Background
Methods
Results
Data at diagnosis
Demographic data
Disease | Number (%) | Gender* | Presentation* | |||
---|---|---|---|---|---|---|
Male | Female | Symptomatic | Asymptomatic | |||
Neonatal | Late | |||||
OTCD | 67 (64.4) | 26 (38.8) | 41 (61.2) | 9 (13.4) 7 males | 52(77.6) 15 males | 6 (9) 4 males |
ASSD | 22 (21.1) | 13 (59) | 9 (61) | 14 (63.6) | 4 (18.2) | 4 (18.2) |
ASLD | 10 (9.61) | 6 (60) | 4 (40) | 2 (20) | 6 (60) | 2 (20) |
CPS1D | 2 (1.92) | 1 (50) | 1 (50) | 1(50) | 1 (50) | |
ARG1D | 2 (1.92) | 2 (100) | 0 | 1 (50) | 1 (50) | |
NAGSD | 1 (0.96) | 1 (100) | 0 | - | 1 (100) | - |
Total | 104 (100) (98 families) | 49 (47.1) | 55 (52.9) | 27 (26) | 64 (61.5) | 13 (12.5) |
Symptoms and biochemical data at diagnosis
Biochemical data * | At clinical onset (N = 91) | At last visit (N = 96) | Normal values |
---|---|---|---|
Ammonia (μmol/L) | 298 (169-615) | 33 (27-42) | 10-55 (80**) |
Glutamine (μmol/L) | 1124 (859-1546) | 716 (545-908) | 350-650 |
Prothrombin activity (%) | 60 (32.6-82) | 91 (85-100) | 75-130 |
ALT (IU/L) | 76 (38-159) | 24 (16-34) | 5-39 |
AST (IU/L) | 53.5 (36.7-161) | 27.5 (19-37.2) | 5-37 |
Bilirrubin (mg/dL) | 0.60 (0.43-3.77) | 0.53 (0.30-0.80) | 0.20-1.10 |
Albumin (g/L) | 3.79 (3-4.41) | 4.30 (3.90-4.50) | 3.80-5.40 |
pH | 7.43 (7.36-7.46) | - | 7.35-7.45 |
Bicarbonate (mmol/L) | 21 (19-24) | - | 23-27 |
Type of UCD | Amino acid* | |
---|---|---|
Citrulline (μmol/L) (NV: 26 ± 8) | Arginine (μmol/L) (NV: 64 ± 24) | |
NAGSD, CPS1D, OTCD | 10 (7-16) | 39 (20-59) |
ASSD | 1654 (984-2400) | 31 (17-41) |
ASLD | 173 (103-256) | 36 (24-81) |
ARG1D | 21 (20.5- 21.5) | 351 (231-470) |
Molecular genetic data
Patient n°/gender/[reference] | Nucleotide | Protein | Onset | Neurologic damage | Alive |
---|---|---|---|---|---|
4 M
|
c.1028C > G*
|
p.Thr343Arg*
| Late | No | Yes |
5 F | c.663 + 2 T > C (IV6 + 2 T > C) | Late | Yes | Yes | |
7 F | c.533C > T | p.Thr178Met | Late | No | Yes |
8 M | c.421C > T | p.Arg141Term | Late | No | Yes |
10 F | c.533C > T | p.Thr178Met | Late | Yes | Yes |
11 F | c.914C > G | p.Pro305Arg | Late | No | Yes |
12 M | c.604C > T | p.His202Tyr | Late | No | Yes |
13 F [27] | c.287C > T | p.Ser96Phe | Late | No | Yes |
14 F
|
del814-816GAG*
|
p.Glu273del*
| Late | No | Yes |
16 F | c.386 + 1G > A (IVS4 + 1G > A) | Late | Yes | Yes | |
20 M | c.365A > G | p.Gln122Gly | Late | Yes | Yes |
21 M | c.119G > A | p.Arg40His | A, FH | No | Yes |
22 M | c.264A > T | p.Lys88Asn | Late | No | Yes |
25 M | c.119G > A | p.Arg40His | Late | No | Yes |
27 F | c.67C > T | p.Arg23Term | Late | Yes | Yes |
32 F [24] | c.386G > A | p.Arg129His | Late | No | Yes |
33 F [25] | c.205C > T | p.Gln69Term | Late | Yes | Yes |
36 F [25] | delOTC gene >1.6 Mb | Late | Yes | Yes | |
37 F | c.583G > A | p.Gly195Arg | A, FH | No | Yes |
38 F | c.386G > A | p.Arg129His | Late | No | Yes |
40 M [27] | c.386 + 5G > A (IVS4 + 5G > A) | Neonatal | No | Yes | |
45 F
|
c.278C > T*
|
p.Thr93Ileu*
| Late | No | Yes |
