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Ldb valecoricerca_zollino_consulenzagenetica

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Ldb valecoricerca_zollino_consulenzagenetica

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Ldb valecoricerca_zollino_consulenzagenetica

  1. 1. Strutturazione della consulenza genetica nella SLA familiare e sporadica Marcella Zollino Istituto di Genetica Medica Università Cattolica Sacro Cuore Policlinico A. Gemelli, Roma Lecce, 20 gennaio 2015
  2. 2. Sclerosi Laterale Amiotrofica (SLA) Forme familiari Forme sporadiche
  3. 3. SLA FAmiliare (FALS)  AUTOSOMICO-DOMINANTE  Autosomico-recessivo  X-linked
  4. 4. EREDITARIETA’ AUTOSOMICO-DOMINANTE
  5. 5. Ereditarietà autosomico-dominante (AD) 1) Il soggetto affetto è eterozigote per la mutazione 2) Affetti: maschi e femmine (1:1)
  6. 6. Ereditarietà autosomico-dominante (AD) 3) Genitore affetto: 50% dei figli affetti trasmissione verticale genitore-figlio 4) Un genitore sano non trasmette la malattia
  7. 7. Ereditarietà autosomico-dominante (AD) 4) Se genitori sani: prima mutazione caso sporadico nella famiglia
  8. 8. Malattie autosomiche dominanti. Rischio riproduttivo relativo
  9. 9. Albero genealogico con esempio di trasmissione verticale di una mutazione autosomica dominante
  10. 10. Irregolarità della trasmissione autosomica dominante “Salto di generazione” per difetto di penetranza
  11. 11. EREDITARIETA’ AUTOSOMICO-RECESSIVA
  12. 12. Ereditarietà autosomico-recessiva (AR) 1) Il soggetto affetto è omozigote per la mutazione - eterozigote composto (alleli mutati diversi) - omozigote (stesso allele mutato) 2) Genitori sani, ma portatori eterozigoti di mutazione
  13. 13. Ereditarietà autosomico-recessiva (AR) 3) Affetti: sia maschi che femmine (geni autosomici)
  14. 14. Ereditarietà autosomico-recessiva (AR) 4) Rischio riproduttivo per genitori eterozigoti: 25 % figli affetti 25 % figli omozigoti sani 50 % figli eterozigoti per la mutazione Rischio di ricorrenza in ogni futura gravidanza: 25%
  15. 15. Ereditarietà autosomico-recessiva (AR) 5) Consanguineità nei genitori mutazioni rare stesso allele in omozigosi N.B. Quanto più frequente è lo stato di portatore eterozigote, meno influente è la consanguineità nei genitori
  16. 16. EREDITARIETA’ X-LINKED
  17. 17. La maggior parte delle mutazioni presenti sul cromosoma X sono recessive e quindi si manifestano solo nei maschi (per la loro condizione di emizigoti) -La presenza della malattia dipende dal sesso (sono malati solo i maschi) -La malattia non si trasmette mai da maschio malato a figlio ma da maschio malato a circa la metà dei nipoti maschi, attraverso femmine sane (che sono portatici).
  18. 18. Malattie a trasmissione X-linked. Rischi riproduttivi relativi a: A) femmina eterozigote e maschio emizigote normale
  19. 19. 2) Assenza di trasmissione da maschio malato a figlio maschio malato 3) Maschio malato: 100% di figlie femmine portatrici
  20. 20. Sclerosi Laterale Amiotrofica (SLA)  Definizione SLA familiare (FALS) e SLA sporadica (SALS)
  21. 21. Sclerosi Laterale Amiotrofica (SLA)  Definizione SLA familiare (FALS) e SLA sporadica (SALS)  Le FALS sono tutte mendeliane?
