Arginase deficiency in Bulgaria: first cases and potential endemic region for the disorder.

Arginase deficiency is an autosomal recessive urea cycle disorder caused by pathogenic variants in the ARG1 gene. The clinical features of the disease include spasticity, tremour, ataxia, hypotonia, microcephaly and seizures. Growth delay can also be observed in the affected individuals. Here we describe the results from molecular-genetic analysis of two patients with arginase deficiency. In the first case, we reported a novel homozygous missense variant c.775G>A p.(Gly259Ser) in a patient with Bulgarian ethnic origin. In the second case, a novel homozygous splice site variant c.329+1G>A was detected in a patient from a consanguineous family of Roma ethnic origin. A hundred samples of newborns of Roma origin were screened for variant c.329+1G>A and one individual was found to be a heterozygous carrier of variant c.329+1G> A. The results from this study indicated the necessity for screening of the Roma population with respect to the disease arginase deficiency in Bulgaria.

Epidemiology, methods of diagnosis, and clinical management of patients with arginase 1 deficiency (ARG1-D): A systematic review.

BACKGROUND: Arginase 1 Deficiency (ARG1-D) is a rare, progressive, metabolic disorder that is characterized by devastating manifestations driven by elevated plasma arginine levels. It typically presents in early childhood with spasticity (predominately affecting the lower limbs), mobility impairment, seizures, developmental delay, and intellectual disability. This systematic review aims to identify and describe the published evidence outlining the epidemiology, diagnosis methods, measures of disease progression, clinical management, and outcomes for ARG1-D patients. METHODS: A comprehensive literature search across multiple databases such as MEDLINE, Embase, and a review of clinical studies in ClinicalTrials.gov (with results reported) was carried out per PRISMA guidelines on 20 April 2020 with no date restriction. Pre-defined eligibility criteria were used to identify studies with data specific to patients with ARG1-D. Two independent reviewers screened records and extracted data from included studies. Quality was assessed using the modified Newcastle-Ottawa Scale for non-comparative studies. RESULTS: Overall, 55 records reporting 40 completed studies and 3 ongoing studies were included. Ten studies reported the prevalence of ARG1-D in the general population, with a median of 1 in 1,000,000. Frequently reported diagnostic methods included genetic testing, plasma arginine levels, and red blood cell arginase activity. However, routine newborn screening is not universally available, and lack of disease awareness may prevent early diagnosis or lead to misdiagnosis, as the disease has overlapping symptomology with other diseases, such as cerebral palsy. Common manifestations reported at time of diagnosis and assessed for disease progression included spasticity (predominately affecting the lower limbs), mobility impairment, developmental delay, intellectual disability, and seizures. Severe dietary protein restriction, essential amino acid supplementation, and nitrogen scavenger administration were the most commonly reported treatments among patients with ARG1-D. Only a few studies reported meaningful clinical outcomes of these interventions on intellectual disability, motor function and adaptive behavior assessment, hospitalization, or death. The overall quality of included studies was assessed as good according to the Newcastle-Ottawa Scale. CONCLUSIONS: Although ARG1-D is a rare disease, published evidence demonstrates a high burden of disease for patients. The current standard of care is ineffective at preventing disease progression. There remains a clear need for new treatment options as well as improved access to diagnostics and disease awareness to detect and initiate treatment before the onset of clinical manifestations to potentially enable more normal development, improve symptomatology, or prevent disease progression.

Arginase 1 Deficiency: using genetic databases as a tool to establish global prevalence.

