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Journal of Inherited Metabolic Disease Jan 2023Arginase 1 Deficiency (ARG1-D) is a rare urea cycle disorder that results in persistent hyperargininemia and a distinct, progressive neurologic phenotype involving... (Review)
Review
Arginase 1 Deficiency (ARG1-D) is a rare urea cycle disorder that results in persistent hyperargininemia and a distinct, progressive neurologic phenotype involving developmental delay, intellectual disability, and spasticity, predominantly affecting the lower limbs and leading to mobility impairment. Unlike the typical presentation of other urea cycle disorders, individuals with ARG1-D usually appear healthy at birth and hyperammonemia is comparatively less severe and less common. Clinical manifestations typically begin to develop in early childhood in association with high plasma arginine levels, with hyperargininemia (and not hyperammonemia) considered to be the primary driver of disease sequelae. Nearly five decades of clinical experience with ARG1-D and empirical studies in genetically manipulated models have generated a large body of evidence that, when considered in aggregate, implicates arginine directly in disease pathophysiology. Severe dietary protein restriction to minimize arginine intake and diversion of ammonia from the urea cycle are the mainstay of care. Although this approach does reduce plasma arginine and improve patients' cognitive and motor/mobility manifestations, it is inadequate to achieve and maintain sufficiently low arginine levels and prevent progression in the long term. This review presents a comprehensive discussion of the clinical and scientific literature, the effects and limitations of the current standard of care, and the authors' perspectives regarding the past, current, and future management of ARG1-D.
Topics: Child, Preschool; Humans; Hyperargininemia; Arginase; Arginine; Urea Cycle Disorders, Inborn; Hyperammonemia
PubMed: 36175366
DOI: 10.1002/jimd.12564 -
European Journal of Case Reports in... 2024Hyperargininemia is a rare inherited metabolic disorder of the urea cycle with an autosomal recessive transmission. It occurs due to a deficiency of the enzyme arginase...
BACKGROUND
Hyperargininemia is a rare inherited metabolic disorder of the urea cycle with an autosomal recessive transmission. It occurs due to a deficiency of the enzyme arginase I and causes progressive neurological damage. Very few cases are diagnosed in adulthood, with the majority being diagnosed before the age of 4. Currently, this condition is diagnosed by a mass spectrometry technique in neonatal screening, which has been implemented in Portugal since 2007; births before that were not screened for this entity.
CASE DESCRIPTION
We present a case of a 23-year-old woman referred to the internal medicine and neurology departments with a history of two hospital admissions for rhabdomyolysis at the age of 18, consanguineous parents, learning difficulties and multiple falls since the age of 8. In addition, the patient also had behavioural changes so she had psychological counselling at school, but lacked family support. Neurological examination showed mild proximal paraparesis, and spastic and paraparetic gait. The aetiological study revealed a pathological variant in homozygosity and increased blood levels of arginine. Therefore, the diagnosis of hyperargininemia was confirmed.
CONCLUSIONS
Compared to other urea cycle disorders, hyperargininemia is the rarest one. It is important to recognise the characteristic clinical features and diagnose it early because a favourable outcome can be achieved with appropriate treatment. This case shows a delayed diagnosis of hyperargininemia and highlights the importance of the internist's role in diagnosing rare diseases.
LEARNING POINTS
Hyperargininemia is a rare hereditary metabolic disease of the urea cycle and the rarest of the disorders affecting this cycle.The diagnosis is almost always made within the first four years of life and very few are diagnosed in adulthood.Early diagnosis is essential to reduce the progression of neurological damage, through appropriate treatment.
PubMed: 38584907
DOI: 10.12890/2024_004379 -
Clinical Pathology (Thousand Oaks,... 2022Hyperargininemia due to Arginase 1 deficiency is a rare inborn error of the urea cycle with an incidence estimated at 1:950 000. It has typical severe and progressive...
OBJECTIVE
Hyperargininemia due to Arginase 1 deficiency is a rare inborn error of the urea cycle with an incidence estimated at 1:950 000. It has typical severe and progressive abnormal neurological features with biochemical findings of hyperargininemia and hyperexcretion of orotic acid. The aim of our study is to review the clinical and biochemical presentations of 4 children diagnosed with Arginase 1 deficiency in Malaysia and compare with the literature review.
DESIGN AND METHODS
We retrospectively reviewed the medical records of 4 patients with molecularly confirmed Arginase 1 deficiency. Patients were identified from a selective high-risk screening of 51 682 symptomatic patients from January 2006 to December 2020.
