Gravidanza

Anomalie genetiche dei genitori e gravidanza

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Le anomalie cromosomiche sono alterazioni del numero o della struttura dei  cromosomi che si verificano all’incirca nel 7,5% dei concepimenti. Nella maggior parte dei casi  esse sono incompatibili con la vita e portano a morte fetale, aborto spontaneo precoce, aborti ripetuti spontanei (ARS). Ne consegue che solo lo 0,6% dei nati vivi è affetto da malattie cromosomiche e raggiunge l’età fertile.
I cromosomi sono sono strutture presenti in tutte le cellule costituite da Acido Desossiribo- Nucleico (DNA) e proteine. Il DNA contenuto nei cromosomi è costituito da singoli geni responsabili del  mantenimento e trasmissione dei caratteri ereditari dell’individuo. Ciascuna cellula ha un corredo cromosomico 46,XX per la femmina e 46,XY per il maschio.  Sono 22 coppie di eterocromosomi ed una coppia di cromosomi sessuali (XX per le femmine, XY per i maschi).
Le anomalie numeriche dei cromosomi vengono distinte in monosomie, quando manca un cromosoma e trisomie quando sono presenti tre copie di uno stesso cromosoma (anche se esistono, in rari casi, donne che presentano quattro o cinque cromosomi X).
Le anomalie strutturali possono consistere nella perdita più o meno estesa di una frammento di cromosoma (delezioni e microdelezioni), nell’esistenza di due copie di uno stesso frammento nello stesso cromosoma (duplicazione e microduplicazione), nel riposizionamento di un frammento in posizione differente da quella originaria dopo una rotazione di 180° (inversione) o nel trasferimento di frammenti tra due o più cromosomi diversi (traslocazione).
Le persone affette da patologie genetiche possono, anche se spesso con difficoltà, essere fertili. In caso di gravidanza trasmetteranno all’embrione i geni e la patologia ad essi associata secondo le leggi mendeliane,  Le gravidanze delle coppie in cui uno o entrambi i coniugi sono affetti da alterazioni genetiche, sono gravate da un alto tasso di morte fetale e aborti ripetuti spontanei (3-4% vs. 0,3% della popolazione generale) o morte neonatale (1,2).
Alcune anomalie cromosomiche nei genitori e morte fetale:
La  m. di Tay-Sachs provoca una precoce morte fetale per l’accumulo del ganglioside GM2 nel cervello, e conseguente decerebrazione, a causa del deficit dell’enzima esosaminidasi A. Il gene che causa la malattia si trova sul  cromosoma 15 (15q23).
La sclerosi tuberosa o m. di Bourneville-Pringle o m. di Hippel-Lindau  è una malattia genetica a carattere autosomico dominante caratterizzata dalla presenza di amartromi ed altre neoformazioni benigne in diversi organi come il cervello, cuore, reni, polmoni, cute che frequentemente conduce a morte fetale o nascita di neonato con gravi disturbi renali, oculari e comportamentali.  Due sono i geni responsabili della malattia: il  TSC1 – la cui probabile localizzazione è il braccio lungo del cromosoma 9 – e il  TSC2, localizzato sul braccio corto del cromosoma 16.
L’α-Talassemia, provocata da alterazioni del cromosoma 16,  è caratterizzata da emoglobina senza catene α. L’Hb  si presenta quindi come un tetramero β4 o emoglobina H dell’adulto; nel feto invece l’emoglobina risulta formata da 4 subunità γ (emoglobina di Bart). La morte del feto avviene in epoca gestazionale tardiva per idrope fetale (11).
Eteromorfismo cromosomico: consiste in  una variazione morfologica e strutturale dei cromosomi in regioni di DNA ripetuto. Sono più frequentemente interessati i cromosomi 1, 9, 16.  Non costituisce una patologia con segni clinicamente evidenti sul fenotipo, ma la sua presenza è stata messa in relazione con una condizione di subfertilità e aborti ripetuti spontanei (9,10).
L’inversione del cromosoma 9 (p11q12) è risultata molto frequente  in coppie con figli Down rispetto alla popolazione di controllo (8). Ciò potrebbe suggerire una possibile alterazione dei meccanismi che regolano la disgiunzione meiotica in presenza di eterocromatismo cromosomico (9-10). L’esempio più conosciuto é dato dalla S. di Martin-Bell.
“Siti fragili”: zone cromosomiche in cui facilmente si verificano rotture cromatidiche  e ciò spiegherebbe possibili delezioni presenti nei gameti. Anche per i siti fragili é stato evidenziato uno stretto rapporto con gli ARS  (1-4).
HLA System (Human leukocyte antigen): il sistema più importante di istocompatibilità presente nel corpo umano. Si ritrova sulla superficie cellulare e costituisce gli antigeni che generano la risposta immunitaria quando vengono a contatto con cellule di individui estranei. Gli antigeni HLA finora identificati sono circa 100 e raggruppati in serie: DLA-DR, HLA-DQ, HLA-DP etc..  I geni preposti alla regolazione del sistema HLA sono localizzati sul braccio corto del cromosoma 6. Questi geni sono stati chiamati in causa nell’etiopatogenesi dell’ARS sia per una mancata attivazione dei sistemi bloccanti la risposta immunitaria materna (2,3).
ADA: L’adenosindeaminasi (ADA) ha un particolare rilievo in campo immunologico. E’ ben noto, infatti, come la drastica riduzione di attività enzimatica ADA, possa causare immunodeficienza combinata facendo mancare un’adeguata protezione contro gli effetti letali dell’incompatibilità ABO materno-fetali con comparsa di idrope fetale, anasarca, morte fetale (4,5).
ABO: Numerosi lavori presenti in letteratura hanno descritto l’associazione tra ARS e incompatibilità di tipo ABO. Vi è un aumento di coppie incompatibili per l’antigene eritrocitario A. Invece l’incompatibilità per l’antigene eritrocitario B sembrerebbe essere «protettiva» poichè risulta inferiore all’atteso nel gruppo di coppie con ARS (1) .
 
