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.

Health care resource utilization in the management of patients with Arginase 1 Deficiency in the US: a retrospective, observational, claims database study.

BACKGROUND: Arginase 1 Deficiency (ARG1-D) is an inherited metabolic disease that leads to significant morbidity. AIMS: Despite the recognized burden of disease, information on health care resource utilization (HCRU) among patients with ARG1-D is lacking. We, therefore, sought to evaluate HCRU in ARG1-D relative to non-ARG1-D cohort. MATERIALS AND METHODS: Patients with ≥2 ICD-10-CM diagnosis codes for ARG1-D were identified (first diagnosis code = index date) using professional fee claims linked with prescription claims. Patients with ARG1-D were matched 1:1 to a comparator cohort of patients with other medical conditions. Matching variables included age, sex, index year, payer type (Medicare, Medicaid, third party) and geographic region. RESULTS: A total of 77 patients met the inclusion criteria for the ARG1-D cohort, with a median age of 15 years, 52% <18 years, and 52% male. Several concurrent diagnoses were recorded at a higher frequency in the ARG1-D cohort versus the matched comparator (spasticity 7 times higher; developmental delay ∼2 times higher; intellectual disability 5 times higher; and seizures 8 times higher). Emergency room visits occurred twice as often, laboratory tests were performed 1.5 times more often, hospitalization was required 3 times more often, and mean length of stay was longer for patients with ARG1-D than the comparator cohort (2.4 days vs. 0.3 days). LIMITATIONS: A relatively short study period while the burden of ARG1-D increases over a lifetime due to disease progression. CONCLUSIONS: Patients with ARG1-D had significantly greater HCRU compared with those without the disease; they presented with a more extensive comorbidity profile, accessed the health care system more frequently, required more intense monitoring and management, and had more frequent and longer hospitalizations relative to the comparator group. These findings demonstrate a high health burden in ARG1-D that is not mitigated by standard-of-care measures and emphasize the need for improved treatment options.

The effect of liver transplantation for argininemia-the largest experiences in a single center.

Background: Argininemia, a rare urea cycle disorder resulting from an arginase-1 deficiency, is characterized by a progressive spastic paraplegia. While advances in diagnosis and treatment have increased the management of this condition, not all symptoms are resolved in response to traditional therapies. Interestingly, there exist some rare reports on the use of liver transplantation (LT) for the treatment of argininemia. Methods: We conducted a retrospective study of eleven patients with argininemia receiving a LT as performed at our center over the period from January 2015 to November 2019. These patients were included due to their poor responses to protein restriction diets and alternative therapies of nitrogen scavengers. Detailed information on coagulation, liver function, histopathological and morphological examination of liver samples, and other clinical presentations were extracted from these patients. A grading scale was used for evaluating the neurological status, classification of physical growth and quality of life of these patients in response to the LT. Results: Prior to LT, high levels of arginine were detected in all of argininemia patients and liver enzymes were elevated in nine of those patients. Nine patients presented with coagulation dysfunction without bleeding symptoms. Spastic paraplegia, irritability, intellectual developmental disability, and growth deficits were hallmarks of these nine patients, while four patients showed repeated, generalized tonic-clonic seizures before the operation. Seven novel mutations were found in these patients. The indication for LT in this series of patients was a presentation of progressive neurological impairments. After LT, the coagulation index and plasma arginine levels returned to normal and episodes of seizure were controlled in four patients. To date, all patients have survived and their LT has resulted a restoration of arginine metabolism and liver function, along with preventing further neurological deterioration, all of which provided an opportunity for future recuperation. Overall, the neurological status, growth deficits and quality of life were all significantly improved after LT with no evidence of severe complications. Conclusions: LT can serve as an effective treatment for argininemia in patients who respond poorly to traditional therapy. An early intervention of LT should be conducted in these patients to prevent neurological damage and improve their quality of life.

Phenotypic Pleiotropy in Arginase Deficiency: A Single Center Cohort.

