Background
Methods
Multi-centre evaluation
Clinical grading scale
In vitro contracture test
Genetic screening
Ca2+ Release in isolated SR
Statistical analysis
Results
Differing in vitro effects of volatile anaesthetics and succinylcholine
Multi-centre evaluation
Trigger | No. of patients | Clinical grading scale | ||
---|---|---|---|---|
(raw score) | ||||
MHS | MHE | MHS | MHE | |
Vol. anesthetics
| 30 | 6 | 40.5 (28.5 - 61.0) | 34.0 (30.8 - 41.0) |
SCh
| 1 | 1 | 15 | 25 |
Vol. anesthetics + SCh
| 134 | 28 | 43.0 (30.0 - 55.0) | 33.0 (15.0 - 40.0) |
Total
|
165
|
35
|
43.0 (30.0 - 55.8)
|
33.0 (19.0 - 40.0)
|
Genetic evaluation
In vitro contracture test | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Contracture | Threshold | ||||||||||||
Exon | Nucleotide | Substitution | No. of patients in this study | 2 vol% halothane [mN] | 2 mmoll-1caffeine [mN] | Halothane [vol%] | Caffeine [mmoll-1] | Clinical grading scale | Causative mutation? | PolyPhen2 predictions | Sift predictions | Mutation Taster predictions | Reference |
2 | c.130C>T | p.R44C | 1 | 12.0 | 10.8 | 0.5 | 1.0 | 78.0 | No | Tammaro et al. 2003 [28] | |||
3
|
c.178G>T
|
p.D60Y
|
1
|
13.0
|
4.5
|
1.0
|
2.0
|
30.0
|
No
|
+
|
+
|
+
|
This study, V. Sorrentino
|
11 | c.1021G>A | p.G341R | 3 | 14.3 ± 4.8 | 13.7 ± 3.1 | 0.8 ± 0.2 | 0.8 ± 0.5 | 54.3 ± 4.9 | Yes | Quane et al. 1994 [29] | |||
11
|
c.1024G>A
|
p.E342K
|
1
|
37.8
|
23.8
|
0.5
|
0.5
|
30.0
|
No
|
+
|
+
|
+
|
This study, K. Jurkat-Rott
|
11 | c.1100G>A | p.R367Q | 1 | 10.0 | 4.1 | 0.5 | 1.5 | 15.0 | No | Galli et al. 2006 [30] | |||
12 | c.1201C>T | p.R401C | 1 | 17.0 | 7.0 | 1.0 | 1.5 | 18.0 | No | Davis et al. 2002 [31] | |||
12 | c.1202G>A | p.R401H | 1 | 21.0 | 12.0 | 1.0 | 1.5 | 55.0 | No | Rüffert et al. 2002 [32] | |||
15
|
c.1655G>A
|
p.R552Q*
|
1
|
36.0
|
8.0
|
0.5
|
1.5
|
38.0
|
No
|
+
|
-
|
+
|
This study, V. Sorrentino
|
17 | c.1840C>T | p.R614C | 25 | 13.7 ± 8.9 | 10.5 ± 8.3 | 0.9 ± 0.5 | 1.3 ± 0.7 | 50.8 ± 22.3 | Yes | Gillard et al. 1992 [33] | |||
17 | c.1841G>T | p.R614L | 2 | 16.6 ± 2.6 | 8.3 ± 2.3 | 0.5 ± 0.0 | 1.0 ± 0.5 | 30.5 ± 2.5 | Yes | Quane et al. 1997 [34] | |||
34
|
c.5011G>A
|
p.A1671T
|
1
|
8.0
|
24.8
|
2.0
|
0.5
|
35.0
|
No
|
+
|
+
|
-
|
This study, K. Jurkat-Rott
|
38 | c.6178G>T | p.G2060C* | 1 | 16.4 | 8.0 | 0.5 | 1.0 | 88.0 | No | Robinson et al. 2006 [6] | |||
39 | c.6377G>A | p.R2126Q | 1 | 26.8 | 8.8 | 0.5 | 2.0 | 35.0 | No | Kraeva et al. 2011 [7] | |||
39 | c.6387C>G | p.D2129E | 1 | 10.0 | 11.0 | 2.0 | 1.0 | 45.0 | No | Rüffert et al. 2001 [35] | |||
