The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation

Kölker, Stefan; Cazorla, Angeles Garcia; Valayannopoulos, Vassili; Lund, Allan M.; Burlina, Alberto; Sykut-Cegielska, Jolanta; Wijburg, Frits A.; Teles, Elisa Leão; Zeman, Jiří; Dionisi‐Vici, Carlo; Barić, Ivo; Karall, Daniela; Augoustides‐Savvopoulou, Persephone; Aksglæde, Lise; Arnoux, Jean Baptiste; Avram, Paula; Baumgartner, Matthias R.; Blasco‐Alonso, Javier; Chabrol, B.; Chakrapani, Anupam; Chapman, Kimberly A.; Saladelafont, Elisenda Cortès i; Couce, María L.; Meırleır, Linda De; Dobbelaere, Dries; Dvořáková, Veronika; Furlan, Francesca; Gleich, Florian; Gradowska, Wanda; Grünewald, Stéphanie; Jalan, Anil; Häberle, Johannes; Haege, Gisela; Lachmann, Robin; Laemmle, Alexander; Langereis, Eveline J.; Lonlay, Pascale de; Martinelli, Diego; Matsumoto, Shirou; Mühlhausen, Chris; Baulny, Hélène Ogier de; Ortez, C.; Quintana, Luis Peña; Ramadža, Danijela Petković; Rodrigues, Esmeralda; Scholl‐Bürgi, Sabine; Sokal, Étienne; Staufner, Christian; Summar, Marshall; Thompson, NP; Vara, Roshni; Piñera, Inmaculada Vives; Walter, John H.; Williams, Monique; Burgard, Peter

doi:10.1007/s10545-015-9839-3

Cited by 191 publications

(211 citation statements)

References 62 publications

(59 reference statements)

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“…Estimated incidences are 1:35,000 for UCD (Summar et al 2014) and 1:21,000 for OA (Dionisi-Vici et al 2002). Recently, the natural course of the diseases has been described in two large samples (K€ olker et al 2015a;K€ olker et al 2015b;Waisbren et al 2016). These reports highlight that IT-IEM have a major impact on patients' lives: Strict diet, daily intake of medication, the permanent risk of severe metabolic crises, and neurological sequelae are only some of the issues that the growing number of long-term surviving patients and their families face.…”

Section: Introductionmentioning

confidence: 99%

Development and Psychometric Evaluation of the MetabQoL 1.0: A Quality of Life Questionnaire for Paediatric Patients with Intoxication-Type Inborn Errors of Metabolism

et al. 2017

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Introduction: This study is part of the "European network and registry for intoxication type metabolic diseases" (E-IMD) project. Intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders (UCD) and organic acidurias (OA) have a major impact on patients' lives. Patients have to adhere to strict diet and medication and may suffer from metabolic crises and neurocognitive impairment. Disease-specific health-related quality of life (HrQoL) assessment questionnaires are the method of choice to estimate the subjective burden of a Communicated by: Pascale de Lonlay "Peter Burgard," "Markus A. Landolt," and "Martina Huemer" are contributed equally to this project. Electronic supplementary material:The online version of this chapter

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Section: Introductionmentioning

confidence: 99%

Development and Psychometric Evaluation of the MetabQoL 1.0: A Quality of Life Questionnaire for Paediatric Patients with Intoxication-Type Inborn Errors of Metabolism

et al. 2017

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“…It may be assumed that individuals with the mild phenotype identified by NBS may remain asymptomatic throughout their lives [30]. This hypothesis is supported by family studies identifying asymptomatic individuals with biochemical evidence of IVA and genotypes identical to their younger siblings identified by NBS [30] and by the reported increase in the prevalence of organic acidurias in screened cohorts as compared to clinical ascertainment [32,37,48,66,67].…”

Section: Clinical Presentationmentioning

confidence: 97%

“…The first life-threatening catabolic episode in patients with the acute form usually occurs by the end of the first week of life ("acute neonatal form") [38,39,66]. Depending on the time of NBS sampling and turnaround time, patients with this form may even present clinically before the NBS result is reported [32].…”