References:
[1] Parazzini F et al. Università di Milano: “L’epidemiologia dell’aborto spontaneo”. SIGO, 2002.
[2] Abel EL, Hannigan JH. Maternal risk factors in fetal alcohol syndrome: provocative and permissive influences. Neurotoxicol Teratol 1995, 17: 445-462.
[3] Parazzini F et al. Università di Milano: “L’epidemiologia dell’aborto spontaneo”. SIGO, 2002.
4. Linee guida per la diagnosi citogenetica. Consensus, 2007.
5. Linee guida dell’American College of Medical Genetics. 
6. Sasiadek M, Haus O, Lukasik-Majchrowska M, Slezak Paprocka-Borowicz M, Busza H, Plewa R, et al. Cytogenetic analysis in  couples with spontaneous abortions. Ginekol Pol 1997;68:248-52. 
7. Mozdarani H, Meybodi AM, Karimi H. Impact of pericentric inversion of Chromosome 9 [inv (9) (p11q12)] on infertility. Indian
Journal of Human Genetics. 2008. 13:26-29.
8. Rocco L., Bencivenga S., Valentino V.I., Mottola F., Galileo C., Fasano R.: “Gli eteromorfismi cromosomici: l’inversione pericentrica del cromosoma 9”.  Seconda Università degli Studi di Napoli. Giornate Scientifiche di Ateneo 2011, 28 giugno 2011
9. Scriver C. et al.:  “The metabolic and molecular bases of inherited diseases”. McGraw Hill, New York, 1995.
10. Bunn H. e Forget B.: “Hemoglobin: molecular, genetic and clinical aspects”. Saunders, Filadelfia, 1986.
11. Higgs D.:  “Alfa thalassemia”. Bailliere’s Clin.Hematol. 1993; 6: 117-150.

 

CROMOSOMA 9

 


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