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Ldb valecoricerca_sabatelli_clinica
- 1. Centro di RiferimentoRegionale per la Sclerosi Laterale Amiotrofica SLA: i fenotipi
- 2. UMN-D C.A: 41 years 4years after the onset
- 3. Eterogeneità fenotipica dellaSLA Età di esordio Durata di malattia Combinazione relativa di segni di UMN e LMN Sede di esordio (bulbare vs spinale) Condizioni associate: FTD, Parkinson, psicosi, neuropatia, miopatia, coinvolgimento del sistema autonomico
- 4. Eterogeneità fenotipica dellaSLA Età di esordio Durata di malattia (forme a lenta progressione vs forme aggressive) Combinazione relativa di segni di UMN e LMN Sede di esordio (bulbare vs spinale) Condizioni associate: FTD, Parkinson, psicosi, neuropatia, miopatia, coinvolgimento del sistema autonomico
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- 6. Juvenile amyotrophic lateralsclerosis (JALS) • Esordio nelle prime 2 decadi • Nella gran parte dei casi sono forme familiari con trasmissione AR • Progressione molto lenta • Geni individuati • ALS2 • SIGMAR1 • Spatacsin • SETX
- 7. Ex14c.2580-2A>G Ex4c.299 G>T. Maschi,27 aa e 21 aa Esordio: 3 aa e 6 aa rispettivamente difficoltà nel deambulare parlare Quadro clinico dominato dalla spasticità con atrofie distali Funzioni cognitive integre
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- 13. Young-adult ALS • Esordiotra i 20-40 aa • 11% delle SLA sporadiche • Marcata prevalenza del sesso maschile • Prevalenza marcata di segni piramidali (59.6%) • Sopravvivenza maggiore
- 14. Eterogeneità fenotipica dellaSLA Età di esordio Durata di malattia (forme a lenta progressione vs forme aggressive) Combinazione relativa di segni di UMN e LMN Sede di esordio (bulbare vs spinale) Condizioni associate: FTD, Parkinson, psicosi, neuropatia, miopatia, coinvolgimento del sistema nervoso autonomico
- 15. 38 m Short survivors longsurvivors 991 sporadic ALS
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- 18. Means and Mediansfor Survival Time 5,925 ,581 4,787 7,063 4,000 ,559 2,904 5,096 22,152 2,206 17,828 26,476 19,000 2,190 14,707 23,293 11,722 1,043 9,678 13,766 7,000 ,773 5,485 8,515 tolerability not tolerated tolerated Overall Estimate Std. Error Lower Bound Upper Bound 95% Confidence Interval Estimate Std. Error Lower Bound Upper Bound 95% Confidence Interval Mean a Median Estimation is limited to the largest survival time if it is censored.a. Overall Comparisons 73,503 1 ,000Log Rank (Mantel-Cox) Chi-Square df Sig. Test of equality of survival distributions for the different levels of tolerability.
- 19. Eterogeneità fenotipica dellaSLA Età di esordio Durata di malattia (forme a lenta progressione vs forme aggressive) Combinazione relativa di segni di UMN e LMN Sede di esordio (bulbare vs spinale) Condizioni associate: FTD, Parkinson, psicosi, neuropatia, miopatia,coinvolgimento del sistema autonomico
- 20. MND Phenotypes:MND Phenotypes: relativemix of UMN andrelative mix of UMN and LMN signsLMN signs ALSALS PMAPMAPLSPLS 6%5% 89%
- 21. MND FenotipiMND Fenotipi ALSALSPMAPMA I segni clinici ed elettrofisiologici (PEM) di UMN possono essere mascherati dai segni LMN • PEM (50-60%) • Autopsia (50%) • 30% sviluppano UMN entro 18 mesi 2.5-11%
- 22. MND Phenotypes:MND Phenotypes: relativemix of UMN andrelative mix of UMN and LMN signsLMN signs ALSALSPLSPLS
- 24. 56 pazienti M/F: 1 Etàmedia: 57 aa (37-80) Esordio bulbare: 47%. 2 pazienti solo disartria dopo 37 e 77 mesi
- 25. PLSPLS ALSALS 21.5%21.5% Di 56pazienti: -12 hanno sviluppato una SLA 18% PLS/ALSPLS/ALS -10 hanno sviluppato denervazione scarsa in singoli muscoli
- 31. SLA con marcatisegni di I motoneurone UMN-D Classic P Età di esordio 52 61.4 <0.0001 sopravvivenza 56 m 33m <0.001 M/F <40Y: 4.85 > 40Y: 0.84 < 40 y: 1.25 > 40 y: 1.29
- 32. Forme di MalattiedelForme di Malattie del motoneuronemotoneurone SLA senza demenza FTDSLA/FTD SLA senza demenza FTDSLA/FTD PLSSLA PLS con minimi segni di LMN SLA con UMN-D SLA con lievi Deficit cognitivi
