Background
Methods
Patients and blood samples
Enzyme-linked immunosorbent assay (ELISA)
Neutralizing assay in serum
Neutralizing assay in leukocytes
Alpha-N-acetylgalactosaminidase (NAGA) neutralizing assay
Plasma lysoGb3
Statistical analysis
Results
Patients
Antibodies, genotype and phenotype (Table 1)
Ab-positive | Ab-negative | n* | p-value | |
---|---|---|---|---|
N | 18 | 27 | 45 |
–
|
Age visit (y.) | 43.7 [32.8–49.2] | 46.3 [41.4–59.6] | 45 |
0.12
£
|
Age diag (y.) | 28.8 [20.1–41.5] | 41.1 [28.1–53.7] | 45 |
0.09
£
|
Agalsidase exposure A/B/AB | 4/8/6 | 9/11/7 | 45 |
0.70
|
Current migalastat | 1 | 1 | 45 |
1
$
|
Cumul. Exp. (y.) | 10.6 [3.3–12.2] | 4.3 [3.2–7.0] | 45 |
0.22
£
|
MTP/Missense | 10/8 | 3/21 | 42d |
0.006
$
|
RRA (%)b | 0.38 [0.25–1.0] | 1.10 [0.95–1.1] | 43 |
0.0003
£
|
LysoGb3c (ng/ml) | 25.4 [18.9–48.8] | 10.2 [3.1–17.1] | 33 |
0.0005
£
|
Mainz score total | 23.5 [14.0–32.5] | 22.0 [15.5–27] | 45 |
0.74
£
|
Mainz cardiovascular score | 2.5 [0.0–9.8] | 9.0 [2.5–12.5] | 45 |
0.14
£
|
Mainz renal score | 8.0 [0–18] | 0.0 [0.0–8.0] | 45 |
0.22
£
|
Mainz neurological score | 5.5 [2.3–8.8] | 5.0 [1.5–8.0] | 45 |
0.65
£
|
Mainz general score | 4.5 [2.5–6.8] | 4.0 [1.5–6.5] | 45 |
0.33
£
|
Dialysis or kidney transplant | 6 | 1 | 45 |
0.012
$
|
Classic/ Non classic phenotype | 17/1 | 12/15 | 45 |
0.0005
$
|
Age (y.) | Mutation | ERT | Ab Titer ag. alfa | Ab Titer ag. beta | IgG1 | IgG2 | IgG3 | IgG4 | RRA alfa | RRA beta | lysoGb3 (ng/ml) | Renal event | Clinical phenotype | MSSI | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Exposure | Total | Cardio-vasc | General | Neuro | Renal | ||||||||||||||||
Type | Time (months) | ||||||||||||||||||||
1 M | 43.8 | c.233C>G | p.Ser78* | B | 182.0 | 1,638,400 | 1,638,400 | ++++ | ++++ | ++++ | ++++ | 4% | 1% | 41.0 | yes | Classic | 45 | 15 | 7 | 5 | 18 |
2 M | 33.4 | c.847C>T | p.Gln283* | B | 159.3 | 1,638,400 | 1,638,400 | +++ | ++++ | ++++ | ++++ | 42% | 32% | 48.0 | Classic | 14 | 9 | 2 | 3 | 0 | |
3 M | 47.7 | c.522T>A | p.Cys174* | B | 3.2 | 1,638,400 | 1,638,400 | ++++ | +++ | +++ | + | 20% | 17% | 21.7 | Classic | 12 | 0 | 4 | 0 | 8 | |
4 M | 46.1 | c.901C>T | p.Arg301* | A | 78.2 | 819,200 | 819,200 | ++++ | ++++ | ++++ | ++++ | 41% | 35% | 60.0 | Classic | 28 | 3 | 11 | 14 | 0 | |