39 | c.6488G>C | p.R2163P | 1 | 20.0 | 4.0 | 1.0 | 2.0 | 55.0 | No | Robinson et al. 2006 [6] | |||
39 | c.6502G>A | p.V2168M | 6 | 22.5 ± 7.1 | 12.3 ± 5.0 | 0.5 ± 0.0 | 1.1 ± 0.3 | 58.8 ± 20.5 | Yes | Manning et al. 1998 [36] | |||
40 | c.6599C>T | p.A2200V | 1 | - | 3.0 | - | 2.0 | 10.0 | No | Sambuughin et al. 2005 [37] | |||
40 | c.6617C>T | p.T2206M | 9 | 20.5 ± 10.7 | 10.4 ± 4.9 | 0.9 ± 0.4 | 1.0 ± 0.4 | 50.4 ± 16.2 | Yes | Manning et al. 1998 [36] | |||
41
|
c.6710G>A
|
p.C2237Y
|
1
|
6.0
|
6.0
|
0.5
|
1.0
|
38.0
|
No
|
+
|
+
|
+
|
This study, M. Snoeck
|
43 | c.7007G>A | p.R2336H | 4 | 12.8 ± 4.5 | 11.7 ± 6.1 | 0.8 ± 0.3 | 1.1 ± 0.2 | 47.3 ± 4.4 | No | Levano et al. 2009 [38] | |||
43 | c.7025A>G | p.N2342S | 1 | 3.0 | 0.0 | 2.0 | 4.0 | 30.0 | No | Marchant et al. 2004 [39] | |||
44
|
c.7034G>C
|
p.S2345T
|
1
|
32.0
|
24.0
|
0.5
|
1.0
|
28.0
|
No
|
(+)
|
-
|
+
|
This study, V. Sorrentino
|
44 | c.7048G>A | p.A2350T | 1 | 22.0 | 9.0 | 1.0 | 1.0 | 55.0 | Yes | Sambuughin et al. 2001 [40] | |||
44
|
c.7076G>A
|
p.R2359Q
|
1
|
3.0
|
4.0
|
2.0
|
2.0
|
15.0
|
No
|
(+)
|
-
|
+
|
This study, H. Rüffert
|
44 | c.7085A>G | p.E2362G | 1 | 16.0 | 8.0 | 0.5 | 1.0 | 43.0 | No | Galli et al. 2006 [30] | |||
44 | c.7112A>G | p.E2371G | 1 | 16.0 | 10.0 | 1.0 | 1.5 | 91.0 | No | Zullo et al. 2009 [26] | |||
44 | c.7124G>C | p.G2375A | 2 | 19.5 ± 0.5 | 20.5 ± 1.5 | 0.5 ± 0.0 | 0.8 ± 0.3 | 59.5 ± 11.5 | Yes | Rüffert et al. 2002 [41] | |||
45 | c.7300G>A | p.G2434R | 5 | 24.3 ± 14.4 | 12.2 ± 8.2 | 0.7 ± 0.2 | 1.1 ± 0.6 | 57.4 ± 19.9 | Yes | Sambuugghin et al. 2001 [42] | |||
46 | c.7354C>T | p.R2452W | 1 | 8.0 | 20.0 | 1.0 | 1.5 | 48.0 | No | Chamley et al. 2000 [43] | |||
46 | c.7358T>C | p.I2453T | 1 | 7.0 | 7.0 | 1.0 | 1.5 | 63.0 | No | Rüffert et al. 2002 [41] | |||
46 | c.7360C>T | p.R2454C | 1 | 9.2 | 6.0 | 0.5 | 1.0 | 28.0 | Yes | Brandt et al. 1999 [44] | |||
46 | c.7361G>A | p.R2454H | 3 | 15.3 ± 5.7 | 13.0 ± 6.5 | 0.8 ± 0.2 | 1.0 ± 0.4 | 48.0 ± 12.2 | Yes | Barone et al. 1999 [45] | |||
46 | c.7372C>T | p.R2458C | 2 | 7.3 ± 1.3 | 2.0 ± 1.0 | 1.0 ± 0.0 | 2.0 ± 0.0 | 41.5 ± 31.5 | Yes | Manning et al. 1998 [46] | |||
71 | c.10616G˃A | p.R3539H | 1 | 7.0 | 8.0 | 2.0 | 1.5 | 38.0 | No | Dekomien et al. 2005 [47] | |||
85 | c.11708G>A | p.R3903Q | 2 | 4.8 ± 0.2 | 2.5 ± 0.5 | 2.0 ± 0.0 | 2.0 ± 0.0 | 25.0 ± 5.0 | No | Galli et al. 2006 [30] | |||
85
|
c.11723A>T
|
p.N3908I
|
1
|
8.0
|
4.8
|
1.0
|
1.5
|
20.0
|
No
|
+
|
+
|
+
|
This study, K. Jurkat-Rott
|
90
|