Background: Arginase deficiency is considered a masquerader of diplegic cerebral palsy. The rarity of hyperammonemic crisis and the slowly progressive course has made it a unique entity among the urea cycle defects. Objectives: The aim of our study is to describe the varied phenotypic spectrum of children with arginase deficiency. Methodology: This retrospective study included children and adolescents aged <18 years with a biochemical or genetic diagnosis of arginase deficiency from May 2011 to May 2022. Data were collected from the hospital's electronic database. The clinical presentation, laboratory parameters at baseline and during metabolic decompensation, neuroimaging, electroencephalography findings, and molecular studies were analyzed. Results: About 11 children from nine families with biochemically or genetically proven arginase deficiency were analyzed. The male: female ratio was 2.7:1. Consanguineous parentage was observed in all children. The median age at presentation was 36 months (Range: 5 months-18 years). All children with onset of symptoms in early childhood had a predominant delay in motor milestones of varying severity. Metabolic decompensation with encephalopathy occurred in all except two children (n = 9, 81.8%). Pyramidal signs were present in all patients and additional extrapyramidal signs in two children. Positive family history was present in four probands. Seizures occurred in all children. Epilepsy with electrical status in slow wave sleep and West syndrome was noted in three children. All children had elevated ammonia and arginine at the time of metabolic crisis. The spectrum of neuroimaging findings includes periventricular, subcortical, and deep white matter signal changes and diffusion restriction. The mean duration of follow-up was 38.6 ± 34.08 months. All patients were managed with an arginine-restricted diet and sodium benzoate with or without ornithine supplementation. Conclusion: Spastic diparesis, recurrent encephalopathy, presence of family history, and elevated serum arginine levels must alert the clinician to suspect arginase deficiency. Atypical presentations in our cohort include frequent metabolic crises and epileptic encephalopathy. Early identification and management will ensure a better neurodevelopmental outcome.

Progress in the diagnosis, treatment and pathogenesis of argininemia / 中华实用儿科临床杂志

Argininemia is a rare autosomal recessive inherited disease, characterized by complex and diverse clinical symptoms.Its pathogenesis remains unclarified.The oligodendrocytes and neuro injury caused by energy meta-bolism disorders may account for neurosystem damage.The basic treatment methods for argininemia are the low-protein diet and nitrogen scavenger, which, however, cannot effectively prevent the progress of the neurological damage.Enzyme replacement or gene therapy is an ideal regimen for argininemia.However, gene editing therapy has not been applied in clinical practice.Liver transplantation (LT) is currently a practical option for argininemia treatment.Although LT cannot repair genetic defects in patients, but it can supplement arginase I, normalize plasma arginine and its metabolites, prevent progressive damage, relieve neurological symptoms, and improve the patients quality of life.For the low incidence of argininemia, it is not fully understood.In this paper, the clinical characteristics, pathogenesis, diagnosis, and treatment of argininemia were reviewed, in order to further more people′s understanding of this disease.

Neurophysiological characteristics in argininemia: a case report.

Argininemia is a rare inherited disorder characterized by progressive spastic paraplegia, leading by mutation of the ARG1 gene. Liver transplantation (LT) had been reported to prevent symptoms progression, while its pathophysiology is still unclear. A 13-year-old male patient with argininemia for progressive neurological impairment was admitted to our center. Plasma amino acid screening showed a high concentration of arginine, and gene sequencing showed heterozygous mutation of the ARG1 gene. Spastic Paraplegia Rating Scale (SPRS), motor evoked potentials (MEPs), somatosensory evoked potentials (SEPs), F-wave, electromyography, nerve conduction velocity (NCV), and brain MRI were used to evaluate the patient. Herein, we describe the clinical characteristics of this patient, attempting a correlation between clinical, neurophysiological, and neuroimaging data in argininemia. Pyramidal tract dysfunction of lower limbs affected him, while only MEPs showed abnormalities among all neurophysiological evaluations, and mild cerebellum atrophy was observed. He responded poorly to traditional treatment such as a protein restriction diet and sodium benzoate. The symptoms of speech disorder, irritability, and dyskinesia were gradually deteriorating, so living-donor LT (LDLT) was done to prevent the progression. The symptoms improved significantly six months after LT, and the spasticity severity score decreased 50%. The findings suggest that LDLT is effective to argininemia, and the phenotypical similarities to other disorders that affect the urea cycle (HHH syndrome and pyrroline-5-carboxylate synthetase deficiency) suggest a common mechanism may contribute to maintaining the integrity of the corticospinal tract.

Neurological Deterioration in Three Siblings: Exploring the Spectrum of Argininemia.

Argininemia or hyperargininemia is a urea cycle disorder caused by deficiency of the enzyme arginase 1. It is inherited in an autosomal recessive fashion. It commonly leads to spastic diplegia in childhood, but other important features include cognitive deterioration and epilepsy. Unlike other disorders of the urea cycle, hyperammonemia is not prominent. The authors report three siblings with genetically proven argininemia who presented with diverse phenotypes but with spasticity being a common feature. Sibling 1 developed motor regression in early childhood, sibling 2 developed delayed motor milestones from early infancy, whereas sibling 3 had global developmental delay in late infancy after a period of normal development. All siblings had mild hyperammonemia only. Early recognition is imperative, not only to initiate ammonia scavenging therapy which may lead to definite clinical improvement, but also to provide genetic counselling.