- 33. Eterogeneità fenotipica dellaSLA Età di esordio Durata di malattia (forme a lenta progressione vs forme aggressive) Combinazione relativa di segni di UMN e LMN Sede di esordio Condizioni associate: FTD, Parkinson, psicosi, neuropatia, miopatia, coinvolgimento del sistema autonomico
- 35. Gowers WR. Diseases ofthe Nervous systemDiseases of the Nervous system 18881888 Flail arm phenotype VulpianBernhart syndrome
- 36. FLAIL ARM 0 2 4 6 8 10 12 10-20 21-3031-40 41-50 51-60 61-70 71-80 >80 onset (years) n.pts…. FEMALES MALES M:F=2.5
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- 41. 43 m30 m Il15% presenta un precoce coinvolgimento respiratorio
- 42. Eterogeneità fenotipica dellaSLA Età di esordio Durata di malattia (forme a lenta progressione vs forme aggressive) Combinazione relativa di segni di UMN e LMN Sede di esordio Condizioni associate: FTD, Parkinson, psicosi, neuropatia, coinvolgimento del sistema autonomico
- 43. SLA E DISTURBICOGNITIVI ALS-FTD Phukan and Hardiman JNNP (2011)
- 44. FALS and FTD Red:ALS Blue: FTD
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- 47. PLSPLS ALSALS 38%38% 1/3 dopo4 anni1/3 dopo 4 anni
- 48. HSP PLS età <40>40 Arti superiori raro sempre Bulbare mai freq evoluzione Molto lenta lenta Familiarità freq Mai (?)
- 49. SOD1 • 19 mutazioni •Nessuno con esordio bulbare • 16 pazienti con LMN (7 pseudopolinevritiche) • 1 UMN-D • 2 classica
- 50. Prevalenza: 0.6/100.000 Età diesordio: 40 aa (22-66) M: 38 anni; F:45 M/F: 2.7 Distal arm: 61% Distal leg: 34% Proximal arm: 5% Diagnosi iniziale: MND nel 35% Anti GM1: 43% Blocco di conduzione: 81% Risposta alle IVIg: 94%
- 51. Ben Hamida. 1984 79%: forme familiari
- 52. Means and Mediansfor Survival Time 66,656 11,765 43,596 89,716 49,000 12,643 24,220 73,780 Estimate Std. Error Lower Bound Upper Bound 95% Confidence Interval Estimate Std. Error Lower Bound Upper Bound 95% Confidence Interval Mean a Median Estimation is limited to the largest survival time if it is censored.a. SOD1: 19 patients A4V, G85S: survival < 1 y
- 53. FALS: algoritmo? • Etàdi esordio < 25 anni: FUS • Durata di malattia molto prolungata: SOD1 • Forma molto aggressiva: SOD1 • SLA/FTD: C9orf72
Editor's Notes
- #2 ALS is a neurodegenerative condition that targets primarily motor neurons, resulting in progressive paralysis and death within a few years from onset. Just like Alzheimer, Parkinson, and other neurodegenerative diseases, a proportion (10%) of ALS is dominantly inherited, with the remaining 90% (referred to as sporadic) of unknown origin. The identification in 1993 of mutation in the gene encoding superoxide dismutase 1 (SOD1) as the first or second most common form of inherited ALS (Rosen et al., 1993), and subsequent generation of transgenic mice expressing ALS-causing mutants in SOD1, initiated the molecular era of deciphering disease mechanism.
- #3 He is the father of the “anatomo-clinical method.” by which he attempted to to determine the correlation between clinical signs detected during life and anatomical lesions seen at autopsy
- #4 On the other hand , clinical heterogeneity is a recognized feature of the disease, with respect to several factor, the most important being age of onset and survival. It shoul be considered that topographic distribution of the clinical signs, duration of the disease, and age at onset. Based on the clinical pattern in the initial phases of illness, different variants have been described, including spinal, bulbar, and pseudoneuritic forms,4 flail arm syndrome,5 and Mill’s hemiparetic type.6 Most patients dis- There are no clear boundaries among ALS clinical phenotypes, since they represent points on a spectrum and each form may have multiple aetiologies as suggested by genetic studies in FALS. Nevertheless, efforts to better clarify different clinical categories may be helpful for properly addressing biological research. .
