Sindromul X fragil Sindromul MartinBell Sd X fragil

Sindromul X- fragil (Sindromul Martin-Bell)

Sd. X- fragil se manifesta cu precadere la barbati printr-un retard mental grav

Sindromul X- fragil Ø Se datorează unei mutaţii dinamice ( = din generatie numarul de repetitii trinucleotidice poate creste ) Ø In gametogeneza materna (cu precadere) are loc amplificarea secventei de 3 baze azotate [codon]. Ø Denumirea este data de faptul ca initial, prin analiza citogenetica cromozomul X parea sa prezinte o ruptura la nivelul telomerului bratului q, adica s-a presupus existenta la acest nivel a unui “situs fragil” (zona cz. cu rupturi frecvente) Ø Astazi, se stie ca, aspectul citogenetic este datorat multiplicarii excesive a codonului CGG la nivelul promotorului genei FMR 1(Fragile X Mental Retardation) Ø La baieţii cu o astfel de amplificare, unde codonul CGG este deci supranumerar, apare un retard psihomotor grav. Ø Sindromul X-fragil este cea mai cunoscuta cauza de autism

Situsul fragil, indicat prin sageti in imaginea alaturata (d), este de fapt, un codon amplificat anormal DISMORFISMUL CRANIO-FACIAL este evident: macrocefalie, fata alungita, frunte lunga si proeminenta, urechi mari si proeminente, maxilare proeminente

Diagnosticul clinic este certificat prin analize moleculare, ce evidentiaza prezenta repetitiilor trinucleotidice.

Tabloul clinic al sindromului asociaza retardul mental de la moderat la sever, macroorhidia (postpubertara, cu testicule avand volumul > 40 ml) si dismorfismul cranio-facial specific. http: //www. nfxf. org/html/facial. htm In majoritatea cazurilor sindromul este cauzat de expansiunea trinucleotidica instabila CGG de la nivelul genei FMR 1 si metilarea anormala, care produce supresia transcriptiei si consecutiv nivele scazute ale proteinei FMRP la nivel cerebral. Sindromul X- fragil determina aproape o jumatate din cazurile de retard mental si este ca frecventa a doua cauza de handicap psihic dupa sindromul Down. In OMIM pe langa sd. X-fragil, apare ca entitate de sine-statatoare si FXTAS (fragile X tremor/ataxia syndrome) produs de o premutatie urmata de cresterea sintezei de FMR 1.

Interpretare: I 1 prezinta premutatia (pe singurul sau cz. X), pe care fiica sa, II 2, o mosteneste de aceeasi marime; II 2 are 2 cz. X deci unul cu premutatia de la tata si unul cu gena FMR 1 normala, mostenit de la mama, care nu mai este reprezentata in arborele genealogic; III 1 are mutatia completa, adica sd. X-fragil, amprenta ADNului sau aproape ca nu s-a deplasat de la punctul de start. II 1 are un cz. X cu gena normala raspunsul de mai jos. Interpretati desenul alaturat, apoi rasturnati de agaroza. mai mare, cu atat mai greu se va deplasa in gelul de la minus la +; cu cat fragmentul de ADN este In analiza Southern blot alaturata ADNul migreaza

Numarul de repetitii ale Situs fragil codonului detectabil (CGG) (citogenetic) Barbati cu 50 -200 repetitii Nu (premutatie =“PM”) Barbati cu 200 -2000 repetitii Da (mutatie completa=“M”) Femei cu 50 -200 repetiţii Nu Inteligenta Descendenti Normala Fete purtatoare (PM) (barbat purtator) Baieti normali (fara PM) Retard moderat Fete purtatoare (M) pana la sever Baieti normali (fara PM) Normala Baieti bolnavi (M) (premutatie) Fete normale (fara PM) sau purtatoare (PM) Femei cu 200 -2000 repetiţii (mutatie completa) Da De la normal Baieti bolnavi (M) retard moderat Fete normale (fara PM) sau cu M

Femeile cu sindromul X-fragil • Femeile purtatoare de premutatie pot prezenta: – insuficienta ovariana, menopauza instalandu-se inainte de varsta de 40 de ani, – menopauza prematura, instalata inainte de varsta de 45 de ani sau – o disfunctie ovariana ( fertilitate redusa) in general • Scaderea fertilitatii este corelata cu cresterea de FSH si alte modificari hormonale. • Femeile purtatoare ale mutatiei complete nu au riscurile de mai sus. Marimea mutatiei nu se coreleaza cu gravitatea clinica datorita inactivarii cz. X (cromatina sexuala) • Sfatul genetic dupa o testare prenatala pozitiva nu poate prezice cu fidelitate afectarea intelectuala, comportamentala sau psihologica in cazul fetelor cu mutatia completa. Tulburarile se manifesta de la foarte usoare pana la retard sever si autism.