RESULTS
Our patients exhibited heterogeneous clinical presentations with acute and progressive neurological abnormalities and varying degrees of plasma arginine and urine orotic acid excretions. Interestingly, an unusual hyperexcretion of homocitrulline was found in 3 patients.
CONCLUSIONS
Hyperargininemia due to Arginase 1 deficiency can present acutely and hyperexcretion of homocitrulline can be an additional biochemical feature of Arginase 1 deficiency.
PubMed: 35465134
DOI: 10.1177/2632010X221093274 -
Molecular Genetics and Metabolism 2022Arginase 1 Deficiency (ARG1-D) is a rare, progressive, metabolic disorder that is characterized by devastating manifestations driven by elevated plasma arginine levels.... (Review)
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.
Topics: Infant, Newborn; Humans; Child, Preschool; Arginase; Intellectual Disability; Hyperargininemia; Seizures; Muscle Spasticity; Arginine; Amino Acids, Essential; Disease Progression; Nitrogen
PubMed: 36049366
DOI: 10.1016/j.ymgme.2022.08.005 -
Movement Disorders Clinical Practice Jan 2023Arginase 1 Deficiency (ARG1-D) is a rare autosomal recessive urea cycle disorder (UCD) characterized by pathologic elevation of plasma arginine and debilitating... (Review)
Review
BACKGROUND
Arginase 1 Deficiency (ARG1-D) is a rare autosomal recessive urea cycle disorder (UCD) characterized by pathologic elevation of plasma arginine and debilitating manifestations. Based on clinical commonalities and low disease awareness, ARG1-D can be diagnosed as hereditary spastic paraplegia (HSP), leading to treatment delays.
CASES
A Hispanic woman with unremarkable medical history experienced progressive lower-limb spasticity in her 20s and received a diagnosis of HSP. She developed significant gait abnormalities and is unable to walk without assistance. More recently, two Hispanic brothers with childhood-onset manifestations including lower-limb spasticity, developmental delays, and seizures presented with suspected HSP. All three patients were ultimately diagnosed with ARG1-D based on plasma arginine several-fold above normal levels and loss-of-function variants. Disease progression occurred before ARG1-D was correctly diagnosed.
LITERATURE REVIEW
Retrospective analyses demonstrate that diagnostic delays in ARG1-D are common and can be lengthy. Because of clinical similarities between ARG1-D and HSP, such as insidious onset and progressive spasticity, accurate diagnosis of ARG1-D is challenging. Timely ARG1-D diagnosis is critical because this UCD is a treatable genetic cause of progressive lower-limb spasticity.
CONCLUSIONS
Arginase 1 Deficiency should be considered in HSP differential diagnosis until biochemically/genetically excluded, and should be routinely included in HSP gene panels.
PubMed: 36698992
DOI: 10.1002/mdc3.13612 -
JIMD Reports Nov 2022Individuals suspected of or diagnosed with a rare disorder, including inherited metabolic disorders (IMD), often need frequent and/or urgent vascular access for blood...
Individuals suspected of or diagnosed with a rare disorder, including inherited metabolic disorders (IMD), often need frequent and/or urgent vascular access for blood draws and treatment, making central indwelling catheters commonly used devices in this patient population. These indwelling catheters are prone to thrombosis, limiting vascular access. This complication is frequently resolved with the use of altepase, a recombinant tissue plasminogen activator (tPA). This report describes two individuals, one with a known IMD and one undergoing evaluation for an IMD, who were found to have hyperargininemia (>500 μM; reference 10-140 μM) by plasma amino acid (PAA) analysis of a specimen collected ~1.5-3 h after clearance of an indwelling catheter with tPA. In both cases, hyperargininemia resolved with repeat testing, suggesting pseudo-hyperargininemia secondary to tPA administration. Quantitative amino acid analysis of the administered tPA demonstrated an arginine level of ~200 mM, supporting tPA as the cause of pseudo-hyperargininemia. Certain formulations of tPA contain high concentrations of arginine, which if not cleared properly can result in marked elevations of arginine, mimicking arginase deficiency or suggesting arginine supplementation. Thus, the possibility of pseudohyperargininemia due to tPA administration should be considered when obtaining PAAs from an indwelling catheter in any individual being evaluated or managed for an IMD.