Development of a Protein Scaffold for Arginine Sensing Generated through the Dissection of the Arginine-Binding Protein from Thermotoga maritima.

Arginine is one of the most important nutrients of living organisms as it plays a major role in important biological pathways. However, the accumulation of arginine as consequence of metabolic defects causes hyperargininemia, an autosomal recessive disorder. Therefore, the efficient detection of the arginine is a field of relevant biomedical/biotechnological interest. Here, we developed protein variants suitable for arginine sensing by mutating and dissecting the multimeric and multidomain structure of Thermotoga maritima arginine-binding protein (TmArgBP). Indeed, previous studies have shown that TmArgBP domain-swapped structure can be manipulated to generate simplified monomeric and single domain scaffolds. On both these stable scaffolds, to measure tryptophan fluorescence variations associated with the arginine binding, a Phe residue of the ligand binding pocket was mutated to Trp. Upon arginine binding, both mutants displayed a clear variation of the Trp fluorescence. Notably, the single domain scaffold variant exhibited a good affinity (~3 µM) for the ligand. Moreover, the arginine binding to this variant could be easily reverted under very mild conditions. Atomic-level data on the recognition process between the scaffold and the arginine were obtained through the determination of the crystal structure of the adduct. Collectively, present data indicate that TmArgBP scaffolds represent promising candidates for developing arginine biosensors.

Analysis of AGR1 gene variants in an infant with early-onset argininemia / 中华医学遗传学杂志

Objective@#To explore the genetic basis for an infant with early-onset argininemia.@*Methods@#Potential variant was detected with an Ion Torrent semiconductor sequencer using a gene panel for inherited diseases. Suspected variants were verified by Sanger sequencing.@*Results@#Genetic testing indicated that he has carried c. 560+ 2T>C and c. 811T>C compound heterozygous variant of the AGR1 gene, which were inherited from his father and mother, respectively. Among these, c. 560+ 2T>C was suspected to be pathogenic, while c. 811T>C was of unknown clinical significance, and both were not reported previously.@*Conclusion@#The c. 560+ 2T>C and c. 811T>C compound heterozygous variants of the AGR1 gene probably underlies the argininemia in this child. Above finding has enriched the variant spectrum of the AGR1 gene.

Coagulation Disturbances in Patients with Argininemia.

BACKGROUND: Argininemia is an autosomal recessive urea cycle disorder (UCD). Unlike other UCD, hyperammonemia is rarely seen. Patients usually present in childhood with neurological symptoms. Uncommon presentations like neonatal cholestasis or cirrhosis have been reported. Although transient elevations of liver transaminases and coagulopathy have been reported during hyperammonemia episodes, a permanent coagulopathy has never been reported. METHODS: In this retrospective study, coagulation disturbances are examined in 6 argininemia patients. All of the patients were routinely followed up for hepatic involvement due to argininemia. Laboratory results, including liver transaminases, albumin, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and clotting factor levels, were assessed in all of the patients. RESULTS: All of the patients had a prolonged PT and an increased INR, while none of the patients had a prolonged aPTT. Five patients had slightly elevated liver transaminases. A liver biopsy was performed in 1 patient but neither cirrhosis nor cholestasis was documented. Five of the 6 patients had low factor VII and factor IX levels, while other clotting factors were normal. CONCLUSIONS: Argininemia patients should be investigated for coagulation disorders even if there is no apparent liver dysfunction or major bleeding symptoms.

Domain swapping dissection in Thermotoga maritima arginine binding protein: How structural flexibility may compensate destabilization.

Thermotoga maritima Arginine Binding Protein (TmArgBP) is a valuable candidate for arginine biosensing in diagnostics. This protein is endowed with unusual structural properties that include an extraordinary thermal/chemical stability, a domain swapped structure that undergoes large tertiary and quaternary structural transition, and the ability to form non-canonical oligomeric species. As the intrinsic stability of TmArgBP allows for extensive protein manipulations, we here dissected its structure in two parts: its main body deprived of the swapping fragment (TmArgBP20-233) and the C-terminal peptide corresponding to the helical swapping element. Both elements have been characterized independently or in combination using a repertoire of biophysical/structural techniques. Present investigations clearly indicate that TmArgBP20-233 represents a better scaffold for arginine sensing compared to the wild-type protein. Moreover, our data demonstrate that the ligand-free and the ligand-bound forms respond very differently to this helix deletion. This drastic perturbation has an important impact on the ligand-bound form of TmArgBP20-233 stability whereas it barely affects its ligand-free state. The crystallographic structures of these forms provide a rationale to this puzzling observation. Indeed, the arginine-bound state is very rigid and virtually unchanged upon protein truncation. On the other hand, the flexible ligand-free TmArgBP20-233 is able to adopt a novel state as a consequence of the helix deletion. Therefore, the flexibility of the ligand-free form endows this state with a remarkable robustness upon severe perturbations. In this scenario, TmArgBP dissection highlights an intriguing connection between destabilizing/stabilizing effects and the overall flexibility that could operate also in other proteins.

