Early prediction of phenotypic severity in Citrullinemia Type 1

Zielonka, Matthias; Kölker, Stefan; Gleich, Florian; Stützenberger, Nicolas; Nagamani, Sandesh C.S.; Gropman, Andrea; Hoffmann, Georg F.; Garbade, Sven F.; Posset, Roland; Sarajlija, Adrijan; Schulze, Andreas; García‐Cazorla, Ángeles; Am, Lund; Jalan, Anil; Morris, Andrew A. M.; Dionisi‐Vici, Carlo; Laet, Corinne De; Teles, Elisa Leão; Diaz, GA; Berry, G.J.; Payan‐Walters, Irma; Blasco‐Alonso, Javier; Seminara, Jennifer; Bedoyan, Jirair K.; Merritt, J. Lawrence; Burrage, Lindsay C.; Schiff, Manuel; Baumgartner, Matthias; Mew, Nicholas Ah; Himmelreich, Nastassja; Freisinger, Peter; Hasselt, Peter M. van; Vara, Roshni; Berry, Susan A.; Hollander, Suzanne

doi:10.1002/acn3.50886

Cited by 33 publications

(42 citation statements)

References 33 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Strategy of FLAG‐ and MYC‐tagged wildtype expression vector generation has been described in detail previously (Zielonka, Kolker et al, 2019). Briefly, the ASL coding sequence was amplified by PCR from cDNA (human fibroblasts) with FLAG or MYC‐tags introduced at the C‐ or N‐terminus using specific primer pairs and inserted into the Bam HI and Not I restriction sites in the open‐reading frame of the eukaryotic expression vector pcDNA5 (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…RNA was extracted with TRIzol reagent (Invitrogen) by the standard procedure as previously described (Zielonka, Kolker et al, 2019). Briefly, equal amounts from each sample (500–800 ng) were used for cDNA synthesis using the Maxima first‐strand cDNA synthesis kit (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…Clinical variables used for data analyses were retrieved from the UCDC and E‐IMD databases as recently reported (Zielonka, Kolker et al, 2019). The following numerical clinical variables were used: Peak plasma ammonium concentration (NH 4 + max ), number of HAEs (with NH 4 + max > 100 µmol/l) per year of observation (defined as time between date of birth and last regular visit), NH 4 + max during the most severe hyperammonemic decompensation, and cognitive standard deviation scores (SDS) at the most recent visit being calculated using the normative data from the standardization sample of each cognitive test.…”

Section: Methodsmentioning

confidence: 99%

“…Statistical analyses were performed as previously described (Zielonka, Kolker et al, 2019). All analyses were performed using R (http://www.r-project.org).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we have been able to show that enzymatic activity of argininosuccinate synthetase 1, as determined by a newly established biallelic expression system, predicts the clinical disease course and neurocognitive outcome in individuals with citrullinemia type 1 (CTLN1; Zielonka, Kolker et al, 2019). To analyze whether this approach might also be of predictive value for the heterogeneous clinical phenotype in individuals with ASA and to quantitatively determine the effect of the various pathogenic variant combinations, we applied the mammalian biallelic expression system to ASA for the functional investigation of exonic variants and correlated enzymatic ASL activity with individuals’ biochemical, clinical, and neurological follow‐up data, retrieved from the two largest observational natural history studies worldwide, that is, the North American Urea Cycle Disorders Consortium (UCDC; https://www.rarediseasesnetwork.org/cms/ucdc) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD; https://www.eimd-registry.org/).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria

et al. 2020

Self Cite

View full text Add to dashboard Cite

Human Mutation. 2020;41:946-960. wileyonlinelibrary.com/journal/humu 946 | Abstract Argininosuccinic aciduria (ASA) is an inherited urea cycle disorder and has a highly variable phenotypic spectrum ranging from individuals with lethal hyperammonemic encephalopathy, liver dysfunction, and cognitive deterioration, to individuals with a mild disease course. As it is difficult to predict the phenotypic severity, we aimed at identifying a reliable disease prediction model. We applied a biallelic expression system to assess the functional impact of pathogenic argininosuccinate lyase (ASL) variants and to determine the enzymatic activity of ASL in 58 individuals with ASA.This cohort represented 42 ASL gene variants and 42 combinations in total.Enzymatic ASL activity was compared with biochemical and clinical endpoints from the UCDC and E-IMD databases. Enzymatic ASL activity correlated with peak plasma ammonium concentration at initial presentation and with the number of hyperammonemic events (HAEs) per year of observation. Individuals with ≤9% of enzymatic activity had more severe initial decompensations and a higher annual frequency of HAEs than individuals above this threshold. Enzymatic ASL activity also correlated with the cognitive outcome and the severity of the liver disease, enabling a reliable severity prediction for individuals with ASA. Thus, enzymatic activity measured by this novel expression system can serve as an important marker of phenotypic severity.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Statistical analyses were performed as previously described (Zielonka, Kolker et al, 2019). All analyses were performed using R (http://www.r-project.org).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency

Scharre

Posset

Garbade

et al. 2022

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

Objective: Ornithine transcarbamylase deficiency (OTC-D) is an X-linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity-adjusted classification system based on in vitro residual enzymatic OTC activity. Methods: Applying a cell-based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC-D (mOTC-D) as reported in the UCDC and E-IMD registries. Results: Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC-D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. Interpretation: Residual enzymatic OTC activity reliably predicts the disease severity in mOTC-D and could thus serve as a tool for severity-adjusted evaluation of therapeutic strategies and counselling patients and parents.

show abstract

Clinical findings of patients with hyperammonemia affected by urea cycle disorders with hepatic encephalopathy

Lopes

Sitta

Coelho

et al. 2022

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

Urea cycle disorders (UCD) are a group of genetic diseases caused by deficiencies in the enzymes and transporters involved in the urea cycle. The impairment of the cycle results in ammonia accumulation, leading to neurological dysfunctions and poor outcomes to affected patients. The aim of this study is to investigate and describe UCD patients' principal clinical and biochemical presentations to support professionals on urgent diagnosis and quick management, aiming better outcomes for patients. We explored medical records of 30 patients diagnosed in a referral center from Brazil to delineate UCD clinical and biochemical profile. Patients demonstrated a range of signs and symptoms, such as altered levels of consciousness, acute encephalopathy, seizures, progressive loss of appetite, vomiting, coma, and respiratory distress, in most cases combined with high levels of ammonia, which is an immediate biomarker, leading to a UCD suspicion. The most prevalent UCD detected were ornithine transcarbamylase deficiency, followed by citrullinemia type 1, hyperargininemia, carbamoyl phosphate synthase 1 deficiency, and argininosuccinic aciduria. Clinical symptoms were highly severe, being the majority developmental and neurological disabilities, with 20% of death rate. Laboratory analysis revealed high levels of ammonia (mean AE SD: 860 AE 470 μmol/L; reference value: ≤80 μmol/L), hypoglycemia, metabolic acidosis, and high excretion of orotic acid in the urine (except in carbamoyl phosphate synthetase 1 [CPS1] deficiency). We emphasize the need of urgent identification of UCD clinical and biochemical conditions, and immediate measurement of ammonia, to

show abstract

Early prediction of phenotypic severity in Citrullinemia Type 1

Cited by 33 publications

References 33 publications

From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria

From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria

Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency

Clinical findings of patients with hyperammonemia affected by urea cycle disorders with hepatic encephalopathy

Contact Info

Product

Resources

About