Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2014

Open Access 01-12-2014 | Research

Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases

Authors: Elena Martín-Hernández, Luis Aldámiz-Echevarría, Esperanza Castejón-Ponce, Consuelo Pedrón-Giner, María Luz Couce, Juliana Serrano-Nieto, Guillem Pintos-Morell, Amaya Bélanger-Quintana, Mercedes Martínez-Pardo, María Teresa García-Silva, Pilar Quijada-Fraile, Isidro Vitoria-Miñana, Jaime Dalmau, Rosa A Lama-More, María Amor Bueno-Delgado, Mirella del Toro-Riera, Inmaculada García-Jiménez, Concepción Sierra-Córcoles, Mónica Ruiz-Pons, Luis J Peña-Quintana, Inmaculada Vives-Piñera, Ana Moráis, Elena Balmaseda-Serrano, Silvia Meavilla, Pablo Sanjurjo-Crespo, Celia Pérez-Cerdá

Published in: Orphanet Journal of Rare Diseases | Issue 1/2014

Login to get access

Abstract

Background

Advances in the diagnosis and treatment of urea cycle disorders (UCDs) have led to a higher survival rate. The purpose of this study is to describe the characteristics of patients with urea cycle disorders in Spain.

Methods

Observational, cross-sectional and multicenter study. Clinical, biochemical and genetic data were collected from patients with UCDs, treated in the metabolic diseases centers in Spain between February 2012 and February 2013, covering the entire Spanish population. Heterozygous mothers of patients with OTC deficiency were only included if they were on treatment due to being symptomatic or having biochemistry abnormalities.

Results

104 patients from 98 families were included. Ornithine transcarbamylase deficiency was the most frequent condition (64.4%) (61.2% female) followed by type 1 citrullinemia (21.1%) and argininosuccinic aciduria (9.6%). Only 13 patients (12.5%) were diagnosed in a pre-symptomatic state. 63% of the cases presented with type intoxication encephalopathy. The median ammonia level at onset was 298 μmol/L (169-615). The genotype of 75 patients is known, with 18 new mutations having been described. During the data collection period four patients died, three of them in the early days of life. The median current age is 9.96 years (5.29-18), with 25 patients over 18 years of age. Anthropometric data, expressed as median and z-score for the Spanish population is shown. 52.5% of the cases present neurological sequelae, which have been linked to the type of disease, neonatal onset, hepatic failure at diagnosis and ammonia values at diagnosis. 93 patients are following a protein restrictive diet, 0.84 g/kg/day (0.67-1.10), 50 are receiving essential amino acid supplements, 0.25 g/kg/day (0.20-0.45), 58 arginine, 156 mg/kg/day (109-305) and 45 citrulline, 150 mg/kg/day (105-199). 65 patients are being treated with drugs: 4 with sodium benzoate, 50 with sodium phenylbutyrate, 10 with both drugs and 1 with carglumic acid.

