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Centro di Riferimento Regionale
per la
Sclerosi Laterale Amiotrofica
SLA: i fenotipi
UMN-D
C.A: 41 years
4 years after the onset
Eterogeneità fenotipica della SLA
 Età di esordio
 Durata di malattia
 Combinazione relativa di segni di UMN e LMN
 Se...
Eterogeneità fenotipica della SLA
 Età di esordio
 Durata di malattia (forme a lenta progressione vs forme aggressive)
...
Juvenile
ALS
Young-adult
ALS
Juvenile amyotrophic lateral sclerosis
(JALS)
• Esordio nelle prime 2 decadi
• Nella gran parte dei casi sono forme famili...
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...
Pol.Gemelli,
Pol.Gemelli,
Young-adult ALS
• Esordio tra i 20-40 aa
• 11% delle SLA sporadiche
• Marcata prevalenza del sesso maschile
• Prevalenza m...
Eterogeneità fenotipica della SLA
 Età di esordio
 Durata di malattia (forme a lenta progressione vs forme aggressive)
...
38 m
Short survivors
long survivors
991 sporadic ALS
71 m
36 m
Means and Medians for 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 ...
Eterogeneità fenotipica della SLA
 Età di esordio
 Durata di malattia (forme a lenta progressione vs forme aggressive)
...
MND Phenotypes:MND Phenotypes:
relative mix of UMN andrelative mix of UMN and
LMN signsLMN signs
ALSALS PMAPMAPLSPLS
6%5%
...
MND FenotipiMND Fenotipi
ALSALS PMAPMA
I segni clinici ed elettrofisiologici (PEM) di UMN
possono essere mascherati dai se...
MND Phenotypes:MND Phenotypes:
relative mix of UMN andrelative mix of UMN and
LMN signsLMN signs
ALSALSPLSPLS
56 pazienti
M/F: 1
Età media: 57 aa (37-80)
Esordio bulbare: 47%.
2 pazienti solo disartria dopo 37 e 77 mesi
PLSPLS ALSALS
21.5%21.5%
Di 56 pazienti:
-12 hanno sviluppato una SLA
18% PLS/ALSPLS/ALS
-10 hanno sviluppato denervazione...
SLA con marcati segni di I
motoneurone
UMN-D Classic P
Età di esordio 52 61.4 <0.0001
sopravvivenza 56 m 33m <0.001
M/F <4...
Forme di Malattie delForme di Malattie del
motoneuronemotoneurone
SLA senza
demenza
FTDSLA/FTD
SLA senza
demenza
FTDSLA/FT...
Eterogeneità fenotipica della SLA
 Età di esordio
 Durata di malattia (forme a lenta progressione vs forme aggressive)
...
Gowers WR.
Diseases of the Nervous systemDiseases of the Nervous system
18881888
Flail arm phenotype
VulpianBernhart
syndr...
FLAIL ARM
0
2
4
6
8
10
12
10-20 21-30 31-40 41-50 51-60 61-70 71-80 >80
onset (years)
n.pts….
FEMALES
MALES
M:F=2.5
734 paz
56
33
SLA Bulbare
43 m30 m
Il 15% presenta un precoce
coinvolgimento respiratorio
Eterogeneità fenotipica della SLA
 Età di esordio
 Durata di malattia (forme a lenta progressione vs forme aggressive)
...
SLA E DISTURBI COGNITIVI
ALS-FTD
Phukan and Hardiman JNNP (2011)
FALS and FTD
Red: ALS
Blue: FTD
FALS
FUS
C9ORF72
SOD1
TARDBP
UNKNOWN
FALS
PLSPLS ALSALS
38%38%
1/3 dopo 4 anni1/3 dopo 4 anni
HSP PLS
età <40 >40
Arti superiori raro sempre
Bulbare mai freq
evoluzione Molto lenta lenta
Familiarità freq Mai (?)
SOD1
• 19 mutazioni
• Nessuno con esordio bulbare
• 16 pazienti con LMN (7
pseudopolinevritiche)
• 1 UMN-D
• 2 classica
Prevalenza: 0.6/100.000
Età di esordio: 40 aa (22-66)
M: 38 anni; F:45
M/F: 2.7
Distal arm: 61%
Distal leg: 34%
Proximal a...
Ben Hamida. 1984
79% : forme familiari
Means and Medians for Survival Time
66,656 11,765 43,596 89,716 49,000 12,643 24,220 73,780
Estimate Std. Error Lower Boun...
FALS: algoritmo?
• Età di esordio < 25 anni: FUS
• Durata di malattia molto prolungata: SOD1
• Forma molto aggressiva: SOD...
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
Ldb valecoricerca_sabatelli_clinica
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Ldb valecoricerca_sabatelli_clinica

