Abstract
Background
The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood.
Aims
To evaluate the complex clinical phenotype of OAD and UCD patients at different ages.
Results
Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut0 patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population.
Conclusions
Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.
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Abbreviations
- ARG1:
-
Arginase 1
- ASL:
-
Argininosuccinate lyase
- ASS:
-
Argininosuccinate synthetase
- CPS1:
-
Carbamylphosphate synthetase 1
- E-IMD:
-
European registry and network for intoxication type metabolic diseases
- GA1:
-
Glutaric aciduria type 1
- HHH:
-
Hyperornithinemia-hyperammonemia-homocitrullinuria
- IVA:
-
Isovaleric aciduria
- MMA:
-
Methylmalonic aciduria (isolated forms)
- NAGS:
-
N-acetylglutamate synthase
- OAD:
-
Organic aciduria
- OTC:
-
Ornithine transcarbamylase
- PA:
-
Propionic acidurias
- SDS:
-
Standard deviation score
- UCD:
-
Urea cycle disorder
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Acknowledgments
We are indebted to all patients and their families who have been willing to contribute to this study, to share their experience on living with a rare disease, and for their trust, and we thank all colleagues very much for their contribution to the project. We are grateful for fruitful collaboration with the following clinical partners, patient support groups and industrial partners (in alphabetical order of countries): Lut de Baere, Nathalie Stroobant (Belgische Organisatie voor Kinderen en Volwassenen met een Stofwisselingsziekte VZW [BOKS], Belgium), Nela Carić (Hrvatska udruga za rijetke bolesti, Croatia), Veronika Dvorakova (Charles University and General University of Prague, First Faculty of Medicine, Prague, Czech Republic), Annika and Kennet Rovsing (PND – Protein Nedbrydnings Defekt Foreningen, Denmark), Samantha Parker (Orphan Europe SARL, France), EURORDIS, European Organisation for Rare Disease (France), Erich Bauchart (Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Reference Center for Inherited Metabolic Disease, Necker-Enfants Malades University Hospital and IMAGINE Institute, Paris, France), Markus Ott, Beate Szczerbak (Nutricia Metabolics GmbH, Germany), Hubertus von Voss, Raimund Schmid (Kindernetzwerk e. V., Germany), Mandy Kretschmer (Glutarazidurie e. V., Germany), Reinhild Link (Wiesbaden, representing the SSIEM Dieticians Group), Persephone Augoustides-Savvopoulou (University A’Pediatric Department, Metabolic Laboratory, ‘Hippocration’ General Hospital of Thessaloniki), Zarifis Dimitroulis (KRIKOS ZOIS – Society for patients and friends of patients with inherited metabolic diseases), Evridiki Drogari (University of Athens, Aghia Sophia Children’s Hospital, Unit of Metabolic Diseases, Athens), Renza Barbon Galluppi (UNIAMO FIMR, Italy), Susan Udina (COMETA ASMME – Associazione Studio Malattie Metaboliche Ereditarie – ONLUS, Italy), Hanka Meutgeert (Volwassenen en Kinderen met Stoffwisselingsziekten [VKS], Netherlands), Vanessa Ferreira (Associação Portuguesa CDG, Portugal), Miguel Macedo (Apofen, Portugal), Sérgio Braz Antão (Rarrisimas, Portugal), Sergi Faber (Catalana de Trastorns Metabòlics Hereditaris, Spain), Sofia Nordin (Svedish Orphan Biovitrium AB [SOBI], Sweden), Steven Hannigan (CLIMB, Children Living with Inherited Metabolic Diseases, National Information Centre for Metabolic Diseases, and EMDA, the European Metabolic Disorders Alliance) and Robin Lachmann (National Hospital for Neurology and Neurosurgery, Charles Dent Metabolic Unit, London, United Kingdom).
This publication arises from the project “European registry and network for intoxication type metabolic diseases” (E-IMD; EAHC no 2010 12 01) which has received funding from the European Union, in the framework of the Health Programme. After the end of the EU funding period the E-IMD patient registry has been sustained by funding from the Kindness-for-Kids Foundation (Munich, Germany) and the Dietmar Hopp Foundation (St. Leon-Rot, Germany).
M. Baumgartner and J. Häberle (Zurich, Switzerland) are supported by radiz – Rare Disease Initiative Zurich, a clinical research priority program of the University of Zurich.
Drs Murphy and Lachmann were supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre
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All procedures followed were in accordance with the ethical standards of the responsible committee on human studies (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients or their legal guardians prior to being included in the study in countries where this was needed by law. This article does not contain animal subjects.
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Supplementary Table 1
Growth: the impact of age at disease onset (DOCX 39 kb)
Supplementary Table 2
Growth: the impact of movement disorders (DOCX 37 kb)
Supplementary Table 3
Movement disorder (DOCX 35 kb)
Supplementary Table 4
Laboratory tests evaluating the liver (DOCX 38 kb)
Supplementary Table 5
Whole blood cell count (DOCX 37 kb)
Supplementary Table 6
Synopsis of organ-specific manifestations in OAD and UCD patients (DOCX 30 kb)
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Kölker, S., Valayannopoulos, V., Burlina, A.B. et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis 38, 1059–1074 (2015). https://doi.org/10.1007/s10545-015-9840-x
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DOI: https://doi.org/10.1007/s10545-015-9840-x