Se observa caracteristica acestui tip particular de transmitere si anume BARBATII PURTATORI (I 3, IV 1 si IV 2). Acestia au premutatia si deci boala nu se manifesta la intensitatea maxima, adica nu au un retard mental grav

La fel cum transmiterea acestui sindrom este particulara. Cu siguranta este o transmitere X-lincata, gena FMR 1 fiind pe cz. X. Unii autori considera transmiterea X-lincata dominanta (http: //ghr. nlm. nih. gov/condition/fragile -x-syndrome) iar altii X-lincata recesiva (http: //www. genetics. edu. au/pdf/factsheets/fs 42. pdf) Poate cel mai corect este sa se adopte parerea ca, bolile determinate de gene de pe cz. X sunt “doar” X-lincate, cum propunea deja in 2004 Dobyns de la Universitatea Illinois din Chicago (Am J Med Genet A. 2004 Aug 30; 129 A(2): 136 -43. Inheritance of most X-linked traits is not dominant or recessive, just X-linked. )

In acest arbore genealogic este specificat numarul de repetitii trinucleotidice ale fiecarei persoane. Pe langa prezenta femeilor si barbatilor purtatori de PM, un caz special il reprezinta IV 5, care mutatia completa, dar nu este bolnava!

Urmatoarele sindroame sunt cele mai frecvent intalnite boli cauzate de mutatii dinamice.

Pentru cine nu se asaza doar pe carti, cateva date suplimentare in continuare, dar in original

FMR 1 gene contains 17 exons spanning 38 kb. http: //bioquest. org/icbl_details. php? product_id=3783

FMRP - The highest levels were observed in neurons, while glial cells contained very low levels.

Text la imag anterioara • • Expansion of CGG repeats in the fragile X mental retardation 1 (FMR 1) gene that encodes FMRP underlies fragile X syndrome (FRAXA). Repeats that contain >200 copies (full mutation) lead to loss of FMRP expression. FMRP contains two domains that bind RNA: the KH 2 domain and the RGG box. The Ile 304 Asn mutation in the KH 2 domain, which prevents FMRP from binding targets that contain the kissing complex motif, gives rise to a severe mental retardation phenotype. a | Abnormal dendritic spine morphology in patients with FRAXA. An increased density of long, immature dendritic spines indicates that FMRP has a role in synaptic maturation and pruning, possibly through its regulation of gene products that are involved in synaptic development. FMRP might also have a regulatory role in activitydependent translation at the synapse. Stimulation of postsynaptic metabotropic glutamate receptors (m. Glu. Rs) results in increased protein synthesis and subsequent internalization of amino-3 -hydroxy-5 -methyl-4 -isoxazole propionic acid (AMPA) receptors, which is important in the expression of long-term depression. FMRP, which is also upregulated by m. Glu. Rs, serves to dampen this process. The absence of FMRP in FRAXA results in over-amplification of this response. b | FMRP modulates the translation of its targets, probably through its association with the RNA-induced silencing complex (RISC). FMRP is transported to dendritic spines, together with its associated RNAs and proteins. m. RNP, messenger ribonucleoprotein particle; NES, nuclear export signal; NMDA, N-methyl-D-aspartate; NLS, nuclear localization signal http: //www. nature. com/nrg/journal/v 6/n 10/full/nrg 1691. html

http: //www. nature. com/nrn/journal/v 6/n 5/fig_tab/nrn 1667_F 1. html

Text la imag. ant • Fragile X mental retardation protein (FMRP) enters the nucleus and could function through two possible mechanisms. In the first (1), FMRP could interact with other proteins, with itself (for example, the FMRPhomologous proteins FXR 1 P and FXR 2 P), and with RNA/m. RNA to form a ribonucleocomplex that is probably involved in m. RNA export from the nucleus to the cytoplasm. Once in the cytoplasm, a 'core' complex, containing FMRP and some of its nuclear partners, would interact with cytoplasm-specific proteins (such as cytoplasmic FMRP-interacting protein 1 (CYFIP 1), CYFIP 2 and Staufen) and move along dendrites to the synapses, transporting RNA/m. RNA and, later, regulating synaptic protein synthesis. In the second mechanism (2), FMRP could be involved in the nuclear RNA interference pathway that is associated with small, non-coding RNAs (short hairpin RNAs or sh. RNAs) and specific nuclear partners (that is, nucleolin and Y-box binding protein 1 (YB 1)). mi. RNA, micro. RNA; nc. RNA, non-coding RNA .