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Ldb valecoricerca_sabatelli_clinica

  1. 1. Centro di Riferimento Regionale per la Sclerosi Laterale Amiotrofica SLA: i fenotipi
  2. 2. UMN-D C.A: 41 years 4 years after the onset
  3. 3. Eterogeneità fenotipica della SLA  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. 4. Eterogeneità fenotipica della SLA  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
  5. 5. Juvenile ALS Young-adult ALS
  6. 6. Juvenile amyotrophic lateral sclerosis (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. 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
  8. 8. Pol.Gemelli,
  9. 9. Pol.Gemelli,
  10. 10. Young-adult ALS • Esordio tra i 20-40 aa • 11% delle SLA sporadiche • Marcata prevalenza del sesso maschile • Prevalenza marcata di segni piramidali (59.6%) • Sopravvivenza maggiore
  11. 11. Eterogeneità fenotipica della SLA  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
  12. 12. 38 m Short survivors long survivors 991 sporadic ALS
  13. 13. 71 m 36 m
  14. 14. Means and Medians for 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.
  15. 15. Eterogeneità fenotipica della SLA  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
  16. 16. MND Phenotypes:MND Phenotypes: relative mix of UMN andrelative mix of UMN and LMN signsLMN signs ALSALS PMAPMAPLSPLS 6%5% 89%
  17. 17. MND FenotipiMND Fenotipi ALSALS PMAPMA 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%
  18. 18. MND Phenotypes:MND Phenotypes: relative mix of UMN andrelative mix of UMN and LMN signsLMN signs ALSALSPLSPLS
  19. 19. 56 pazienti M/F: 1 Età media: 57 aa (37-80) Esordio bulbare: 47%. 2 pazienti solo disartria dopo 37 e 77 mesi
  20. 20. PLSPLS ALSALS 21.5%21.5% Di 56 pazienti: -12 hanno sviluppato una SLA 18% PLS/ALSPLS/ALS -10 hanno sviluppato denervazione scarsa in singoli muscoli
  21. 21. SLA con marcati segni 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
  22. 22. Forme di Malattie delForme 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
  23. 23. Eterogeneità fenotipica della SLA  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
  24. 24. Gowers WR. Diseases of the Nervous systemDiseases of the Nervous system 18881888 Flail arm phenotype VulpianBernhart syndrome
  25. 25. FLAIL ARM 0 2 4 6 8 10 12 10-20 21-30 31-40 41-50 51-60 61-70 71-80 >80 onset (years) n.pts…. FEMALES MALES M:F=2.5
  26. 26. 734 paz 56 33
  27. 27. SLA Bulbare
  28. 28. 43 m30 m Il 15% presenta un precoce coinvolgimento respiratorio
  29. 29. Eterogeneità fenotipica della SLA  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
  30. 30. SLA E DISTURBI COGNITIVI ALS-FTD Phukan and Hardiman JNNP (2011)
  31. 31. FALS and FTD Red: ALS Blue: FTD
  32. 32. FALS
  33. 33. FUS C9ORF72 SOD1 TARDBP UNKNOWN FALS
  34. 34. PLSPLS ALSALS 38%38% 1/3 dopo 4 anni1/3 dopo 4 anni
  35. 35. HSP PLS età <40 >40 Arti superiori raro sempre Bulbare mai freq evoluzione Molto lenta lenta Familiarità freq Mai (?)
  36. 36. SOD1 • 19 mutazioni • Nessuno con esordio bulbare • 16 pazienti con LMN (7 pseudopolinevritiche) • 1 UMN-D • 2 classica
  37. 37. Prevalenza: 0.6/100.000 Età di esordio: 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%
  38. 38. Ben Hamida. 1984 79% : forme familiari
  39. 39. Means and Medians for 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
  40. 40. FALS: algoritmo? • Età di esordio < 25 anni: FUS • Durata di malattia molto prolungata: SOD1 • Forma molto aggressiva: SOD1 • SLA/FTD: C9orf72

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