pruning of dendritic excess and elimination of the synaptic excess may be produced. Therefore in FXS there is an overpopulation of synaptic buttons, with anomalous tracts of white substance, last cause of the sensory dysfunction and of the cognitive, neurological and behavioral disorders that people affected by full mutation present. This genotype is thoroughly documented with a phenotype both physical as cognitivebehavioral in boys but it is less known in girls, with scarce number of publications about them. The state of the permutation ha been an object of interest in the adult age above all since the late 90´s when cognitive deterioration in carriers of premutation males began observed in the context of semiology that in the beginning it was confused with illness of Parkinson atypical. Up to know, during this century, the syndrome FXTAS (Fragile X Tremor Ataxy Syndrome) has been described as a syndrome that is accompanied by cerebelosa alteration with intoxication of the cells of Purkinje due to an of mRNA that permutation possess. Trembling, ataxy and dementia constitute the clinic of this syndrome that it was believed to be present only in sexagenarian premutation carriers males, but that has begun to be detected also in permutation carriers women thus at the present moment the FMR1 gene is considered responsible for two well defined illnesses that run with cognitive affectation: the X Fragile Syndrome , in children and adults with complete mutation; and the Fragile X Tremor Ataxy Syndrome, in adults with permutation. Therefore the concept of cognitive normality has changed in permutations (55 to 200 CGG repetitions) not only against the evidence of FXTAS but also by the works that have determined that in some permutations can exist a decrease of the rate of protein according to a low rate of aforesaid protein. This change in concepts concerning the cognitive affectation of premutations in the adult, it is not corresponding with a similar interest in childhood. Premutations in this age go unnoticed and they are still considered as having low or nil cognitive risk; when the genotype is found in the gray zone of the permutation (40-55) repetitions, the emptiness in the literature is the norm, and they are not considered children of high risk of cognitive affectation at all. We have found this phenotype manifested with the same intensity in children whose rank of CGG repetitions places them in the premutation and gray zone. This is the casuistry we have constituted at this time by thirteen patients –9 boys and 4 girls born between 1989 and 2000- whose anamnesis and exploration can be summarized as follows. First alarm data: global retardation of development with a delay in the acquisition of the capacity to walk and of language in all cases with a particular incidence on language capacity, as well as behavioral and communication disorders in one case. Family antecedents of XFS not known of any of the kids. Rank of CGG repetitions between 46 and 53. Physical phenotype present in one of the cases. Cognitive-behavioral phenotype in all cases. Average to low intelligence in one case only, and severe retardation in another. The rest of the children shows slight retardation or limit intelligence. Epilepsy in two patients with crisis of rebellion against treatment, and absence of language in one girl. Epileptoid paroxysm without clinical crisis in one of the cases. In the family study of this children, the premutated allele was carried by the mother and the children have received it in a stable way. To recapitulate, if we should summarize the Fragile X Syndrome in a few lines we could say that it is a multisystemic, hereditary, genetic illness which is produced by the mutation of a gene (FMR1) the clinical characteristics of which are of a very wide range, so we might speak of a clinical spectrum of the people affected. This spectrum is defined by the diverse severity with which the cognitive-behavioral phenotype manifests itself. It is the aforementioned phenotype that sets the objectives of intervention, whose priority points are pedagogy, psychology and speech therapy. To this we must add cooperative participation from multiple disciplines according to the needs of each kid, among which the medical and pharmacological approaches are but one aspect. And if we should summarize in a few lines what the present situation is in terms of knowledge of the syndrome, the reality of the clinic shows that the relationship genotype-phenotype is far from being properly known. There is much more left to investigate, including the agreement upon what the ranks of the premutation and the gray zone are. Also, the children who carry the premutation and the gray zone, although most of them will be kids without any kind of affection, the possibility still remains that some of them will behave clinically as if complete mutations existed. Direcciones de contacto: María Teresa Ferrando Lucas [email protected], [email protected], [email protected]