German Clinical Trials Register

Acronym/abbreviation of the study

EPArg

URL of the study

No Entry

Brief summary in lay language

Arginase deficiency is a rare, inherited metabolic disorder and is one of the so-called urea cycle defects. Children with arginase deficiency typically develop progressive spastic paralysis in late infancy. Spasticity is an increase in muscle tension that leads to permanent cramping of the muscles. Developmental disorders or seizures can also occur. It is estimated that one in 950,000 newborns is affected (prevalence). However, the symptoms described above overlap with other diseases (especially with so-called "infantile cerebral palsy"), which is why we assume that arginase deficiency is sometimes not recognised. As part of the planned study, the prevalence of confirmed arginase deficiency in children and adolescents up to the age of 18 is to be determined using the survey system "Survey of rare neurological diseases in childhood" (ESNEK) via a survey of all children's clinics, social pediatric centers (SPZ) and registered neuropaediatricians in Germany, Austria and Switzerland (D-A-CH region). In addition, patients in this age group with unexplained typical symptoms of arginase deficiency are to be offered a free diagnostic service (examination of a test card with dried blood spots) via the doctors treating them. Doctors can report the number of affected patients to the ESNEK center. For patients with already confirmed arginase deficiency, the treating physicians complete an anonymised questionnaire (without prior informed consent). Patients with unexplained symptoms that indicate an arginase deficiency are offered the opportunity to test for the disease using a test card with dried blood spots. After informed consent of patients, the treating physicians are asked to complete the questionnaire once and send in the test card with dried blood spots. They are then informed of the result of the analysis and, if the result is positive, receive recommendations for confirmatory diagnostics and treatment initiation. No study visits or additional physical examinations will take place as part of the study. The data collected will be used to determine the actual prevalence and describe the clinical picture of arginase deficiency in more detail. This additional knowledge should make it possible to recognize and treat the disease earlier in the future.

Brief summary in scientific language

Arginase deficiency (ARG1-D, argininemia) is a very rare, autosomal recessive inherited urea cycle disorder, which is also classified as a hereditary spastic paraplegia due to its clinical presentation. The disease is caused by pathogenic variants in the ARG1 gene (locus: 6q23.2), which result in a deficiency of arginase 1 and the associated inadequate degradation of arginine to ornithine and urea. In contrast to other urea cycle disorders, hyperammonemic derailments rarely occur or are completely absent in arginase deficiency. Affected children characteristically develop progressive spastic paraplegia in the first two years of life. They are often accompanied by cognitive developmental disorders and epilepsy. Failure to thrive or hepatopathy have also been described (Schlune et al. 2015, Amino Acids. 47(9):1751-62). An isolated elevated arginine level in plasma, which can be detected by tandem mass spectrometry on dried blood spots, is of diagnostic value. This method is already occasionally used in newborn screening (NGS) programs or as part of NGS pilot projects. In Germany, Austria and Switzerland, however, arginase deficiency is not yet part of regular newborn screening. Since 2016, screening for arginase deficiency has been offered in Heidelberg as part of the pilot study "Evaluation of an extension of newborn screening to include 28 additional target diseases" (S-533/2015). Molecular genetic testing is recommended to confirm the disease after positive screening. Standard therapy consisting of a low-protein diet and drug treatment with so-called nitrogen scavengers (sodium benzoate, sodium phenylbutyrate and glycerol phenylbutyrate) biochemically aims to permanently reduce arginine concentrations and ammonia levels, but is not able to reliably halt the development of progressive spastic paraplegia. Studies evaluating the effects of therapy on the long-term course are rare (Schlune et al. 2015, Amino Acids. 47(9):1751-62). Liver transplantation can be considered as a curative option in individual cases. Since December 15, 2023, the enzyme replacement therapy Loargys® (pegzilarginase, Immedica Pharma AB) has been approved as the first disease-modifying therapy for arginase deficiency from the age of two. In Germany, Austria and Switzerland (D-A-CH region), the estimated prevalence is around 1:1,150,000 live births (Catsburg et al. 2022, Orphanet J Rare Dis. 17(1):94). Due to the clinically variable phenotype, a lack of comprehensive NGS and low awareness of this rare disease, underdiagnosis or misdiagnosis (DD "infantile cerebral palsy") can be assumed (Catsburg et al. 2022, Orphanet J Rare Dis. 17(1):94; McNutt et al. 2022, Mov Disord Clin Pract. 10(1):109-114). The absence of the severe hyperammonemic metabolic derailments characteristic of other urea cycle defects further delays the establishment of a suspected diagnosis and the initiation of targeted diagnostics and therapy. The aim of the study is to determine the prevalence of arginase deficiency in children and adolescents in Germany, Austria and Switzerland and to precisely describe the phenotypic spectrum of this rare disease. In the cohort of children with aetiologically unexplained, progressive spastic syndrome, the early diagnosis of children and adolescents with arginase deficiency should also be made possible. The findings from this study should help to promote awareness of this rare disease and enable early diagnosis and initiation of treatment.