Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Analyzed Variables
2.3. Statistical Analysis
3. Results
3.1. Patient Cohort Characteristics
3.2. Epidemiological and Demographic Data
3.3. Follow-Up Outcomes
3.3.1. Profile of Patients Diagnosed Through NBS
3.3.2. Anthropometric Data
3.3.3. Neurological Outcome
3.3.4. Liver Disease
3.3.5. Treatment
Medical Treatment
Transplanted Patients
4. Discussion
- Epidemiologic data revealed a cumulative incidence over the past decade of approximately 1 in 36,063 live births, a prevalence of 1 in 238,200 by the end of 2023, and a 14.9% mortality rate with a median follow-up of 10.6 years.
- Mortality rates varied by UCD subtype, being higher in patients with CPS1D and in males with OTCD. Neonatal onset and peak ammonia levels at diagnosis were also linked to increased mortality. NBS-diagnosed patients had a favorable short-term prognosis; however, long-term outcomes need to be reassessed over time.
- Neurological disability was observed in 44.0% of patients, especially among those with ASLD, ARG1D, and HHH. Notably, neurological impairment was reduced to 36.0% in patients diagnosed within the past decade, compared to 50.0% in earlier cases.
- Liver transplantation was performed in 18.0% of those surviving the neonatal period, yielding excellent survival rates. However, neurological outcomes and growth in transplanted patients were similar to those medically managed.
Strengths and Weaknesses
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ARG1D | Arginase 1 deficiency |
ASLD | Argininosuccinate lyase deficiency |
ASS1D | Argininosuccinate synthetase deficiency |
CAVAD | Carbonic anhydrase VA deficiency |
CITD | Citrin deficiency |
CPS1D | Carbamoylphosphate synthetase 1 deficiency |
EO | Early-onset |
GPB | Glycerol phenylbutyrate |
HAE | Hyperammonemia episode |
HHH | Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome |
HRFS | High-risk family screening |
INE | Instituto Nacional de Estadística |
IQR | Interquartile range |
LO | Late-onset |
LT | Liver transplantation |
MM | Medical management |
NAGS | N-acetylglutamate synthase deficiency |
NBS | Newborn screening |
NaBZ | Sodium benzoate |
NaPB | Sodium phenylbutyrate |
ORNT1D | Ornithine/citrulline antiporter deficiency |
OTCD | Ornithine transcarbamylase deficiency |
REDcap | Research Electronic Data Capture |
SD | Standard deviation |
UCD | Urea cycle disorder |
UCDC | Urea Cycle Disorders Consortium |
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Disease | Patients N = 255 | Gender N = 255 | Presentation N = 254 | Evolution N = 255 | Treatment in Patients Under Follow-Up N = 204 | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Male | Female | Symptomatic | Asymptomatic | Alive | Died | Lost | MM | LT | |||
EO | LO | ||||||||||
OTCD, N (%) | 133 (52.1) | - | - | 27 (20.3) | 88 (66.2) | 17 (12.8) | 105 (78.9) | 21 (15.8) | 7 (5.3) | 82 (68.7) | 23 (17.3) |
OTCD-M (%) | - | 56 (42.1) | - | 23 (41.1) | 26 (46.4) | 6 (10.7) | 36 (64.3) | 17 (30.3) | 3 (5.4) | 28 (77.8) | 8 (22.2) |
OTCD-F (%) | - | - | 77 (57.9) | 4 (5.2) | 62 (80.5) | 11 (14.3) | 69 (89.6) | 4 (5.2) | 4 (5.2) | 54 (78.3) | 15 (21.7) |
ASS1D, N (%) | 54 (21.2) | 36 (66.6) | 18 (33.3) | 27 (50.0) | 8 (14.8) | 19 (35.2) | 44 (81.5) | 6 (11.1) | 4 (7.4) | 37 (84.1) | 7 (15.9) |
