The phenotypic spectrum of organic acidurias and urea cycle - PDF document

J Inherit Metab Dis DOI 10.1007/s10545-015-9839-3 ORIGINAL ARTICLE The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation Stefan Kölker & Angeles Garcia Cazorla & Vassili Valayannopoulos & Allan M. Lund & Alberto B. Burlina & Jolanta Sykut-Cegielska & Frits A. Wijburg & Elisa Leão Teles & Jiri Zeman & Carlo Dionisi-Vici & Ivo Bari ć & Daniela Karall & Persephone Augoustides-Savvopoulou & Lise Aksglaede & Jean-Baptiste Arnoux & Paula Avram & Matthias R. Baumgartner & Javier Blasco-Alonso & Brigitte Chabrol & Anupam Chakrapani & Kimberly Chapman & Elisenda Cortès i Saladelafont & Maria L. Couce & Linda de Meirleir & Dries Dobbelaere & Veronika Dvorakova & Francesca Furlan & Florian Gleich & Wanda Gradowska & Stephanie Grünewald & Anil Jalan & Johannes Häberle & Gisela Haege & Robin Lachmann & Alexander Laemmle & Eveline Langereis & Pascale de Lonlay & Diego Martinelli & Shirou Matsumoto & Chris Mühlhausen & Hélène Ogier de Baulny & Carlos Ortez & Luis Peña-Quintana & Danijela Petkovi ć Ramad ž a & Esmeralda Rodrigues & Sabine Scholl-Bürgi & Etienne Sokal & Christian Staufner & Marshall L. Summar & Nicholas Thompson & Roshni Vara & Inmaculada Vives Pinera & John H. Walter & Monique Williams & Peter Burgard Received: 28 August 2014 /Revised: 21 January 2015 /Accepted: 26 January 2015 # SSIEM 2015 Abstract vomiting and/or muscular hypotonia. Neonatal onset of symp- Background The clinical presentation of patients with organic toms was most frequent in argininosuccinic synthetase and acidurias (OAD) and urea cycle disorders (UCD) is variable; lyase deficiency and carbamylphosphate 1 synthetase defi- symptoms are often non-specific. ciency, unexpectedly low in male OTC deficiency, and least Aims/methods To improve the knowledge about OAD and UCD frequently in GA1 and female OTC deficiency. For patients the E-IMD consortium established a web-based patient registry. with MMA, propionic aciduria (PA) and OTC deficiency Results We registered 795 patients with OAD (n=452) and (male and female), hyperammonemia was more severe in met- UCD (n=343), with ornithine transcarbamylase (OTC) defi- abolic crises during than after the newborn period, whereas ciency (n=196), glutaric aciduria type 1 (GA1; n=150) and metabolic acidosis tended to be more severe in MMA and PA methylmalonic aciduria (MMA; n=149) being the most fre- patients with late onset of symptoms. Symptomatic patients quent diseases. Overall, 548 patients (69 %) were symptom- without metabolic crises (n=94) often presented with a move- atic. The majority of them (n=463) presented with acute met- ment disorder, mental retardation, epilepsy and psychiatric abolic crisis during (n=220) or after the newborn period (n= disorders (the latter in UCD only). 243) frequently demonstrating impaired consciousness, Conclusions The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neona- tal crisis and those with late-onset of symptoms are both at risk Communicated by: K. Michael Gibson of delayed or missed diagnosis. For a complete list of affiliations of all authors see end of this article. Electronic supplementary material The online version of this article Abbreviations (doi:10.1007/s10545-015-9839-3) contains supplementary material, ARG1 Arginase 1 which is available to authorized users. ASL Argininosuccinate lyase S. Kölker ( * ) : F. Gleich : G. Haege : C. Staufner : P. Burgard ASS Argininosuccinate synthetase Department of General Pediatrics, Division of Inherited Metabolic CPS1 Carbamylphosphate synthetase 1 Diseases, University Children ’ s Hospital Heidelberg, Im E- European network and registry for homocystinurias Neuenheimer Feld 430, D-69120 Heidelberg, Germany HOD and methylation defects e-mail: Stefan.Koelker@med.uni-heidelberg.de