Conclusions

Studies like this make it possible to analyze the frequency, natural history and clinical practices in the area of rare diseases, with the purpose of knowing the needs of the patients and thus planning their care.
Appendix
Available only for authorised users
Literature
1.
Brusilow SW: Arginine, an indispensable amino acid for patients with inborn errors of urea synthesis. J Clin Invest. 1984, 74: 2144-2148. 10.1172/JCI111640.CrossRefPubMedPubMedCentral
2.
Brusilow S, Horwich A: Urea cycle enzymes. The Metabolic and Molecular Bases of Inherited Diseases. Edited by: Scriver C, Beaudet A, Sly W, Valle D. 2001, McGraw –Hill, New York, 1909-1963. 8
3.
Applegarth DA, Toone JR, Lowry RB: Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000, 105 (1): e10-10.1542/peds.105.1.e10.CrossRefPubMed
4.
Dionisi-Vici C, Rizzo C, Burlina AB, Caruso U, Sabetta G, Uziel G, Abeni D: Inborn errors of metabolism in the Italian pediatric population. J Pediatr. 2001, 140: 321-327. 10.1067/mpd.2002.122394.CrossRef
5.
Sanderson S, Green A, Perece M, Burton H: The frequency of inherited metabolic disorders in the west midlands, United Kigdom. Arch Dis Child. 2006, 91: 896-899. 10.1136/adc.2005.091637.CrossRefPubMedPubMedCentral
6.
Keskinen P, Siitonen A, Salo M: Hereditary urea cycle diseases in Finland. Acta Paediatr. 2008, 97: 1412-1419. 10.1111/j.1651-2227.2008.00923.x.CrossRefPubMed
7.
Summar ML, Stefan Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B: The incidence of urea cycle disorders. Mol Genet Metab. 2013, 110: 179-180. 10.1016/j.ymgme.2013.07.008.CrossRefPubMedPubMedCentral
8.
Saudubray JM, Nassogne MC, de Lonlay P, Touati G: Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatol. 2002, 7: 3-15. 10.1053/siny.2001.0083.CrossRefPubMed
9.
Summar ML, Dobbelaere D, Brusilow S, Lee B: Diagnosis, symptoms frequency and mortality of 260 patients with urea cycle disorders from a 21-year multicenter study of acute hyperammonaemic episodes. Acta Paediatr. 2008, 97: 1420-1425. 10.1111/j.1651-2227.2008.00952.x.CrossRefPubMedPubMedCentral
10.
Wijburg FA, Nassogne MC: Disorders of the urea cycle and related enzymes. Inborn Metabolic Diseases, Diagnosis and Treatment. Edited by: Saudubray JM, Berghe G, Walter JH. 2012, Springer- Verlag, Berlin Heidelberg, 297-309. 10.1007/978-3-642-15720-2_20. 5CrossRef
11.
Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C: Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012, 7: 32-10.1186/1750-1172-7-32.CrossRefPubMedPubMedCentral
12.
Sander J, Janzen N, Sander S, Steuerwald U, Das AM, Scholl S, Trefz FK, Koch HG, Haberle J, Korall H, Marquardt I, Korenke C: Neonatal screening for citrullinaemia. Eur J Pediatr. 2003, 162: 417-420.PubMed
13.
Mercimek-Mahmutoglu S, Moeslinger D, Häberle J, Engel K, Herle M, Strobl MW, Scheibenreiter , Muehl A, Stöckler-Ipsiroglu : Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria. Mol Genet Metab. 2010, 100: 24-28. 10.1016/j.ymgme.2010.01.013.CrossRefPubMed
14.
Summar M: Current strategies for the management of neonatal urea cycle disorders. J Pediatr. 2001, 138: S30-S39. 10.1067/mpd.2001.111834.CrossRefPubMed
15.
Couce ML, Bustos G, García-Alixc A, Lázaro A, Martínez-Pardo M, Molina A, Saénz de Pipaón M, Serrano M, Sanjurjo P: Guía clínica de diagnóstico y tratamiento urgente de hiperamonemia neonatal. An Pediatr (Barc). 2009, 70: 183-188. 10.1016/j.anpedi.2008.10.007.CrossRef
16.
Schaefer F, Straube E, Oh J, Mehls O, Mayatepek E: Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant. 1999, 14: 910-918. 10.1093/ndt/14.4.910.CrossRefPubMed
17.
Picca S, Dionisi-Vici C, Abeni D, Pastore A, Rizzo C, Orzalesi M, Sabetta G, Rizzoni G, Bartuli A: Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol. 2001, 16: 862-867. 10.1007/s004670100702.CrossRefPubMed
18.
Scaglia F: New insights in nutritional management and amino acid supplementation in urea cycle disorders. Mol Genet Metab. 2010, 100 (Suppl 1): S72-S76. 10.1016/j.ymgme.2010.02.019.CrossRefPubMed
19.
Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A: Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. 2007, 356: 2282-2292. 10.1056/NEJMoa066596.CrossRefPubMed
20.