48 M [24] | c.386G > A | p.Arg129His | Neonatal | No | Yes |
49 M | c.86C > T | p.Ala209Val | Late | Yes | Yes |
50 F | c.476 T > C | p.Ile159Thr | Late | Yes | Yes |
51 M [24] | c.386G > A | p.Arg129His | Late | No | Yes |
52 F [25] | c.514A > T | p.Ile172Phe | Late | No | Yes |
53 M | c.829C > T | p.Arg277Trp | Late | No | Yes |
54 M [26] | c.571C > T | p.Leu191Phe | Late | Yes | Yes |
55 M | c.622G > A | p.Ala208Thr | Late | Yes | Yes |
56 M
|
c.263A > C*
|
p.Lys88Thr*
| Late | No | Yes |
59 M | c.622G > A | p.Ala208Thr | A, FH | No | Yes |
60 F
|
c.298 + 1G > C (IVS3 + 1G > C)*
| Late | No | Yes | |
68 F | c.1018C > T | p.Ser340Pro | Late | Yes | Yes |
69 F [26] | c.1022C > T | p.Leu341Pro | Late | Yes | Yes |
72 F | c.482A > G | p.Asn161Asp | Late | No | Yes |
73 M
|
c.144delT*
|
p.Phe48Leufs*16*
| Neonatal | - | No |
74 F
|
c.254 T > G*
|
p.Ileu85Ser*
| Late | No | Yes |
75 F | c.583G > A | p.Gly195Arg | A, FH | No | Yes |
76 M | c.119G > A | p.Arg40His | A, FH | No | Yes |
77 M | c.119G > A | p.Arg40His | Late | Yes | Yes |
79 F | c.154G > A | p.Glu52Lys | Late | Yes | Yes |
80 F | c.583G > A | p.Gly195Arg | Late | Yes | Yes |
82 M | c.622G > A | p.Ala208Thr | Late | Yes | Yes |
83 M | c.932 T > A | p.Val311Glu | Neonatal | No | Yes |
88 F | c.605A > T | p.His202Leu | Late | No | Yes |
91 F | c.386 + 2 T > C (IVS4 + 2 T > C) | Late | No | Yes | |
94 F
|
c.630delA*
|
p.Lys210Asnfs*20*
| Late | Yes | Yes |
95 F | delOTC gene >1.6 Mb | Late | Yes | Yes | |
97 M | c.958C > T | p.Arg320Term | Neonatal | - | No |
100 F | c.386G > A | p.Arg129His | Late | No | Yes |
103 F [27] | c.211G > T | p.Gly71Term | Late | Yes | Yes |
Patient n°/ [reference] | Gene | Nucleotide | Protein | Onset | Neurologic damage |
---|---|---|---|---|---|
1 | ASS | c.256C > T / c.256C > T | p.Arg86Cys / p.Arg86Cys | Late | No |
3 | ASS | c.206 T > C / c.206 T > C | p.Val69Ala / p.Val69Ala | Neonatal | Yes |
18
|
ASS
|
c.557 T > G / c.557 T > G*
|
p.Met186Arg / p.Met186Arg*
| Neonatal | Yes |
24 | ASS | c.970G > A / c.970G > A | p.Gly324Ser / p.Gly324Ser | Late | No |
41 | ASS | c.971G > T / c.1168G > A | p.Gly324Val / p.Gly390Arg | Neonatal | Yes |
46 | ASS | c.1168G > A /c.1168G > A | p.Gly390Arg / p.Gly390Arg | Neonatal | Yes |
66 [28] | ASS | c.350G > A / c.1168G > A | p.Gly117Asp / p.Gly390Arg | Late | Yes |
84
|
ASS
| c.970G > A / c.271A > G* | p.Gly324Ser / p.Thr91Ala* | A, NBS | No |
85 | ASS | c.256C > T / c.256C > T | p.Arg86Cys / p.Arg86Cys | A, NBS | No |
86 | ASS | c.256C > T / c.256C > T | p.Arg86Cys / p.Arg86Cys | Late | No |
96D | ASS | c.1168G > A /c.1168G > A | p.Gly390Arg / p.Gly390Arg | Neonatal | - |
98 [28] | ASS | c.323G > T + c.356C > T / NF | p.Arg108Leu + p.Thr119Ile / NF | Neonatal | Yes |
99 | ASS | c.892delG / c.1168G > A | p.Glu298Argfs*/ p.Gly390Arg | Neonatal | Yes |
101 | ASS | c.919C > T / NF | p.Arg307Cys / NF | A, NBS | No |
9
|
ASL
|
c.133 T > A* / c.947G > A*
|
p.Tyr45Asn* / p.Gly316Glu*
| Late | Yes |
29
|
ASL
|
c.623C > G / c.623C > G*
|
p.Pro208Arg / p.Pro208Arg*
| Late | Yes |
