1 / 37

Nuove eziologie in epilessia: dalla genetica all’autoimmunità

Nuove eziologie in epilessia: dalla genetica all’autoimmunità. Maurizio Elia UOC di Neurologia e Neurofisiopatologia Clinica e Strumentale IRCCS “Associazione Oasi Maria SS. Troina (EN) melia@oasi.en.it. (Scheffer et al., 2017). Genetica delle epilessie - Epidemiologia.

rsell
Download Presentation

Nuove eziologie in epilessia: dalla genetica all’autoimmunità

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Nuove eziologie in epilessia: dalla genetica all’autoimmunità Maurizio Elia UOC di Neurologia e Neurofisiopatologia Clinica e Strumentale IRCCS “Associazione Oasi Maria SS. Troina (EN) melia@oasi.en.it

  2. (Scheffer et al., 2017)

  3. Genetica delle epilessie - Epidemiologia • Le epilessie genetiche costituiscono circa il 30% di tutte le epilessie • Le epilessie genetiche possono verificarsi sia in assenza di un danno cerebrale dimostrabile (epilessie idiopatiche), che in presenza di lesione cerebrale (epilessie sintomatiche), che può essere essa stessa geneticamente determinata (malformazione cerebrale, malattia metabolica ecc.) • Più alto rischio di ricorrenza tra fratelli, tipicamente nel range 3–5%, comparato a 1% per la popolazione normale (Anderson et al., 1991; Hemminki et al., 2006) • Più alto grado di concordanza delle crisi in gemelli monozigotici (G 80%, F 36%) rispetto a quelli dizigotici (Berkovic et al., 1998; Kjeldsen et al., 2001)

  4. (Orsini et al., 2017)

  5. Copy numbervariants • a form of structural variation in the genome that consists of differences in the number of copies of a particular region in the genome • up to about 12% of the human genome is CNV, with CNVs contributing between 0.12% and 7.3% of the genomic variabilityseenwithinhumans • array CGH is capable of detecting copy number changes of varying sizes (from a few bp up to multimillion bp in size) (Choyet al., 2010)

  6. 15q13 microdeletion: Clinical cases SA

  7. BP3-BP5 (n=2) or BP4-BP5 (n=15) deletion behavioural problems (10/17 probands, 59%): poor attention span, hyperactivity, aggressive and impulsive behaviour hypotonia (8/17 probands, 47%) prominent or bulbous nasal tip (6/17 probands, 35%) short stature (4/17 probands, 24%) strabismus (3/17 probands, 18%) large ears (4/17 probands, 24%) cardiac defects (3/18 probands, 17%) clinodactyly of the 5th fingers (4/17 probands, 24%) pigmented naevi (3/17 probands, 18%) seizures 2/17 (12%) [if all BP4-BP5 carriers, probands and relatives are considered, the frequency becomes even lower(6%)]

  8. Proband 1 Proband 2 Proband 4

  9. 15q13.3 microdeletion and epilepsy phenotype • the clinical course is not properly benign, with the occurrence of absence status with eyelid myoclonia and seizures persisting in the elderly • response to valproate is incomplete and seizure control is difficult, requiring polytherapy • ID is present in most of cases (Coppola et al., 2013)

  10. 1234 pts with IGE from North-western Europe • 3022 controls from Germany

  11. NGS study of EEs - Troina • Methods: • Platform: Ion Torrent PGM (Life Technologies) • Kit: Ion AmpliSeq IAD59480_182 (Life Technologies) • Data analysys: Torrent Suite 4.2.1, VariantCaller 4.2.1, CoverageAnalysis 4.2.1.4, wANNOVAR (Chang and Wang 2012), Ion Reporter 4.2 • Genes analyzed and coverage: ALDH7A1 (100%), ALG13 (99%), ARHGEF15 (92%), ARHGEF9 (100%), ARX (79%), ATP1A2 (100%), BRD2 (98%), CACNA1A (90%), CACNA1H (88%), CACNA2D2 (93%), CACNB4 (99%), CASK (99%), CASR (99%), CDKL5 (99%), CHD2 (99%), CHRNA2 (98%), CHRNA4 (92%), CHRNA7 (83%), CHRNB2 (98%), CLCN2 (92%), CLCN4 (99%), CNTNAP2 (99,4%), CSTB (97%), EEF1A2 (97%), EFHC1 (99%), EPM2A (78%), FLNA (92%), FOXG1 (60%), GABRA1 (100%), GABRB3 (81%), GABRD (93%), GABRG2 (100%), GNAO1 (99%), GPR98 (98%), GRIN1 (91%), GRIN2A (99%), GRIN2B (99%), HCN1 (98%), HNRNPU (92%), IQSEC2 (87%), KCNH5 (100%), KCNMA1 (98%), KCNQ2 (90%), KCNQ3 (93%), KCNT1 (96%), KCTD7 (88%), MAGI2 (89%), MAPK10 (100%), MBD5 (99%), ME2 (95%), MECP2 (99%), MEF2C (100%), MTOR (99%), NEDD4L (98%), NHLRC1 (99%), NRXN1 (99%), PCDH19 (97%), PIGA (100%), PIGO (94,8%), PIGV (100%), PLCB1 (98,9%), PNKP (94%), PNPO (100%), PRICKLE1 (99%), PRICKLE2 (99%), PRRT2 (100%), RNASEH2A (92%), RNASEH2B (98%), RNASEH2C (78%), SAMHD1 (99%), SCARB2 (100%), SCN1A (100%), SCN1B (95,6%), SCN2A (98%), SCN8A (100%), SCN9A (97%), SLC25A22 (77,7%), SLC2A1 (99%), SLC35A2 (100%), SLC9A6 (95%), SPTAN1 (99,8%), STXBP1 (97%), SYN1 (97%), SYNGAP1 (97%), SZT2 (97%), TBC1D24 (100%), TCF4 (98%), TREX1 (85%), UBE3A (94%), ZEB2 (99%)