5 M | 33.2 | c.548G>C | p.Gly183Ala | A/B | 157.4 | 1,638,400 | 1,638,400 | ++++ | ++++ | + | ++++ | 20% | 20% | 76.0 | Classic | 11 | 0 | 9 | 2 | 0 | |
6 M | 43.3 | c.169C>T | p.Gln57* | A/B | 170.4 | 819,200 | 819,200 | ++++ | ++++ | ++++ | ++++ | 3% | 4% | 31.3 | yes | Classic | 45 | 17 | 4 | 6 | 18 |
7 M | 47.3 | c.847C>T | p.Gln283* | B | 156.2 | 819,200 | 819,200 | ++++ | ++++ | ++ | ++++ | 46% | 36% | 25.4 | Classic | 12 | 10 | 2 | 0 | 0 | |
8 M | 50.6 | c.802-3_802-2del | unknown | B | 16.0 | 204,800 | 204,800 | ++++ | ++ | +++ | ++++ | 98% | 76% | na | Classic | 38 | 18 | 5 | 7 | 8 | |
9 M | 32.7 | c.884T>G | p.Phe295Cys | B | 46.6 | 102,400 | 102,400 | ++++ | no | no | no | mig | mig | 10.0 | yes | Classic | 29 | 0 | 2 | 9 | 18 |
10 M | 59.1 | c.758T>C | p.Ile253Thr | A | 7.8 | 102,400 | 102,400 | ++++ | no | ++ | ++ | 75% | 61% | 10.8 | Non classic | 23 | 13 | 1 | 1 | 8 | |
11 M | 17.5 | c.902G>A | p.Arg301Gln | B | 5.1 | 102,400 | 102,400 | ++++ | ++ | + | ++++ | 40% | 29% | NA | Classic | 14 | 0 | 6 | 8 | 0 | |
12 M | 27.7 | c.901C>T | p.Arg301* | A/B | 69.3 | 25,600 | 12,800 | +++ | +++ | ++ | ++++ | 54% | 38% | 48.8 | Classic | 19 | 2 | 6 | 11 | 0 | |
13 M | 52.1 | c.798T>A | p.Asp266Glu | A/B | 116.1 | 12,800 | 12,800 | ++++ | ++ | ++ | no | 99% | 103% | na | yes | Classic | 34 | 0 | 8 | 8 | 18 |
14 M | 49.8 | c.847C>T | p.Gln283* | B | 133.5 | 1600 | 1600 | ++++ | + | + | no | 144% | 115% | 84.2 | yes | Classic | 31 | 7 | 4 | 2 | 18 |
15 M | 41.1 | c.1069_1079del | p.Gln357Trpfs*14 | A/B | 146.3 | 800 | 800 | no | no | +++ | ++++ | 142% | 100% | 18.9 | Classic | 24 | 2 | 9 | 5 | 8 | |
16 M | 31.9 | c.875C>T | p.Ala292Val | A | 135.7 | 800 | 800 | +++ | no | ++ | ++++ | 114% | 93% | 15.0 | Classic | 8 | 3 | 2 | 3 | 0 | |
17 M | 51.0 | c.798T>A | p.Asp266Glu | A | 120.5 | 400 | 400 | + | no | no | no | 136% | 106% | na | yes | Classic | 33 | 0 | 5 | 10 | 18 |
18 M | 27.9 | c.729G>C | p.Leu243Phe | A/B | 151.0 | 100 | 100 | no | no | ++ | no | 141% | 110% | na | Classic | 18 | 0 | 4 | 14 | 0 | |
19F | 65.3 | c.695T>C | p.Ile232Thr | A | 1.8 | 6400 | 6400 | no | no | + | no | 120% | 110% | 1.5 | NA | 19 | 15 | 4 | 0 | 0 | |
20F | 43.2 | c.486G>C | p.Trp162Cys | B | 10.2 | 12,800 | 50 | + | no | no | no | 126% | 113% | 4.3 | NA | 13 | 0 | 1 | 8 | 4 |