Mutations and common variants in the human arginase 1 (ARG1) gene: Impact on patients, diagnostics, and protein structure considerations.

The urea cycle disorder argininemia is caused by a defective arginase 1 (ARG1) enzyme resulting from mutations in the ARG1 gene. Patients generally develop hyperargininemia, spastic paraparesis, progressive neurological and intellectual impairment, and persistent growth retardation. Interestingly, in contrast to other urea cycle disorders, hyperammonemia is rare. We report here 66 mutations (12 of which are novel), including 30 missense mutations, seven nonsense, 10 splicing, 15 deletions, two duplications, one small insertion, and one translation initiation codon mutation. For the most common mutations (p.Thr134Ile, p.Gly235Arg and p.Arg21*), which cluster geographically in Brazil, China, or Turkey, a structural rationalization of their effect has been included. In order to gain more knowledge on the disease, we have collected clinical and biochemical information of 112 patients, including the patients' genetic background and ethnic origin. We have listed as well the missense variants with unknown relevance. For all missense variants (of both known and unknown relevance), the conservation, severity prediction, and ExAc scores have been included. Lastly, we review ARG1 regulation, animal models, diagnostic strategies, newborn screening, prenatal testing, and treatment options.

Three novel mutations of ARG1 identified in Chinese patients with argininemia detected by newborn screening.

Argininemia is a rare autosomal recessive genetic disorder caused by deficiency of arginase Ι, resulting from mutations in the ARG1 gene. Few genetic studies of ARG1 mutations in Chinese patients have been reported. In this study, two argininemia patients were initially diagnosed by tandem mass spectrometry in newborn screening. Mutation analysis of the ARG1 gene was performed by direct sequencing. Three novel mutations were identified and in silico methods were used to predict the impact of these mutations on the activity of enzyme. Two missense mutations, p.D100N and p.R71T, in Patient-1 were predicted to lower the stability of arginase Ι by analysis of 3D crystal structure, while two nonsense mutations, p.G12X and p.E42X, in Patient-2 were predicted to lead to truncated protein. Neonatal screening combined with genetic analysis is important for timely diagnosis and initiation of interventions of a potential genetic metabolic disease such as argininemia.

Argininemia as a cause of severe chronic stunting in a low-resource developing country setting: a case report.

BACKGROUND: Argininemia is rare inborn error of metabolism which, when untreated, presents in late infancy with growth delay and developmental regression. In developed countries, argininemia is diagnosed early by newborn screening and is treated immediately with a protein-restricted diet. In developing countries, diagnosis may be delayed by the assumption that stunting is related to malnutrition alone. CASE PRESENTATION: We describe the diagnosis and treatment of argininemia in a 60-month-old Kaqchikel Maya girl in rural Guatemala. The patient initially presented with severe stunting and developmental regression. The initial diagnosis of argininemia was made by a screening test in dried blood spots and confirmed with urine and serum amino acid profiles. The patient was treated with a low-protein diet using locally available foods, leading to significant improvement in her growth and development. CONCLUSIONS: This case demonstrates that the identification, diagnosis and treatment of IEM in developing countries are increasingly feasible, as well as ethically imperative. Providers working with malnourished children in developing countries should suspect IEM in malnourished children who do not respond to standard therapies.

The pathogenesis,clinical manifestation and treatment of argininemia / 国际儿科学杂志

Argininemia(OMIM 207 800) is an autosomal recessive inherited metabolic disease of urea cycle disorders caused by deficiency of arginase I.Arginase I(AI) is the enzyme involved in the final step of the urea cycle which catalyzes the hydrolysis of arginine to ornithine and urea.The patients untreated will undergo the slowly progressive course and spastic tetraplegia,seizures and mental retardation.Unlike other urea cycle disorders,Argininemia is not generally associated with severe hyperammonemia.It is unlikely that elevated plasma ammonia is the main neurotoxic compound in argininemia because hyperammonemia rarely occurs in this condition.These neurological complications could result from the accumulation of arginine and its metabolites.argininemia can be diagnosed by ARG gene analysis or arginase acivity assay.Early diagnosis of argininemia through newborn screening program by tandem mass spectrometry may lead to a better outcome.