ASLD, N (%) | 26 (10.2) | 11 (42.3) | 15 (57.7) | 11 (42.3) | 6 (23.1) | 9 (34.6) | 22 (84.6) | 3 (11.5) | 1 (3.8) | 16 (72.7) | 6 (27.3) |
CPS1D, N (%) | 19 (7.4) | 9 (47.4) | 10 (52.6) | 11 (57.9) | 7 (36.8) | 1 (5.3) | 12 (63.1) | 7 (36.8) | 0 (0) | 10 (83.3) | 2 (16.7) |
ARG1D, N (%) | 9 (3.5) | 4 (44.4) | 5 (55.5) | 1 (11.1) | 5 (55.5) | 3 (33.3) | 9 (100) | 0 (0) | 0 (0) | 7 (77.8) | 2 (22.2) |
NAGSD, N (%) | 4 (1.6) | 2 (50.0) | 2 (50.0) | 3 (50.0) | 1 (50.0) | 0 (0) | 2 (50) | 1 (25.0) | 1 (25.0) | 2 (100) | 0 (0) |
ORNT1D, N (%) | 5 (2.0) | 4 (80.0) | 1 (20.0) | 2 (40.0) | 3 (60.0) | 0 (0) | 5 (100) | 0 (0) | 0 (0) | 5 (100) | 0 (0) |
CITD, N (%) | 3 (1.2) | 3 (100) | 0 (0) | 1 (33.3) | 1 (33.3) | 1 (33.3) | 3 (100) | 0 (0) | 0 (0) | 3 (100) | 0 (0) |
CAVAD, N (%) | 2 (0.8) | 1 (50.0) | 1 (50.0) | 0 (0) | 2 (100) | 0 (0) | 2 (100) | 0 (0) | 0 (0) | 2 (100) | 0 (0) |
TOTAL, N (%) | 255 (100) | 126 (49.4) | 129 (50.6) | 83 (32.7) | 121 (47.6) | 50 (19.7) | 204 (80.0) | 38 (14.9) | 13 (5.1) | 164 (80.4) | 40 (19.6) |
Disease | Total Number of Cases, n (%) | Number of Cases Diagnosed Between 2014 and 2023, n | Incidence in 2014 and 2023 * | Mortality, n (%) |
---|---|---|---|---|
NAGSD | 4 (1.6) | 3 | 1:1,238,172 | 1 (25.0) |
CPS1D | 19 (7.4) | 13 | 1:285,732 | 7 (36.8) |
OTCD | 133 (52.1) | 33 | 1:112,561 | 21 (15.8) |
OTCD males | 56 (42.1) | 16 | 1:232,002 | 17 (30.3) |
OTCD females | 77 (57.9) | 17 | 1:218,355 | 4 (5.2) |
ASS1D | 54 (21.2) | 26 | 1:142,770 | 6 (11.1) |
ASLD | 26 (10.2) | 14 | 1:265,146 | 3 (11.5) |
ARG1D | 9 (3.5) | 7 | 1:530,645 | 0 |
ORNT1D (HHH) | 5 (2.0) | 3 | 1:1,238,172 | 0 |
CITD | 3 (1.2) | 2 | 1:1,857,258 | 0 |
CAVAD | 2 (0.8) | 2 | 1:1,857,258 | 0 |
TOTAL | 255 (100) | 103 | 1:36,063 | 38 (14.9) |
0 ≤ 2 Years (N = 8) | 2–10 Years (N = 62) | 11–18 Years (N = 44) | >18 Years (N = 90) | Global (N = 204) | ||
---|---|---|---|---|---|---|
Age Median years (IQR) | 1.38 (1.18–1.51) | 5.91 (4.19–8.75) | 14.61 (12.92–16.54) | 28.97 (21.46–38.33) | 16.51 (8.23–26.60) | |
Weight Median kg (IQR) Z-score * | 10.09 (8.08–11.35) −0.47 | 21 (15.43–27) −0.05 | 44.45 (37.48–50) −0.87 | 61.15 (55.45–72.83) 0.19 | 45.85 (24.68–60.78) −0.13 | |
Height Median cm (IQR) Z-score * | 79.50 (68.25–82.45) −0.85 | 111 (100.8–125) −0.50 | 153.50 (145.38–161.38) −0.87 | 164.00 (156.10–170) −0.9 | 151.80 (120.13–163) −0.77 | |
HC Median cm (IQR) Z-score * | 48.41 (46.6–49.1) −0.35 | 51 (49.07–51.95) −0.25 | 54.00 (53.86–54.72) 0.21 | 55.11 (54.78–55,81) −0.35 | 52.00 (49.65–54.00) 0.02 | |
Total proteins Median g/kg/d (IQR) | 1.55 (1.43–1.90) | 1.20 (0.9–1.49) | 0.80 (0.58–1.00) | 0.76 (0.63–0.90) | 0.88 (0.70–1.20) | |
EAs Median (g/kg/d) (IQR) (%) | 0.27 (0.24–0.44) (17.4%) | 0.29 (0.2–0.37) (24.0%) | 0.16 (0.11–0.31) (20.0%) | 0.23 (0.11–0.36) (30.0%) | 0.25 (0.15–0.37) (28.4%) | |
Age | <6 m | 6–12 m | 1–10 years | 11–16 years | >16 years | - |
WHO/FAO/UNU ** | 1.77 | 1.31 | 0.92–1.14 | 0.84–0.90 | 0.84–0.87 | - |
UK (N = 45) *** | 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) | - |
n | Neurologically Impaired, n (%) | Not Neurologically Impaired, n (%) | p-Value | |
---|---|---|---|---|
Total | 201 | 88 (43.8) | 113 (56.2) | |
