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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]