  12. MECP2 (1) TBC1D24 (2) SCN8A (1) SLC2A1 (1)

  13. (Mei et al., 2017)

  14. (Mei et al., 2017)

  15. (Mei et al., 2017)

  16. Somaticmutations in cerebralcorticalmalformations. Jamuar SS, Lam AT, Kircher M, D'Gama AM, WangJ, Barry BJ, Zhang X, Hill RS, Partlow JN, Rozzo A, ServattalabS, Mehta BK, Topcu M, Amrom D, Andermann E, Dan B, Parrini E, Guerrini R, Scheffer IE, Berkovic SF, Leventer RJ, Shen Y, Wu BL, Barkovich AJ, Sahin M, Chang BS, Bamshad M, Nickerson DA, ShendureJ, Poduri A, Yu TW, Walsh CA. 2014; 371:733-43

  17. (Orsini et al., 2017)

  18. Encephalitis of any etiology: annual incidence of 2–3/100,000 in northern Europe

  19. (Machado et al., 2012)

  20. N-methyl D-aspartate receptor (NMDAr) encephalitis (1) • several hundred cases have been reported • female predominance, most pts are young adults • an initial viral-like prodrome (fever, malaise, headaches, and anorexia), followed by psychiatric symptoms (anxiety, depression, and psychosis), which progress to include temporal lobe dysfunction (amnesia and seizures) and ultimately culminate in severe neurologic deficits, including autonomic dysfunction, dystonia/dyskinesia, and profound encephalopathy

  21. N-methyl D-aspartate receptor (NMDAr) encephalitis (2) • seizures are most commonly of the generalized tonic-clonic type, but focal seizures have been reported • male patients tend to present more frequently with seizures at onset than female patients • status epilepticus can occur and can be refractory(Gaspard, 2016)

  22. N-methyl D-aspartate receptor (NMDAr) encephalitis (3) • 45% of adult women with NMDAr encephalitis have an underlying ovarian teratoma, but only 9% of young girls had this finding • in women >45 years of age, 23% of women had an ovarian carcinoma instead of a teratoma (Florance et al., 2009)

  23. N-methyl D-aspartate receptor (NMDAr) encephalitis (4) • it is unlikely to have associated brain MRI abnormalities on initial presentation (89%) or follow-up (79%) (Irani et al., 2010) • when brain MR imaging abnormalities are present, these T2-FLAIR hyperintense lesions can typically demonstrate mild transient cortical enhancement without restricted diffusion or hemorrhage

  24. (Kelley et al., 2017)

  25. 2012 23 pts

  26. Voltage-gated potassium channel (VGKC) - complex

  27. Voltage-gated potassium channel (VGKC) encephalitis (1) • more common in men and mostly after the age of 40 • seizures occur in 80% of cases and can be focal or SG seizures; ictal autonomic manifestations, such as piloerection, have been reported • hyponatremia (less than 130 mEq/L) occurs in 30% to 60% of the cases due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (Gaspard et al., 2016)

  28. Voltage-gated potassium channel (VGKC) encephalitis (2) • a peculiar type of seizure, termed faciobrachial dystonic seizure, has been recently described in a subset of patients with anti-LGI1 encephalitis • these seizures occur frequently, up to hundreds of times per day, and are characterized by brief tonic contraction of the arm and face, either on one side or, more commonly, alternating between both sides • EEG changes during faciobrachial dystonic seizures vary but most often consist of diffuse attenuation or bursts of slow waves (Irani et al., 2011)

  29. (Irani et al., 2011)

  30. interictal ictal (Irani et al., 2011)

  31. Voltage-gated potassium channel (VGKC) encephalitis (3) • most patients (69%) demonstrate MRI findings classic for autoimmune encephalitis in the acute setting (T2-FLAIR hyperintense lesions in 1 or both medial temporal lobes) and had an increased propensity to develop chronic findings of mesial temporal sclerosis on follow-up imaging (48%) (Kotsenas et al., 2014) • “extralimbic” involvement in VGKC encephalitis is exceedingly rare (5%)

  32. (Kotsenas et al., 2014)

  33. (Dubey et al., 2016)

More Related