Disease | 0.02 | |||
OTCD male | 35 | 13 (37.1) | 22 (62.8) | |
OTCD female | 68 | 23 (33.8) | 45 (66.2) | |
ASS1D | 43 | 16 (37.2) | 27 (62.8) | |
ASLD | 22 | 15 (68.2) | 7 (31.8) | |
CPS1D | 12 | 7 (58.3) | 5 (41.6) | |
ARG1D | 9 | 7 (77.7) | 2 (22.2) | |
NAGSD | 2 | 1 (50.0) | 1 (50.0) | |
ORNT1D (HHH) | 5 | 4 (80.0) | 1 (20.0) | |
CITD | 3 | 1 (33.3) | 2 (66.6) | |
CAVAD | 2 | 1 (50.0) | 1 (50.0) | |
Onset | <0.0001 | |||
Neonatal | 52 | 37 (71.1) | 15 (28.8) | |
Late | 101 | 45 (44.5) | 56 (55.4) | |
Asymptomatic | 48 | 6 (12.5) | 42 (87.5) | |
Year of diagnosis | 0.05 | |||
2014–2023 | 84 | 30 (35.7) | 54 (64.3) | |
<2014 | 117 | 58 (49.6) | 59 (50.4) | |
Laboratory test at onset | <0.001 | |||
Ammonia (µmol/L) | 92 | 376 (80–800) | 201 (60–316) | |
Treatment | NS | |||
Transplanted | 39 | 20 (51.3) | 19 (48.7) | |
Non-transplanted | 162 | 68 (42.0) | 94 (58.0) |
Drug | Patients, n | Mean ± SD (mg/kg/day) |
---|---|---|
NaPB | 7 | 209 ± 121 |
NaBZ | 11 | 202 ± 3 |
GPB | 86 | 233 ± 94 |
Carglumic acid | 3 | 75 ± 66 |
Arginine | 72 | 148 ± 113 |
Citrulline | 74 | 159 ± 83 |
Patients at Follow-Up N = 204 | LT N = 40 (19.6%) | MM N = 164 (80.4%) | p-Value |
---|---|---|---|
Weight (mean z-score ± SD) | −0.83 ± 1.11 | 0.09 ± 1.41 | <0.001 |
Height (mean z-score ± SD) | −0.80 ± 0.24 | −0.84 ± 1.34 | NS |
HC (mean z-score ± SD) | −0.66 ± 0.96 | −0.3 ± 1.45 | NS |
Neurological involvement (%) | 51.3% | 41.4% | NS |
HAEs/patient/year * (mean ± SD) | 1.57 ± 2.99 | 0.37 ± 1.94 | 0.019 |
HAEs/year in the last two years (mean ± SD) | 0 | 0.16 ± 0.45 | <0.001 |
EO (%) | (50.0%) | (19.5%) | <0.001 |
Ammonia at onset (mean ± SD) (µmol/L) | 507 ± 451 | 342 ± 425 | 0.040 |
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Martín-Hernández, E.; Bellusci, M.; Pérez-Mohand, P.; Correcher Medina, P.; Blasco-Alonso, J.; Morais-López, A.; de las Heras, J.; Meavilla Olivas, S.M.; Dougherty-de Miguel, L.; Couce, M.L.; et al. Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry. Nutrients 2025, 17, 1173. https://doi.org/10.3390/nu17071173
Martín-Hernández E, Bellusci M, Pérez-Mohand P, Correcher Medina P, Blasco-Alonso J, Morais-López A, de las Heras J, Meavilla Olivas SM, Dougherty-de Miguel L, Couce ML, et al. Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry. Nutrients. 2025; 17(7):1173. https://doi.org/10.3390/nu17071173
Chicago/Turabian StyleMartín-Hernández, Elena, Marcello Bellusci, Patricia Pérez-Mohand, Patricia Correcher Medina, Javier Blasco-Alonso, Ana Morais-López, Javier de las Heras, Silvia María Meavilla Olivas, Lucy Dougherty-de Miguel, Maria Luz Couce, and et al. 2025. "Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry" Nutrients 17, no. 7: 1173. https://doi.org/10.3390/nu17071173
APA StyleMartín-Hernández, E., Bellusci, M., Pérez-Mohand, P., Correcher Medina, P., Blasco-Alonso, J., Morais-López, A., de las Heras, J., Meavilla Olivas, S. M., Dougherty-de Miguel, L., Couce, M. L., Villarroya, E. C., García Jiménez, M. C., Moreno-Lozano, P. J., Vives, I., Gil-Campos, M., Stanescu, S., Ceberio-Hualde, L., Camprodón, M., Cortès-Saladelafont, E., ... Quijada-Fraile, P. (2025). Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry. Nutrients, 17(7), 1173. https://doi.org/10.3390/nu17071173