Introduction
Methods
Study population
Genetic analysis of genes encoding CFH, CFI, MCP, C3, CFB, and THBD
Autoantibodies against factor H (αFH) and homozygous deletion of CFHR1 and CFHR3 genes
Results
Patients
Subject code, exon/intron | Mutation | Effect | Known/unknown |
---|---|---|---|
Complement factor H | |||
Exon 23 (n = 1) | c.3628C > T | p.Arg1210Cys | Known |
Exon 23 (n = 3) | c.3572C > T | p.Ser1191Leu | Known |
Exon 9 (n = 1) | c.1198C > A | p.Gln400Lys | Known |
Complement factor I | |||
Intron12 (n = 1a) | g.IVS12 + 5G > T | Splice score decrease from 0.93 to 0.86 | Known |
Exon 9 (n = 1b) | c.1019T > C | p.Ile340Thr | Known |
Exon 10 (n = 1c) | c.1071T > G | p.Ile357Met | Unknown |
Membrane cofactor protein | |||
Exon 6 (n = 1a) | c.811-816delGACAGT | p.delAsp271-Ser272 | Known |
Complement C3 | |||
n = 4b
| c.481C > T | (p.Arg161Trp) | Known [29] |
Complement factor B | |||
n = 2 | c.967A > G | p.Lys323Glu | Known |
Parameter | All patients (no.) | No genetic defect (no.) | Genetic defect (no.) |
CFH (no.) |
CFI (no.) |
MCP (no.) |
CFB (no.) |
C3 (no.) |
∆CFHR1/3 (no.) | αFH (no.) |
---|---|---|---|---|---|---|---|---|---|---|
Male/female | 22/23 (45) | 12/13 (25) | 10/10 (20) | 2/3 (5) | 3/0 (3) | 3/1 (4) | 0/2 (2) | 2/2 (4) | 3/2 (5) | 3/3 (6) |
Familial/sporadic | 11/34 (45) | 2/23 (25) | 9/11 (20) | 3/2 (5) | 1/ 2 (3) | 0/4 (4) | 2/0 (2) | 4/0 (4) | 0/5 (5) | 1/5 (6) |
Age of onset | ||||||||||
0-1 year | 10 (45) | 9 (25) | 1 (20) | 0 (5) | 0 (3) | 0 (4) | 0 (2) | 1 (4) | 0 (5) | 1 (6) |
1-7 years | 24 (45) | 10 (25) | 14 (20) | 4 (5) | 2 (3) | 2 (4) | 1 (2) | 2 (4) | 5 (5) | 5 (6) |
≥7 years | 11 (45) | 6 (25) | 5 (20) | 1 (5) | 1 (3) | 2 (4) | 1 (2) | 1 (4) | 0 (5) | 0 (6) |
Symptoms | ||||||||||
Fever | 13 (41) | 6 (22) | 7 (20) | 0 (4) | 1 (3) | 1 (4) | 0 (2) | 4 (4) | 2 (5) | 3 (6) |
URTI | 14 (31) | 5 (14) | 9 (19) | 2 (5) | 2 (3) | 1 (2) | 2 (2) | 3 (4) | 1 (3) | 2 (4) |
Oligo/anuria | 28 (40) | 15 (21) | 13 (19) | 5 (5) | 1 (3) | 2 (3) | 1 (2) | 3 (4) | 2 (5) | 3 (6) |
Gastrointestinala
| 32 (43) | 17 (23) | 15 (20) | 3 (5) | 2 (3) | 2 (4) | 1 (2) | 4 (4) | 4 (5) | 5 (6) |
Hypertension | 32 (45) | 20 (25) | 12 (20) | 3 (5) | 1 (3) | 1 (4) | 1 (2) | 2 (4) | 5 (5) | 6 (6) |
Biochemical evaluation (mean levels) | ||||||||||
Hemoglobin (g/dl) | 7,6 (45) | 7,7 (25) | 7,5 (20) | 7,0 (5) | 12,4 (3) | 13,7 (4) | 12,2 (2) | 10,6 (4) | 12,7 (5) | 12,2 (6) |
Platelet count (×109/l) | 81 (45) | 86 (25) | 76 (20) | 69 (5) | 136 (3) | 29 (4) | 175b (2) | 114 (4) | 51 (5) | 50 (6) |
LDH (U/l) | 3784 (42) | 4382 (23) | 3062 (19) | 1338 (5) | 4639 (3) | 3688 (3) | 1407 (2) | 3195 (3) | 5147 (5) | 4886 (6) |
Uremia (mmol/l) | 28 (45) | 31 (25) | 25,6 (20) | 27 (5) | 28.5 (3) | 19,8 (4) | 46,6 (2) | 19,4 (4) | 35,1 (5) | 31,5 (6) |
Creatinine (mmol/l) | 248 (45) | 290 (25) | 195 (20) | 193 (5) | 155 (3) | 124 (4) | 459 (2) | 100 (4) | 225 (5) | 199 (6) |
C3 (mg/l)c
| 881 (37) | 862 (22) | 908 (15) | 1276 (5) | 805 (2) | 933 (3) | 335 (2) | 810 (3) | 717 (3) | 705 (4) |
C4 (mg/l)d
| 232 (31) | 227 (19) | 240 (12) | 220 (3) | 193 (2) | 185 (1) | 378 (2) | 230 (1) | 227 (3) | 227 (3) |
