Early prediction of phenotypic severity in Citrullinemia Type 1

Matthias Zielonka,Stefan Kölker,Florian Gleich,Sven F Garbade,Sandesh C S Nagamani,Andrea L Gropman,Nicolas Stützenberger,Roland Posset,Georg F Hoffmann

doi:10.1002/acn3.50886

Abstract

ObjectiveCitrullinemia 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.MethodsWe 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.ResultsResidual 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.InterpretationResidual 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.

Highlights

Citrullinemia type 1 (CTLN1) is an autosomal recessive urea cycle disorder caused by deficiency of the cytosolic enzyme argininosuccinate synthetase 1 (ASS1-D; MIM #215700) due to pathogenic variants in the ASS1 gene located on chromosome 9q34.11
Individuals with CTLN1 confirmed by biallelic pathogenic variants in ASS1 who were enrolled in the observational longitudinal studies Urea Cycle Disorders Consortium (UCDC) (NCT00237315) and E-IMD were included in this analysis
Residual enzymatic ASS1 activity as determined in the biallelic expression system corresponded well with the enzymatic activity measured in patient fibroblasts and reported in the UCDC and E-IMD databases (Table S3)

Summary

Introduction

Citrullinemia type 1 (CTLN1) is an autosomal recessive urea cycle disorder caused by deficiency of the cytosolic enzyme argininosuccinate synthetase 1 (ASS1-D; MIM #215700) due to pathogenic variants in the ASS1 gene located on chromosome 9q34.11. Large observational natural history studies of UCDs in North America [Urea Cycle Disorders Consortium (UCDC; https://www.rarediseasesnetwork.org/cms/ucdc)] and Europe [European registry and network for intoxication type metabolic disease (E-IMD; https:// www.eimd-registry.org/)] have identified clinical variables, such as early disease onset, or biochemical variables, such as high initial peak plasma ammonium concentration (NH4+max), to be correlated with poor long-term outcome.[7,8,9,10] phenotypic severity has not been predictable early during the disease course so far. Given that residual enzymatic activities have already been reported to predict disease severity and survival rates in other inborn errors of metabolism, such as Farber disease and mucopolysaccharidosis type IIIA and VII,[12,13,14] we hypothesized that ASS1 enzyme activity may correlate with disease severity in CTLN1

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Conclusion