c.12398A>G
|
p.E4133G
|
1
|
2.0
|
2.5
|
2.0
|
2.0
|
10.0
|
No
|
+
|
+
|
+
|
This study, V. Sorrentino
|
90 | c.12413T>C | p.I4138T | 1 | 11.0 | 15.0 | 1.0 | 1.0 | 25.0 | No | Robinson et al. 2006 [6] | |||
90
|
c.12532G>A
|
p.G4178S
|
1
|
32.0
|
8.0
|
0.5
|
1.5
|
38.0
|
No
|
+
|
+
|
+
|
This study, V. Sorrentino
|
95 | c.13990T>C | p.C4664R | 1 | 20.0 | 4.0 | 1.5 | 1.5 | 50.0 | No | Zullo et al. 2009 [26] | |||
98
|
c.14204G>A
|
p.R4735Q
|
1
|
7.0
|
5.0
|
1.0
|
1.5
|
50.0
|
No
|
+
|
-
|
+
|
This study, H. Rüffert
|
101 | c.14545G>A | p.V4849I | 3 | 3.8 ± 3.1 | 3.3 ± 0.8 | 1.5 ± 0.5 | 2.0 ± 0.0 | 36.3 ± 8.5 | No | Jungbluth et al. 2002 [48] | |||
101 | c.14627A>G | p.K4876R | 1 | 14.0 | 14.0 | 0.5 | 0.5 | 48.0 | No | Monnier et al. 2005 [49] | |||
103
|
c.14833C>T
|
p.R4945X
|
1
|
9.9
|
23.3
|
0.5
|
0.5
|
15.0
|
No
|
na
|
na
|
+
|
This study, K. Jurkat-Rott
|
106
|
c.15059G>C
|
p.W5020S
|
1
|
1.0
|
2.0
|
-
|
2.0
|
43.0
|
No
|
+
|
+
|
+
|
This study, V. Sorrentino
|
In vitro contracture test | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Contracture | Threshold | ||||||||||||
No. of patients in this study | Exon | Nucleotide | Substitution | Causative mutation? | PolyPhen2 predictions | Sift predictions | Mutation taster predictions | References | 2 vol% halothane [mN] | 2 mmoll-1caffeine [mN] | halothane [vol%] | caffeine [mmoll-1] | CGS |
1
|
11
|
c.1100G>T
|
p.R367L
|
No
|
+
|
-
|
+
|
This study, T. Girard
| 20.0 | 4.5 | 1.0 | 1.5 | 48 |
65 | c.9649T>C | p.S3217P | No | Levano et al. 2009 [38] | |||||||||
1
| 8 | c.677T>A | p.M226K | No | Robinson et al. 2006 [6] | 53.0 | 24.0 | 0.5 | 0.5 | 38 | |||
28 | c.4024A>G | p.S1342G | No | Levano et al. 2009 [39] | |||||||||
1
| 44 | c.7085A>G | p.E2362G | No | Galli et al. 2006 [30] | 56.0 | 57.0 | 0.5 | 0.5 | 35 | |||
93 | c.13513G>C | p.D4505H | No | Groom et al. 2011 [50] | |||||||||
1
| 29 | c.4178A>G | p.K1393R | No | Vukcevic et al. 2010 [51] | 15.0 | 12.0 | 0.5 | 1.5 | 35 | |||
98 | c.14210G>A | p.R4737Q | No | Monnier et al. 2005 [49] |
Classification of RyR1 mutation | Clinical grading scale | Contracture (mN) | Threshold | ||
---|---|---|---|---|---|
2 vol% halothane | 2 mmol l-1caffeine | halothane (vol%) | Caffeine (mmol l-1) | ||
Causative | 51.10 ± 20.67* + | 16.77 ± 9.84 + * | 10.94 ± 7.24* | 0.81 ± 0.44 + * | 1.14 ± 0.63 + * |
Unknown causality | 38.08 ± 17.46* | 11.69 ± 8.99* | 8.73 ± 6.90* | 1.10 ± 0.58* | 1.50 ± 0.64* |
None detected | 37.55 ± 16.90+ | 11.43 ± 10.90+ | 7.52 ± 10.02* | 1.30 ± 0.83+ | 2.35 ± 7.70+ |