PubMed: 36341162
DOI: 10.1002/jmd2.12328 -
American Journal of Medical Genetics.... May 2006The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Urea cycle disorders are a group of inborn errors of hepatic... (Review)
Review
The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Urea cycle disorders are a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia and hyperglutaminemia. Deficiencies of all of the enzymes of the cycle have been described and although each specific disorder results in the accumulation of different precursors, hyperammonemia and hyperglutaminemia are common biochemical hallmarks of these disorders. Arginase is the enzyme involved in the last step of the urea cycle. It catalyzes the conversion of arginine to urea and ornithine. The latter reenters the mitochondrion to continue the cycle. Hyperargininemia is an autosomal recessive disorder caused by a defect in the arginase I enzyme. Unlike other urea cycle disorders, this condition is not generally associated with a hyperammonemic encephalopathy in the neonatal period. It typically presents later in childhood between 2 and 4 years of age with predominantly neurological features. If untreated, it progresses with gradual developmental regression. A favorable outcome can be achieved if dietary treatment and alternative pathway therapy are instituted early in the disease course. With this approach, further neurological deterioration is prevented and partial recovery of skills ensues. Early diagnosis of this disorder through newborn screening programs may lead to a better outcome. This review article summarizes the clinical characterization of this disorder; as well as its biochemical, enzymatic, and molecular features. Treatment, prenatal diagnosis and diagnosis through newborn screening are also discussed.
Topics: Animals; Humans; Hyperargininemia
PubMed: 16602094
DOI: 10.1002/ajmg.c.30091 -
Archives of Disease in Childhood Jan 1975A third case of hyperargininaemia occurring in one family was studied from birth. In cord blood serum arginine concentration was only slightly raised, but arginase...
A third case of hyperargininaemia occurring in one family was studied from birth. In cord blood serum arginine concentration was only slightly raised, but arginase activity in red blood cell haemolysates was very low. In the urine on day 2 a typical cystinuria pattern was present. Arginine concentration in serum increased to 158 mumol/100 ml on the 41st day of life. Later determinations of the arginase activity in peripheral blood showed values below the sensitivity of the method. Blood ammonia was consistently high, and cystinuria was present. The enzymatic defect was further displayed by intravenous loading tests with arginine. Serum urea values were predominantly normal or near the lower limit of normal, suggesting the presence of other metabolic pathways of urea synthesis. In urine there was no excretion of guanidinosuccinic acid, while the excretion of other monosubstituted guanidine derivatives was increased, pointing to a connexion with hyperargininaemia. Owing to parental attitude, a low protein diet (1-5 g/kg) was introduced only late. The infant developed severe mental retardation, athetosis, and spasticity.
Topics: Amino Acids; Ammonia; Arginine; Athetosis; Child, Preschool; Chromatography; Cystinuria; Dietary Proteins; Erythrocytes; Female; Guanidines; Humans; Hyperargininemia; Infant; Infant, Newborn; Intellectual Disability; Metabolism, Inborn Errors; Muscle Spasticity; Ornithine; Umbilical Cord; Urea
PubMed: 1124944
DOI: 10.1136/adc.50.1.57 -
JIMD Reports 2012Hyperargininemia is a rare autosomal recessive disorder of the last step of the urea cycle characterized by a deficiency in liver arginase1. Clinically, it differs from...
Hyperargininemia is a rare autosomal recessive disorder of the last step of the urea cycle characterized by a deficiency in liver arginase1. Clinically, it differs from other urea cycle defects by a progressive paraparesis of the lower limbs (spasticity and contractures) with hyperreflexia, neurodevelopmental delay and regression in early childhood. Growth is affected as well. Hyperammonemia is episodic, if present at all. The disease is caused by mutations in the ARG1 gene; there are approximately 20 different known ARG1 mutations with considerable genetic heterogeneity. We describe two Arab siblings with a late diagnosis of hyperargininemia and present the genetic findings in their family. As ARG1 sequencing was unrevealing despite suggestive clinical and laboratory findings, molecular cDNA analysis was performed. The ARG1 expression pattern identified a 125-bp out-of-frame insertion between exons 3 and 4, leading to the addition of 41 amino acids and a premature termination codon TGA at the sixth codon downstream. The insertion originated at intron 3 and was attributable to a novel c.305 + 1323 t > c intronic base change that enabled an enhancement phenomenon. This is the first reported exon-splicing-enhancer mutation in patients with hyperargininemia. The clinical course and genetic findings emphasize the possibility that hyperargininemia causes neurological deterioration in children and the importance of analyzing the expression pattern of the candidate gene when sequencing at the DNA level is unrevealing.
PubMed: 23430921
DOI: 10.1007/8904_2011_101