BACKGROUND/OBJECTIVE: Arginase 1 Deficiency (ARG1-D) is a rare inherited metabolic disease with progressive, devastating neurological manifestations with early mortality and high unmet need. Information on prevalence is scarce and highly variable due to limited newborn screening (NBS) availability, variability of arginine levels in the first days of life, and high rates of misdiagnosis. US birth prevalence was recently estimated via indirect methods at 1.1 cases per million live births. Due to the autosomal recessive nature of ARG1-D we hypothesize that the global prevalence may be more accurately estimated using genetic population databases. METHODS: MEDLINE and EMBASE were systematically searched for previously reported disease variants. Disease variants in ARG1-D were annotated wherever possible with allele frequencies from gnomAD. Ethnicity-specific prevalence was calculated using the Hardy-Weinberg equation and applied to generate country-specific carrier frequencies for 38 countries. Finally, documented consanguinity rates were applied to establish a birth prevalence for each country. RESULTS: 133 of 228 (58%) known causative alleles were annotated with ethnic-specific frequencies. Global birth prevalence for ARG1-D was estimated at 2.8 cases per million live births (country-specific estimates ranged from 0.92 to 17.5) and population prevalence to be 1.4 cases per million people (approximately 1/726,000 people). Birth prevalence estimates were dependent on population demographics and consanguinity rate. CONCLUSION: Birth prevalence of ARG1-D based on genetic database analysis was estimated to be more frequent than previous NBS studies have indicated. There was a higher degree of confidence in North American and European countries due to availability of genetic databases and mutational analysis versus other regions. These findings suggest the need for greater disease education around signs and manifestations of ARG1-D, as well as more widespread testing and standardization of screening for this severe disease in order to appropriately identify patients prior to disease progression.

Newborn screening for hyperargininemia due to arginase 1 deficiency.

Hyperargininemia caused by Arginase 1 deficiency is a rare disorder of the urea cycle that can be diagnosed by elevation of arginine in newborn screening blood spots when analyzed by tandem mass spectrometry. Hyperargininemia is currently included as a secondary target on the U.S. Recommended Uniform Screening Panel, which directly influences state-based newborn screening. Because of the apparent low disease frequency and lack of case detection and treatment data, detailed attention has not been given to a model newborn screening algorithm including appropriate analytical cutoff values for disease indicators. In this paper we assess the frequency of hyperargininemia in the U.S. identified by newborn screening to date and document the current status and variability of hyperargininemia newborn screening across U.S. newborn screening programs. We also review other data that support improved screening efficacy by utilizing the arginine/ornithine ratio and other amino acid ratios as discriminators in the screening algorithm. Analysis of archived California screening data showed that an arginine cutoff of 50µM combined with an arginine/ornithine ratio of 1.4 would have resulted in a recall rate of 0.01%. Using an arginine cutoff of 60µM and an arginine/(phenylalanine x leucine) ratio of 1.4, reportedly used in one screening program, or the R4S Tool Runner, would have resulted in a recall rate of <0.005%. All 9 diagnosed patients would have been found for either protocol. Thus, use of appropriate ratios as part of the screening algorithm has the potential to increase both screening sensitivity and specificity. Improved newborn screening effectiveness should lead to better case detection and more rapid treatment to lower plasma arginine levels hence improving long term outcome of individuals with hyperargininemia.

Hereditary urea cycle diseases in Finland.

AIM: To estimate the incidence of urea cycle diseases (UCDs) in Finland and determine the course of the various disorders as well as the outcome. METHODS: The original data were collected in the years 1998-2001. The diagnoses made after 2001, as well as the current status of the patients, were updated by surveys in the spring of 2007. RESULTS: We found a total of 55 cases of UCDs in Finland by 2007: 30 cases of ornithine transcarbamylase (OTC) deficiency, 20 of argininosuccinate lyase (ASL) deficiency, 3 of carbamyl phosphate synthetase (CPS-I) deficiency, 1 of type 1 citrullinaemia and 1 of argininaemia. The estimated total incidence of UCDs was 1:39 000. The incidences of individual disorders were: OTC deficiency 1:62 000, ASL deficiency 1:144 000, CPS deficiency 1:539 000 and citrullinaemia 1:1 616 000. Eighteen (33%) of the patients with a diagnosis of UCD have died, most during their first hyperammonaemic crisis. One patient with OTC deficiency has had a liver transplant. Neurological symptoms of varying severity are common among these patients, particularly those with ASL deficiency. CONCLUSION: The first survey on the incidence of UCDs in Finland shows some differences in the occurrence rates compared to other countries. Hyperammonaemia, and the neurological symptoms caused by it, can be avoided in most patients with late-onset UCDs with a standard treatment. However, in patients with ASL deficiency, the development of neurological symptoms seems to be inevitable in spite of careful treatment and avoidance of hyperammonaemia.