Stevenson T, Millan MT, Wayman K, Berquist WE, Sarwal M, Johnston EE, Esquivel CO, Enns GM: Long-term outcome following pediatric liver transplantation for metabolic disorders. Pediatr Transplant. 2009, 14: 268-275. 10.1111/j.1399-3046.2009.01228.x.CrossRefPubMed
21.
Kim IK, Niemi AK, Krueger C, Bonham CA, Concepcion W, Cowan TM, Enns GM, Esquivel CO: Liver transplantation for urea cycle disorders in pediatric patients: a single-center experience. Pediatr Transplant. 2013, 17: 158-167. 10.1111/petr.12041.CrossRefPubMed
22.
Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ, Krischer JP, Batshaw ML: Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008, 94: 397-402. 10.1016/j.ymgme.2008.05.004.CrossRefPubMedPubMedCentral
23.
Kölker S, Dobbelaere D, Chaprani A, Parker S, Burgard P, Hoffmann G, De Baere L, Stroobant N, Haeberle J, Baumgartner M: European registry and network for intoxication type metabolic diseases (E-IMD)(Abstract). J Inher Matabolic Dis. 2011, 34: s93-10.1007/s10545-010-9151-1.CrossRef
24.
García-Pérez MA, Sanjurjo P, Rubio V: Demonstration of the spf-ash mutation in Spanish patients with ornithine transcarbamylase deficiency of moderate severity. Hum Genet. 1995, 95: 183-186. 10.1007/BF00209398.CrossRefPubMed
25.
Climent C, García-Pérez MA, Sanjurjo P, Ruiz-Sanz JI, Vilaseca MA, Pineda M, Campistol J, Rubio V: Identification of a cytogenetic deletion and of four novel mutations (Q69X, I172F, G188V, G197R) affecting the gene for ornithine transcarbamylase (OTC) in Spanish patients with OTC deficiency. Hum Mutat. 1999, 4: 352-353. 10.1002/(SICI)1098-1004(199910)14:4<352::AID-HUMU15>3.0.CO;2-D.CrossRef
26.
Climent C, Rubio V: Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency. Hum Mutat. 2002, 19: 185-186. 10.1002/humu.9011.CrossRefPubMed
27.
Arranz JA, Riudor E, Marco-Marín C, Rubio V: Estimation of the total number of disease-causing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential. J Inherit Metab Dis. 2007, 30: 217-226. 10.1007/s10545-007-0429-x.CrossRefPubMed
28.
Vilaseca MA, Kobayashi K, Briones P, Lambruschini N, Campistol J, Tabata A, Alomar A, Rodès M, Lluch M, Saheki T: Phenotype and genotype heterogeneity in Mediterranean citrullinemia. Mol Genet Metab. 2001, 74: 396-398. 10.1006/mgme.2001.3221.CrossRefPubMed
29.
Hernández M, Castellet J, Narvaiza JL, Rincón JM, Ruiz I, Sánchez E, Sobradillo B, Zurimendi A: Curvas y tablas de crecimiento. Instituto de Investigación sobre Crecimiento y Desarrollo. Fundación F. Orbegozo. Bilbao. 3ª Edición. 2002, Ediciones Ergón, Madrid
30.
Bélanger-Quintana A, Martínez-Pardo M, García MJ, Wermuth B, Torres J, Pallarés E, Ugarte M: Hyperammonaemia as a cause of psicosis in an adolescent. Eur J Pediatr. 2003, 162: 773-775. 10.1007/s00431-002-1126-2.CrossRefPubMed
31.
Stenson PD, Mort M, Ball EV, Shaw K, Phillips AD, Cooper DN: HMGD professional The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014, 133: 1-9. 10.1007/s00439-013-1358-4.CrossRefPubMedPubMedCentral
32.
Protein and Amino Acid Requirements in Human Nutrition, WHO Technical Reports Series 935. 2007, UNU/WHO, Geneva
33.
Adam S, Champion H, Daly A, Dawson S, Dixon M, Dunlop C, Eardley J, Evans S, Ferguson C, Jankowski C, Lowry S, MacDonald A, Maritz C, Micciche A, Robertson L, Stafford J, Terry A, Thom R, van Wyk K, Webster D, White FJ, Wildgoose J: Dietary management of urea cycle disorders: UK practice. J Hum Nutr Diet. 2012, 25: 398-404. 10.1111/j.1365-277X.2012.01259.x.CrossRefPubMed
34.
Rüegger CM, Lindner M, Ballhausen D, Baumgartner MR, Beblo S, Das A, Gautschi M, Glahn EM, Grünert SC, Hennermann J, Hochuli M, Huemer M, Karall D, Kölker S, Lachmann RH, Lotz-Havla A, Möslinger D, Nuoffer JM, Plecko B, Rutsch F, Santer R, Spiekerkoetter U, Staufner C, Stricker T, Wijburg FA, Williams M, Burgard P, Häberle J: Cross-sectional observational study of 208 patients with non-classical urea cycle disorders. J Inherit Metab Dis. 2014, 37: 21-30. 10.1007/s10545-013-9624-0.CrossRefPubMedPubMedCentral
35.
36.
Tuchman M, Morizono H, Rajagopal BS, Plante RJ, Allewell NM: The biochemical and molecular spectrum of ornitine transcarbamylase deficiency. J Inherit Metab Dis. 1998, 21 (Suppl 1): 40-58. 10.1023/A:1005353407220.CrossRefPubMed
37.