J Inherit Metab Dis E- European registry and network for intoxication type presentation of affected individuals. Therefore, the major IMD metabolic diseases aim of this international study is to elucidate the clinical GA1 Glutaric aciduria type 1 presentation of OAD and UCD focusing on the mani- HHH Hyperornithinemia-hyperammonemia- festation of the first symptoms. homocitrullinuria IVA Isovaleric aciduria MMA Methylmalonic aciduria Patients and methods NAGS N-acetylglutamate synthase OAD Organic aciduria European registry and network for intoxication type metabolic OTC Ornithine transcarbamylase diseases (E-IMD) PA Propionic aciduria Q Quartile The European registry and network for intoxication type met- QoL Quality of life abolic diseases (E-IMD, EAHC no. 2010 12 01) is a project UCD Urea cycle disorder which has received funding from the European Union, in the framework of the Health Programme. It has been realized without industrial sponsoring. A detailed description of E- IMD will be published separately (Kölker et al 2015). Inclusion and exclusion criteria Introduction The E-IMD registry is a web-based, password-protected reg- The clinical presentation of patients with inherited organic istry (URL: https://www.eimd-registry.com). It contains acidurias (OAD) and urea cycle disorders (UCD) is variable comprehensive information on patients with confirmed with first symptoms starting as early as the first day of life and diagnosis of an OAD, i.e. glutaric aciduria type 1 (GA1), as late as adulthood. The majority of OAD and UCD patients methylmalonic aciduria (MMA; OMIM #251000, #251100, are thought to experience (recurrent) acute metabolic crises #251110, #277400, #277410), propionic aciduria (PA; OMIM which are often precipitated by conditions that are likely to #606054) and isovaleric aciduria (IVA; (OMIM #243500), or induce a catabolic state, or by excessive protein intake. The an UCD, i.e. inherited deficiency of N-acetylglutamate syn- disease may progress from unspecific symptoms like feeding thase (NAGS; EC 2.3.1.1; OMIM #237310), refusal and vomiting to coma, multi-organ failure and death carbamylphosphate synthetase 1 (CPS1; EC 6.3.4.16; (Ah Mew N et al 2013; Hörster et al 2009; Pena et al 2012; OMIM #237300), ornithine transcarbamylase (OTC, includ- van der Meer et al 1994; Summar et al 2008; Zwickler et al ing female OTC carriers; EC 2.1.3.3; OMIM #311250), 2014). Unlike UCD and classic OAD, untreated patients with argininosuccinate synthetase (ASS; EC 6.3.4.5; OMIM glutaric aciduria type 1 (GA1; OMIM #231670) are at high #215700), argininosuccinate lyase (ASL; EC 4.3.2.1; OMIM risk to develop striatal injury often precipitated by catabolic #207900) or arginase 1 (ARG1; EC 3.5.3.1; OMIM #207800), stress during infancy (Kölker et al 2006; Strauss et al 2007). and hyperornithinemia-hyperammonemia-homocitrullinuria Since metabolic crises are acute life-threatening events, OAD (HHH; OMIM #238970) syndrome. The study was approved and UCD patients require immediate and adequate metabolic by the local ethic committee of the coordinating centre (i.e. emergency treatment (Baumgartner et al 2014; Chapman et al University Hospital Heidelberg, application no. S-525/2010) 2012; Häberle et al 2012; Sutton et al 2012). To prevent met- and then was approved by all clinical partners. Patients with abolic emergencies and to reduce high mortality and morbid- other inherited metabolic diseases, unconfirmed suspicion of ity, early diagnosis and immediate start of metabolic treatment an OAD or UCD, or with unrelated serious comorbidities in asymptomatic newborns is thought to improve the outcome were excluded. We also did not include OAD and UCD pa- (Enns et al 2007; Heringer et al 2010; Kölker et al 2007; tients who died before the starting date of E-IMD (i.e. 1st Kölker et al 2011). Some individuals with OAD and UCD, January 2011). however, may not develop a single episode of acute metabolic emergency during their whole life. They may remain asymp- tomatic or, more likely, may present with late-onset organ- Modular construction and contents of the registry specific symptoms that are likely to reflect chronic toxicity (Pena et al 2012; Rüegger et al 2014; Summar et al 2008). The registry is constructed in a modular way, containing a set Since OAD and UCD are rare diseases and most of common data elements for all OAD and UCD as well as studies have been performed in small cohorts, there is disease-specific follow-up parameters. The pre-defined algo- still uncertainty about the spectrum of the clinical rithm is summarized in Suppl. Table 1.