- #5 On the other hand , clinical heterogeneity is a recognized feature of the disease, with respect to several factor, the most important being age of onset and survival. It shoul be considered that topographic distribution of the clinical signs, duration of the disease, and age at onset. Based on the clinical pattern in the initial phases of illness, different variants have been described, including spinal, bulbar, and pseudoneuritic forms,4 flail arm syndrome,5 and Mill’s hemiparetic type.6 Most patients dis- There are no clear boundaries among ALS clinical phenotypes, since they represent points on a spectrum and each form may have multiple aetiologies as suggested by genetic studies in FALS. Nevertheless, efforts to better clarify different clinical categories may be helpful for properly addressing biological research. .
- #8 In conclusion, we describe the fi rst case of compound heterozygosity in the ALS2 gene in Italian patients, thus adding two novel mutations among those already described. ALS2 gene mutations should be suspected in all cases with an early onset motor neuron disease with a predominant/exclusive upper motor neuron involvement.
- #15 On the other hand , clinical heterogeneity is a recognized feature of the disease, with respect to several factor, the most important being age of onset and survival. It shoul be considered that topographic distribution of the clinical signs, duration of the disease, and age at onset. Based on the clinical pattern in the initial phases of illness, different variants have been described, including spinal, bulbar, and pseudoneuritic forms,4 flail arm syndrome,5 and Mill’s hemiparetic type.6 Most patients dis- There are no clear boundaries among ALS clinical phenotypes, since they represent points on a spectrum and each form may have multiple aetiologies as suggested by genetic studies in FALS. Nevertheless, efforts to better clarify different clinical categories may be helpful for properly addressing biological research. .
- #19 Non tollerata, rifiutata, dall’inizio trial
- #20 On the other hand , clinical heterogeneity is a recognized feature of the disease, with respect to several factor, the most important being age of onset and survival. It shoul be considered that topographic distribution of the clinical signs, duration of the disease, and age at onset. Based on the clinical pattern in the initial phases of illness, different variants have been described, including spinal, bulbar, and pseudoneuritic forms,4 flail arm syndrome,5 and Mill’s hemiparetic type.6 Most patients dis- There are no clear boundaries among ALS clinical phenotypes, since they represent points on a spectrum and each form may have multiple aetiologies as suggested by genetic studies in FALS. Nevertheless, efforts to better clarify different clinical categories may be helpful for properly addressing biological research. .
- #29 It’s nòticeable that the clinical presentation in the remaining 26 pts is really stereotypied in that the peculiar characteristics are
- #30 Bilateral and almost contemporarely wasting and weakness of the distal mus©les at the very beginning of the disease.
- #34 On the other hand , clinical heterogeneity is a recognized feature of the disease, with respect to several factor, the most important being age of onset and survival. It shoul be considered that topographic distribution of the clinical signs, duration of the disease, and age at onset. Based on the clinical pattern in the initial phases of illness, different variants have been described, including spinal, bulbar, and pseudoneuritic forms,4 flail arm syndrome,5 and Mill’s hemiparetic type.6 Most patients dis- There are no clear boundaries among ALS clinical phenotypes, since they represent points on a spectrum and each form may have multiple aetiologies as suggested by genetic studies in FALS. Nevertheless, efforts to better clarify different clinical categories may be helpful for properly addressing biological research. .
- #43 On the other hand , clinical heterogeneity is a recognized feature of the disease, with respect to several factor, the most important being age of onset and survival. It shoul be considered that topographic distribution of the clinical signs, duration of the disease, and age at onset. Based on the clinical pattern in the initial phases of illness, different variants have been described, including spinal, bulbar, and pseudoneuritic forms,4 flail arm syndrome,5 and Mill’s hemiparetic type.6 Most patients dis- There are no clear boundaries among ALS clinical phenotypes, since they represent points on a spectrum and each form may have multiple aetiologies as suggested by genetic studies in FALS. Nevertheless, efforts to better clarify different clinical categories may be helpful for properly addressing biological research. .
- #44 The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, Lynch C, Pender N, Hardiman O. Non-demented ALS patients were then divided into three groups based on the presence or absence of cognitive impairment and whether the executive domain was involved: 1. Impairment in executive dysfunction (ALS-Ex) single domain or in association with impairment in other cognitive domains (multidomain); 2. Non-executive cognitive impairment (ALS-NECI), single domain (eg, language only) or multidomain dysfunction (eg, language and memory); 3. No cognitive impairment.
- #51 Prevalnza inferiore di 13 volte rispetto la SLA
- #53 Sod1 sals e fals 19 casi