  22. 22. Sclerosi Laterale Amiotrofica (SLA)  Definizione SLA familiare (FALS) e SLA sporadica (SALS)  Le FALS sono tutte mendeliane?  Ipotesi multigenica delle SALS e FALS: fatti e prospettive
  23. 23. Sclerosi Laterale Amiotrofica (SLA)  Definizione SLA familiare (FALS) e SLA sporadica (SALS)  Le FALS sono tutte mendeliane?  Consulenza genetica nelle FALS e nelle SALS con mutazione  Ipotesi multigenica delle SALS e FALS fatti e prospettive
  24. 24. Sclerosi Laterale Amiotrofica (SLA)  Definizione SLA familiare (FALS) e SLA sporadica (SALS)  Tempo per esame genetico sistematico nelle SALS?  Le FALS sono tutte mendeliane?  Consulenza genetica nelle FALS e nelle SALS con mutazione  Ipotesi multigenica delle SALS e FALS fatti e prospettive
  25. 25. ALS • Definizione FALS e di SALS
  26. 26. 8 prospective studies: 5.1% Rome ALS Clinic center: -980 patients -5.8% (57 pat.) FALS 5.7%
  27. 27. FALS. Famiglia con mutazione C9ORF72
  28. 28. In tutti i pazienti con sospetta SLA, atrofia muscolare progressiva, sclerosis laterale primaria o demenza fronto-temporale, bisogna raccogliere una dettagliata storia familiare genitori fratelli nonni, cugini zii
  29. 29. PROBABLE FALS POSSIBLE FALS A B
  30. 30. 53 famiglie con SLA 25 % delle SLA ha una SLA familiare definita
  31. 31. SLA Familiare SLA Familiare probabile SLA sporadica definita SLA Familiare possibile
  32. 32. unknown C9ORF72 SOD1 TARDBPFUS 171 FALS (ITALSGEN) Mutazioni nel 61% C9ORF72 SOD1 TARDBP FUS 112 FALS (King’s College) OPTN VCP Mutazioni nel 55% unknown
  33. 33. 77 93
  34. 34. SLA Familiare definita SLA Familiare A B SLA sporadica SLA Familiare possibile 61% 61% 27% 11% 81% 66% 55% 40%
  35. 35. FALS SALS SLA sporadiche e familiari sono clinicamente indistinguibili Inclusioni TDP-43-positive sono presenti in entrambi Tutti i geni trovati nelle SLA familiari son stati identificati anche nelle forme sporadiche
  36. 36. 61/554: 11%
  37. 37. 2,5% 1,7% 0,6% 1,2% 0,6% 2,7% 2,1% 11%89,0% not mutated SOD1 TARDBP FUS ANG OPTN ATXN-2 C9ORF72 SLA sporadica 61/554: 11% 3.2% 2.2% 2%
  38. 38. SLA Familiare definita SLA Familiare probabile A B SLA sporadica SLA Familiare possibile 61% 61% 27% 11% 81% 66% 55% 40% 11% 28%
  39. 39. Spiegazioni Possibili • La diagnosi di SLA sporadica è erronea; sono in realtà familiari – Non ci sono conoscenze sui familiari – Familiari hanno avuto la SLA ma non è stata diagnosticata – Familiari deceduti per altre malattie prima di sviluppare la SLA • Le famiglie sono piccole
  40. 40. Studi genetici in 8 famiglie Spiegazioni possibili: le mutazioni sono de novo
  41. 41. Possibili spiegazioni: pleiotropia
  42. 42. • SOD1: p.E133del, p.L67P, p.D11Y, p.D90A • TARDBP: p.G294V • C9ORF72: 2 pazienti Possibili spiegazioni Bassa penetranza La mutazione dei casi sporadici era presente in familiari asintomatici in 7/8 famiglie:
  43. 43. 92 y * onset 55 y E133del * L67P SOD1 76 y onset 36 y C9orf72 78 y * onset 47 y
  44. 44. p.G294V TARDBP 90 y
  45. 45. penetranza • Concetto generico difficilmente applicabile a singoli pedigrees nel setting clinico • Paradigma SOD1: 170 mutazioni molte delle quali identificate in una o due famiglie. Penetranza (patogenicità?) difficilmente definibile(eccezioni A4V) • C9ORF72: è la mutazione più frequente nelle SLA sporadiche
  46. 46. 37.6% (95% CI 33.7-41.69) 5.8% (95% CI 4.4-7.4) 6.3% (95% CI 5.6-7.1) 25.1% (95% CI 20.9-29.6)
  47. 47. Espansione patologica in 11/7579 controlli sani: 0.15% 1/600 individui In Italia: 100.000 persone
  48. 48. Possibili spiegazioni della penetranza variabile: mutazioni multiple