Tuchman M, Jaleel N, Morizono H, Sheeby L, Lynch MG: Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat. 2002, 19: 93-107. 10.1002/humu.10035.CrossRefPubMed
38.
Mavinakere M, Morizono H, Shi D, Alewell NM, Tuchman M: The clinically variable R40H mutant ornithine carbamoyltransferase shows cytosolic degradation of the precursor protein in CHO cells. J Inherit Metab Dis. 2001, 24: 614-622. 10.1023/A:1012726207870.CrossRefPubMed
39.
Haberle J, Pauli S, Linnebank M, Kleijer WJ, Bakker HD, Wanders RJA, Harms E, Koch HG: Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia. Hum Genet. 2002, 110: 327-333. 10.1007/s00439-002-0686-6.CrossRefPubMed
40.
Kleijer WJ, Garritsen VH, Linnebank M, Mooyer P, Huijmans JG, Mustonen A, Simola KO, Arslan-Kirchner M, Battini R, Briones P, Cardo E, Mandel H, Tschiedel E, Wanders RJ, Koch HG: Clinical, enzymatic and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in 5 unrelated families. J Inherit Metab Dis. 2002, 25: 399-410. 10.1023/A:1020108002877.CrossRefPubMed
41.
Ficicioglu C, Mandell R, Shih VE: Arginosuccinate lyase deficiency: longterm outcome of 13 patients detected by newborn screening. Mol Genet Metab. 2009, 98: 273-277. 10.1016/j.ymgme.2009.06.011.CrossRefPubMedPubMedCentral
42.
Lindner M, Gramer G, Haege G, Fang-Hoffmann J, Schwab KO2, Tacke U, Trefz FK, Mengel E, Wendel U, Leichsenring M, Burgard P, Hoffmann JF: Efficacy and outcome of expanded newborn screening for metabolic diseases - Report of 10 years from South-West Germany. Orphanet J Rare Dis. 2011, 6: 44-53. 10.1186/1750-1172-6-44.CrossRefPubMedPubMedCentral
43.
Consensus statement from a conference for the management of patients with urea cycle disorders. J Pediatr. 2001, 138: s1-s5. 10.1067/mpd.2001.111830.
44.
Acosta PB, Yanicelli S, Ryan AS, Arnold G, Marriage BJ, Plewinska M, Bernstein L, Fox J, Lewis V, Miller M, Velazquez A: Nutritional therapy improves growth and protein status of children with urea cycle enzyme defect. Mol Genet Metab. 2005, 86: 448-455. 10.1016/j.ymgme.2005.08.012.CrossRefPubMed
45.
Singh RH: Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis. 2007, 30: 880-887. 10.1007/s10545-007-0718-4.CrossRefPubMed
46.
Adam S, Almeida MF, Assoun M, Baruteau J, Bernabei SM, Bigot S, Champion H, Daly A, Dassy M, Dawson S, Dixon M, Dokoupil K, Dubois S, Dunlop C, Evans S, Eyskens F, Faria A, Favre E, Ferguson C, Goncalves C, Gribben J, Heddrich-Ellerbrok M, Jankowski C, Janssen-Regelink R, Jouault C, Laguerre C, Le Verge S, Link R, Lowry S, Luyten K, et al: Dietary management of urea cycle disorders: European practice. Mol Genet Metab. 2013, 110: 439-445. 10.1016/j.ymgme.2013.09.003.CrossRefPubMed
Metadata
Title
Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases
Authors
Elena Martín-Hernández
Luis Aldámiz-Echevarría
Esperanza Castejón-Ponce
Consuelo Pedrón-Giner
María Luz Couce
Juliana Serrano-Nieto
Guillem Pintos-Morell
Amaya Bélanger-Quintana
Mercedes Martínez-Pardo
María Teresa García-Silva
Pilar Quijada-Fraile
Isidro Vitoria-Miñana
Jaime Dalmau
Rosa A Lama-More
María Amor Bueno-Delgado
Mirella del Toro-Riera
Inmaculada García-Jiménez
Concepción Sierra-Córcoles
Mónica Ruiz-Pons
Luis J Peña-Quintana
Inmaculada Vives-Piñera
Ana Moráis
Elena Balmaseda-Serrano
Silvia Meavilla
Pablo Sanjurjo-Crespo
Celia Pérez-Cerdá
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2014
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-014-0187-4

Other articles of this Issue 1/2014

Orphanet Journal of Rare Diseases 1/2014 Go to the issue

Research

Treatable inborn errors of metabolism presenting as cerebral palsy mimics: systematic literature review

Research

Orphan drugs expenditure in the Netherlands in the period 2006–2012

Research

TOSCA – first international registry to address knowledge gaps in the natural history and management of tuberous sclerosis complex

Review

Systemic therapy of Cushing’s syndrome

Research

Globotriaosylsphingosine (lyso-Gb3) might not be a reliable marker for monitoring the long-term therapeutic outcomes of enzyme replacement therapy for late-onset Fabry patients with the Chinese hotspot mutation (IVS4+919G>A)

Research

A systematic review of the prevalence of Morquio A syndrome: challenges for study reporting in rare diseases