Section: Clinical Presentationmentioning

confidence: 99%

“…Early symptoms are nonspecific. Newborns are feeding poorly and present with emesis often associated with dehydration, lethargy, and sometimes seizures [39,66,68]. Metabolic acidosis with an elevated anion gap representing the accumulation of organic acids, secondary hyperammonemia, and hyperglycemia or hypoglycemia are reported as laboratory findings [39,66,67].…”

Section: Clinical Presentationmentioning

confidence: 99%

“…The incidence of acute life-threatening catabolic episodes is highest in early infancy and decreases with age. Still, patients may become sick later in childhood with intermittent bouts of illness with vomiting and metabolic acidosis [39,66,67], often precipitated by infections or other physiologic stressors [39]. Interestingly, in a study of 21 children with symptomatic IVA, no such event was observed after nine years of age [39], although acute metabolic decompensations have been reported in adult life [69,70].…”

Section: Clinical Presentationmentioning

confidence: 99%

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Aspects of Newborn Screening in Isovaleric Acidemia

Schlune

Riederer

Mayatepek

et al. 2018

IJNS

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Isovaleric acidemia (IVA), an inborn error of leucine catabolism, is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene, resulting in the accumulation of derivatives of isovaleryl-CoA including isovaleryl (C5)-carnitine, the marker metabolite used for newborn screening (NBS). The inclusion of IVA in NBS programs in many countries has broadened knowledge of the variability of the condition, whereas prior to NBS, two distinct clinical phenotypes were known, an "acute neonatal" and a "chronic intermittent" form. An additional biochemically mild and potentially asymptomatic form of IVA and its association with a common missense mutation, c.932C>T (p.A282V), was discovered in subjects identified through NBS. Deficiency of short/branched chain specific acyl-CoA dehydrogenase (2-methylbutyryl-CoA dehydrogenase), a defect of isoleucine degradation whose clinical significance remains unclear, also results in elevated C5-carnitine, and may therefore be detected by NBS for IVA. Treatment strategies for the long-term management of symptomatic IVA comprise the prevention of catabolism, dietary restriction of natural protein or leucine intake, and supplementation with L-carnitine and/or L-glycine. Recommendations on how to counsel and manage individuals with the mild phenotype detected by NBS are required.

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Early prediction of phenotypic severity in Citrullinemia Type 1

Zielonka

Kölker

Gleich

et al. 2019

Ann Clin Transl Neurol

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Objective Citrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable including individuals with lethal hyperammonemic encephalopathy in the newborn period and individuals with a mild‐to‐moderate or asymptomatic disease course. Since the phenotypic severity has not been predictable early during the disease course so far, we aimed to design a reliable disease prediction model. Methods We used a newly established mammalian biallelic expression system to determine residual enzymatic activity of argininosuccinate synthetase 1 (ASS1; OMIM #215700) in 71 individuals with CTLN1, representing 48 ASS1 gene variants and 50 different, mostly compound heterozygous combinations in total. Residual enzymatic ASS1 activity was correlated to standardized biochemical and clinical endpoints available from the UCDC and E‐IMD databases. Results Residual enzymatic ASS1 activity correlates with peak plasma ammonium and L‐citrulline concentrations at initial presentation. Individuals with 8% of residual enzymatic ASS1 activity or less had more frequent and more severe hyperammonemic events and lower cognitive function than those above 8%, highlighting that residual enzymatic ASS1 activity allows reliable severity prediction. Noteworthy, empiric clinical practice of affected individuals is in line with the predicted disease severity supporting the notion of a risk stratification‐based guidance of therapeutic decision‐making based on residual enzymatic ASS1 activity in the future. Interpretation Residual enzymatic ASS1 activity reliably predicts the phenotypic severity in CTLN1. We propose a new severity‐adjusted classification system for individuals with CTLN1 based on the activity results of the newly established biallelic expression system.

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The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation

Abstract: 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 neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.

Cited by 191 publications

References 62 publications

Development and Psychometric Evaluation of the MetabQoL 1.0: A Quality of Life Questionnaire for Paediatric Patients with Intoxication-Type Inborn Errors of Metabolism

Development and Psychometric Evaluation of the MetabQoL 1.0: A Quality of Life Questionnaire for Paediatric Patients with Intoxication-Type Inborn Errors of Metabolism

Aspects of Newborn Screening in Isovaleric Acidemia

Early prediction of phenotypic severity in Citrullinemia Type 1

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