  49. 49. 64 y 38 y p.I46V ANGC9ORF72 expansion 70 y C9ORF72 expansion + p.I46V ANG **
  50. 50. Mutazioni multiple • 1 paziente: C9ORF72+ANG • 1 paziente: SOD1+ANG La frequenza di mutazioni doppie osservate in pazienti (0.4) era circa 7 volte maggiore di quella attesa per caso (0.05)
  51. 51. Multiple mutations in 5/97 FALS
  52. 52. •L’azione selettiva è responsabile di una marcata eterogeneità allelica •Specifiche per differenti popolazioni (drift)
  53. 53. SLA familare SLA sporadica 28% mutazioni rare 21% mutazioni «comuni» 50% delle SLA sporadiche
  54. 54. MATR3 ATXN2 normale ATXN2 32 triplette
  55. 55. 6471 patients ANG variants: 0.46% 7678 Controls: 0.04%
  56. 56. SLA familiare SLA sporadica Monogenica Digenica Oligogenica Multigenica
  57. 57. • Clinical DNA analysis for gene mutations should only be performed in cases with a known family history of ALS, and in sporadic ALS cases with the characteristic phenotype of the recessive D90A mutation (GCPP). • Clinical DNA analysis for gene mutations should not be performed in cases with sporadic ALS with a typical classical ALS phenotype • In familial or sporadic cases where the diagnosis is uncertain, SMN, androgen receptor or TARDBP, FUS, ANG or SOD1 DNA analysis may accelerate the diagnostic process • Before blood is drawn for DNA analysis, the patient should receive genetic counselling. Give the patient time for consideration. DNA analysis should be performed only with the patients informed consent (GCPP).
  58. 58. Presymptomatic genetic testing should only be per- formed in first-degree adult blood relatives of patients with a known gene mutation. Testing should only be performed on a strictly voluntary basis as outlined and should follow accepted ethical principles . . Results of DNA analysis performed on patients and their relatives as part of a research project should not be used in clinical practice or disclosed to una ectedff rela- tives.Theresearchresultsshouldbekeptinaseparatefile and not in the patients standard medical chart (GCPP).
  59. 59. FALS 225 index SALS 725 mean age of onset 55 years 56 years Median age of onset 55 y (range 21- 85) 58 y (range 21-87) M/F 1.4 1.4 median disease duration 33 m (range 3-336) 48 m (range 1-354) FALS SALS 553 mean age of onset 55. 8 years (53 index) 54.3 years (110 index+r) 60.25 years Cattolica. Roma
  60. 60. • British Twin Study: 10.872 certificati di morte di pz con SLA - identificate 75 coppie di gemelli di cui almeno uno con SLA • Swedish Twin Register: su 86.411 coppie di gemelli identificati 73 coppie di gemelli, di cui almeno uno con SLA • Ereditabilità : 0,61 (0,38-0,78) • Componente ambientale: 0,39 (0,22-0,62)
  61. 61. A gene disease with a penetrance of: 0.9 will seem sporadic in one-third of cases 0.5 will seem sporadic in two-thirds of cases
  62. 62. Psycosis
  63. 63. Double mutations • 1 patient: C9ORF72+ANG • 1 patient: SOD1+ANG the frequency of double mutation found in patients (0.4) was approximately 7 times greater than would be expected by chance (0.05)
  64. 64. Multiple mutations in 5/97 FALS
  65. 65. Stdio di 8 famiglie di SLA sporadiche Spiegazioni possibili La mutazione è de novo
  66. 66. • 172 mutazioni (ALSoD): missenso, non senso, delezioni • No hot spot mutazionale • Quasi tutte in eterozigosi (D90A omozigosi) • Mai riportato coinvolgimento delle funzioni cognitive SOD1
  67. 67. C9ORF72: 3 SOD1: 3 TARDBP: 1 FUS; 1 C9ORF72: 5 SOD1: 2 ATXN2: 1 C9ORF72: 2 SOD1: 2 ATXN2: 1

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