30 | ASL | c.623C > G / c.623C > G | p.Pro208Arg / p.Pro208Arg | Late | Yes |
39 | ASL | c.338G > A / c.338G > A | p.Arg113Gln /p.Arg113Gln | A, Prenatal | Yes |
47
|
ASL
| c.532G > A /c.901G > A* | p.Val178Met / p.Gly301Arg* | Late | Yes |
71 | ASL | c.1143 + 1G > T / c.1143 + 1G > T | - | Neonatal | Yes |
81
|
ASL
| c.1135C > T/c.1367G > A* | p.Arg379Cys / p.Arg456Gln* | A, NBS | No |
19
|
CPS1
|
c.2549G > T*/ NF
|
p.Arg850Leu* / NF
| Late | Yes |
93 [30] |
NAGS
|
c.499A > G* / c.916-2A > G*
|
p.Met167Val */
| Late | No |
Current situation, data at last visit
Demographic data
Anthropometric data
N = 96 | 0-1 year | 1-6 years | 6-12 years | 12-18 years | >18 years** |
---|---|---|---|---|---|
(N = 4) | (N = 20) | (N = 33) | (N = 16) | (N = 23) | |
Age (years)* | 0.68 (0.21-0.75) | 4.10 (2.98-4.97) | 8.61 (7.50-10.2) | 15 (14.1-17) | 25.3 (21.2-33.3) |
Weight (kg)* | 8.25 (5.03-8.63) | 13.7 (12.8-16.7) | 28 (23.9-31.7) | 54.1(46.9-66.7) | 60 (54.2-75) |
Z-score | -0.28 | -0.53 | -0.008 | 0.1 | 0.17 |
Height (cm)* | 67.5 (58.2-70.7) | 95 (91-106) | 124(120-133) | 160 (150-176) | 161(153-171) |
Z-score | 0.71 | -0.48 | -0.14 | -0.06 | -0.63 |
HC (cm)* | 43.2 (39.2-43.9) | 48.5 (46.5-49.8) | 50 (49.5-53) | *** | *** |
Z-score | -0.85 | -1.16 | -0.68 |
Biochemical data
Outcome
N | With neurological impairment % (N) | Without neurological impairment % (N) | p | |
---|---|---|---|---|
Disease
| ||||
OTC | 65 | 44.6 (29, 7males) | 55.4 (36, 17 males) | 0.043* |
ASS | 21 | 66.7 (14) | 33.4 (7) | |
ASL | 10 | 80 (8) | 20 (2) | |
CPS1 | 2 | 100 (2) | 0 | |
ARG1 | 2 | 0 | 2 (100) | |
NAGS | 1 | 0 | 1 (100) | |
Presentation
| ||||
Neonatal | 24 | 75 (18) | 25 (6) | 0.002* |
Late | 64 | 51.6 (33) | 48.4 (31) | |
Asymptomatic | 13 | 15.4 (2) | 84.6 (11) | |
Hepatic failure at diagnosis
| ||||
Yes | 17 | 82.3 (14) | 17.7 (3) | 0.005* |
No | 82 | 45.1 (37) | 54.9 (45) | |
Laboratory test at diagnosis
|
Median (IQR)
|
Median (IQR)
| ||
Ammonia (μmol/L) | 92 | 400 (200-690) | 174 (67.2-270) | < 0.001** |
Glutamine (μmol/L) | 77 | 1126 (891-1672) | 917 (751-1196) | 0.019** |
Treatment
Age (N = 93) | 0-1y (N = 4) | 1-10y (N = 47) | 11-18y (N = 20) | >18y (N = 22) | |
---|---|---|---|---|---|
Total proteins (g/kg/day) | 1.86 (0.90-2.95) | 0.95 (0.7-1.2) | 0.84 (0.65-0.94) | 0.7 (0.57-0.92) | |
Energy (calories) (kcal/kg/day) | 102 (92.5-140) | 72 (58-95) | 40 (32-43,5) | 36 (30-42) | |
Essential Aminoacids (g/kg/day) | 0.39 (0.2-0.5) | 0.3 (0.27-0.43) | 0.25 (0.14-0.48) | 0.2 (0.11-0.41) | |
Age |
<6 m
|
6-12 m
|
1-10y
|
11-16y
|
>16y
|
WHO/FAO/UNU* (safe levels proteins) | 1.77 | 1.31 | 0.92-1.14 | 0.84-0.90 | 0.84-0.87 |
UK practice (N = 45)** Proteins | 2 (0.7-2.5) | 1.6 (1.2-1.8) | 1.3 (1-1.7) | 0.9 (0.7-1.4) | 0.8 (0.4-1.2) |
Drug | Patients (N) | Mean ± SD (mg/kg/day) |
---|---|---|
Sodium phenylbutyrate | 50 | 250 ± 158 |
Sodium benzoate | 4 | 184 ± 92.3 |
Combined treatment | 10 | |
Sodium phenylbutyrate | 250 ± 134 | |
Sodium benzoate | 165 ± 80.5 | |
Carglumic acid | 1 | 15 |