Parameter | All patients (no.) | No genetic defect (no.) | Genetic defect (no.) |
CFH (no.) |
CFI (no.) |
MCP (no.) |
CFB (no.) |
C3 (no.) |
∆CFHR1/3 (no.) | αFH (no.) |
---|---|---|---|---|---|---|---|---|---|---|
Treatment | ||||||||||
Plasma therapya
| 27 (45) | 15 (25) | 12 (20) | 3 (5) | 2 (3) | 3 (4) | 2 (2) | 1 (4) | 3 (5) | 4 (6) |
Dialysis | 20 (45) | 12 (25) | 8 (20) | 2 (5) | 1 (3) | 2 (4) | 1 (2) | 2 (4) | 1 (5) | 1 (6) |
PT and dialysis | 11 (45) | 8 (25) | 3 (20) | 0 (5) | 0 (3) | 2 (4) | 1 (2) | 0 (4) | 0 (5) | 0 (6) |
No PT or dialysis | 9 (45) | 6 (25) | 3 (20) | 2 (5) | 0 (3) | 1 (4) | 0 (2) | 1 (4) | 1 (5) | 1 (6) |
Outcome | ||||||||||
Complete remission | 12 (45) | 9 (25) | 3 (20) | 2 (5) | 0 (3) | 1 (4) | 0 (2) | 0 (4) | 0 (5) | 0 (6) |
Partial remission | 31 (45) | 14 (25) | 17 (20) | 3 (5) | 3 (3) | 3 (4) | 2 (2) | 4 (4) | 5 (5) | 5 (6) |
Chronic PT | 12 (44) | 6 (25) | 6 (20) | 2 (5) | 1 (3) | 1 (4) | 0 (2) | 0 (4) | 3 (5) | 3 (6) |
Chronic dialysis | 7 (45) | 3 (25) | 4 (20) | 2 (5) | 1 (3) | 0 (4) | 1 (2) | 1 (4) | 0 (5) | 0 (6) |
Death | 1 (45) | 1 (25) | 0 (20) | 0 (5) | 0 (3) | 0 (4) | 0 (2) | 0 (4) | 0 (5) | 0 (6) |
Parameter | All patients (no.) | No genetic defect (no.) | Genetic defect (no.) |
CFH (no.) |
CFI (no.) |
MCP (no.) |
CFB (no.) |
C3 (no.) |
∆CFHR1/3 (no.) | αFH (no.) |
---|---|---|---|---|---|---|---|---|---|---|
Relapses | 21 (43) | 9 (23) | 12 (20) | 3 (5) | 1 (3) | 2 (4) | 1 (2) | 3 (4) | 3 (5) | 3 (6) |
No. of relapses | 43 (21) | 14 (9) | 29 (20) | 8 (3) | 4 (1) | 3 (2) | 1 (1) | 8 (3) | 9 (3) | 9 (3) |
Hypertension | 23 (43) | 12 (23) | 11 (19) | 2 (4) | 1 (3) | 2 (4) | 2 (2) | 4 (4) | 3 (5) | 4 (6) |
Proteinuria | 18 (38) | 9 (21) | 9 (17) | 0 (2) | 1 (3) | 1 (2) | 2 (2) | 2 (4) | 2 (5) | 2 (6) |
Renal Tx | 7 (44) | 3 (24) | 4 (20) | 2 (5) | 1 (3) | 1 (4) | 0 (2) | 1 (4) | 0 (5) | 0 (6) |
No. of Tx | 13 (7) | 5 (3) | 8 (4) | 4 (2) | 3 (1) | 1 (1) | 0(0) | 3 (1) | 0 (0) | 0 (0) |
No. of relapses in renal graft | 10 (13) | 4 (5) | 6 (8) | 5 (4) | 2 (3) | 0 (1) | 0 (0) | 2 (3) | 0 (0) | 0 (0) |
Death | 4 (45) | 2 (25) | 2 (20) | 0 (5) | 0 (3) | 1 (4) | 0 (2) | 0 (4) | 1 (5) | 1 (6) |
Parameter | Patient 1 | Patient 2 | Patient 3 | Patient 4 |
---|---|---|---|---|
Combined mutation |
CFI/MCP
|
CFI/C3
|
CFI/∆CFHR1-3/αFH
|
C3/αFH |
Gender | Male | Male | Male | Female |
Age at onset (years) | 13 10/12 | 1 2/12 | 6 6/12 | 6/12 |
Hemoglobin (g/dl) | 7.2 | 6.3 | 9.7 | 5.5 |
Platelet count (×109/l) | 13 | 276 | 120 | 44 |
Creatinine (mmol/l) | 94 | 76 | 294 | 72 |
C3 (mg/l)a
| 1000 | – | 610 | 670 |
C4 (mg/l)b
| 185 | – | 200 | – |
Plasmatherapy | yes | No | yes | Yes |
Dialysis | No | Yes | No | No |
Complete remission | No | No | No | No |
Partial remission | Yes | Yes | Yes | Yes |
Chronic plasmatherapy | No | No | Yes | No |
Chronic dialysis | No | Yes | No | No |
Death | No | No | No | No |
Relapse | No | Yes | No | No |
No. of relapses | – | 4 | – | – |
Renal transplant | No | Yes | No | No |
No. of renal transplants | – | 3 | – | – |
No. of relapses in grafts | – | 2 | – | – |
Death | No | No | No | No |