Text la imag. ant • At synapses, protein synthesis is initiated by different cellular stimuli, and this leads to an independent response of a single synapse that can influence synaptic plasticity. a | In a wildtype spine, stimulation of metabotropic glutamate receptors enhances the synthesis of fragile X mental retardation protein (FMRP), which could act to negatively regulate the translation of proteins that are involved in ionotropic receptor internalization during longterm depression and of proteins that regulate the cytoskeleton (such as microtubuleassociated protein 1 B (MAP 1 B), activity-regulated cytoskeletal-associated protein (ARC), arginine-binding protein 2 (ARGBP 2), postsynaptic density protein 95 (PSD-95) and Rac 1). This receptor-coupled signalling pathway might also be responsible for FMRP phosphorylation and the consequent release of m. RNAs from translational inhibition and/or the activation of translation of other specific dendritic m. RNAs. The correct balance between synthesis and degradation of these proteins would promote and maintain the mature shape of the synapse. b | In a spine of a patient with fragile X syndrome, or in the mouse model of the syndrome, the absence of FMRP would lead to an increase and/or decrease in the translation of protein regulators of the cytoskeleton, both of which might have an effect on the lengthening of dendritic spines. c | The absence of FMRP could also lead to an increase in the translation of proteins that are involved in ionotropic (AMPA (-amino-3 -hydroxy-5 -methyl -4 -isoxazole propionic acid) and NMDA (N-methyl-D-aspartate)) receptor internalization (INT. ) during hippocampal long-term depression, which could lead to fewer receptors being present on the postsynaptic membrane and to thinner spines. m. Glu. R, metabotropic glutamate receptor

The figure shows a hypothetical mechanism through which the absence of fragile X mental retardation protein (FMRP) could lead to failure of synapse pruning and, as a consequence, dendrite pruning, in a typical spiny stellate neuron in a whisker barrel (centre). The model assumes that FMRP regulates the synthesis of structural proteins (for example, postsynaptic density protein 95 (PSD-95)) or signalling proteins that form part of a complex that is important for stabilizing and maturing developing synapses (see Fig. 4 for one possible conceptualization of this process). When FMRP is present, this stabilization complex (carried by the transport granule) is selectively targeted to active synapses (upper left), which results in selective maturation and stabilization of spines (upper right) and pruning of non-stabilized synapses. In the absence of FMRP (lower left), the stabilization complex is equally targeted to active and inactive synapses, which results in a weaker form of maturation and stabilization, and gives rise to greater numbers of synapses and an immature morphology (lower right). article: From m. RNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome Claudia Bagni & William T. Greenough in Nature Reviews Neuroscience 6, 376 -387 (May 2005

Fragile X mental retardation protein (FMRP) binds different neuronal m. RNAs. Four mechanisms of target recognition have been characterized. FMRP could recognize a G-quartet structure (a) or a poly(U) stretch (b) in the m. RNA. Alternatively, FMRP could bind indirectly to the m. RNA through either the small non-coding RNA brain cytoplasmic RNA 1 (BC 1) (c) or micro. RNAs (mi. RNAs) (d). e. IF 2 C 2, eukaryotic translation initiation factor 2 C, 2

In loc de tratament al sd. X

• Factorul major care determina prezenta sau absenta sindromului X-fragil este numarul de repetitii CGG in gena FMR 1 de pe Xq 27. 3. • In mod tipic, numarul de repetitii > 200, declanseaza metilarea insulelor Cp. G din regiunea promotor a genei. • Ca urmare, productia de FMRP (fragile X mental retardation protein) este oprita. Absenta proteinei are ca rezultat aparitia sindromului X-fra • Totusi, exista si cazuri, ce nu se incadreaza nici in premutatii si nici in mutatii complete. Un exemplu este mozaicul, celulele avand grade diferite de metilare urmare a unui numar variat de repetii CGG. Impactul bolii depinde in astfel de cazuri de procentul de celule care sunt afectate si de tipul de tesut implicat • Exceptional , exista persoane cu > 200 repetitii CGG, dar la care gena FMR 1 nu este metilata. Gama de simptome este foarte larga in astfel de cazuri, iar caracteristicile sindromului X-fra sunt mult mai putin severe.

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