UNASSIGNED: 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.
UNASSIGNED: 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 ARG1 and increased blood levels of arginine. Therefore, the diagnosis of hyperargininemia was confirmed.
UNASSIGNED: 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.
CONCLUSIONS: 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.

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Arginase deficiency, which leads to hyperargininaemia is a rare urea cycle disorder caused by a mutation in the ARG1 gene. It is an under-recognized cause of pediatric developmental epileptic encephalopathy, with the key coexistent clinical features being developmental delay or regression and spasticity. Detection of ARG1 gene mutation on genetic testing is the confirmatory diagnostic test. However, elevated levels of plasma arginine and low plasma arginase level can be considered as biochemical markers for diagnosis. We present two cases of arginase deficiency with genetically confirmed ARG1 mutation in one and biochemical confirmation in both. As the spectrum of epilepsy in arginase deficiency has been less explored, we attempted to elucidate the novel electroclinical features and syndromic presentations in these patients. Informed consent was obtained from families of patients. Electroclinical diagnosis was consistent with Lennox Gastaut syndrome (LGS) in the first patient while the second patient had refractory atonic seizures with electrophysiological features consistent with developmental and epileptic encephalopathy. Though primary hyperammonaemia is not a consistent feature, secondary hyperammonaemia in the setting of infectious triggers and drugs like valproate (valproate sensitivity) has been well described as also observed in our patient. In the absence of an overt antecedent in a child with spasticity and seizure disorder, with a progressive course consistent with a developmental epileptic encephalopathy, arginase deficiency merits consideration. Diagnosis often has important therapeutic implications with respect to dietary management and choice of the appropriate antiseizure medications.

UNASSIGNED: 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.
UNASSIGNED: The aim of our study is to describe the varied phenotypic spectrum of children with arginase deficiency.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

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.

UNASSIGNED: 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.
UNASSIGNED: 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 ARG1 variants. Disease progression occurred before ARG1-D was correctly diagnosed.
UNASSIGNED: 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.
UNASSIGNED: Arginase 1 Deficiency should be considered in HSP differential diagnosis until biochemically/genetically excluded, and should be routinely included in HSP gene panels.

Arginase 1(ARG1) deficiency is a rare disorder of the urea cycle. The presentation is usually late, leading to loss of intellectual milestones, spasticity and liver involvement. Hyperammonemic crises are rarely encountered. We herein present a case of a 16-year immigrant girl of Syrian origin who was evaluated for acute onset of fever, vomiting, and seizures. Laboratory analyses showed slightly elevated lactate, creatine kinase, and coagulation parameters. Ammonium levels were also moderately increased. On 5th day of admission, she went into an encephalopathic state. Blood amino acid analysis showed highly elevated arginine levels. An increased level of orotic acid was found in urine organic acid analysis. Molecular genetic analysis of ARG1 gene showed a novel homozygous mutation. Although the presentation of ARG1 deficiency is usually chronic in the majority of patients, an acute crisis of encephalopathy due to hyperammonemia may occur and delayed diagnosis may lead to irreversible neurological damage. Key Words: Urea cycle disorder, Hyperammonemia, Argininemia, Encephalopathy.

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.

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.

UNASSIGNED: Arginase 1 deficiency (ARG1-D) is a rare, progressive and debilitating urea cycle disorder characterized by clinical manifestations including spasticity, seizures, developmental delay, and intellectual disability. The aim of this systematic review was to identify and summarize the natural history of ARG1-D and the unmet needs of patients.
UNASSIGNED: A comprehensive search of published case reports was undertaken to identify patients with ARG1-D regardless of interventions, comparisons, or outcomes. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and other evidence-based medicine literature databases were searched on 20 April 2020. Quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. (PROSPERO registration: CRD42020212142.).
UNASSIGNED: One hundred and fifty seven ARG1-D patients were included from 111 publications (good overall quality based on JBI\'s Checklist); 84 (53.5%) were males. Motor deficits (including spasticity), intellectual disability, and seizures were reported in >50% of the cases. Mean age (SD) at diagnosis was 6.4 years and the laboratory findings most commonly reported to support diagnosis included elevated plasma arginine (81.5%), mutation in ARG1 gene through genetic testing (60%), and absence/reduction of red blood cell arginase activity (51%). Reported management approaches mainly included dietary protein restriction (68%), nitrogen scavengers (45%), and essential amino acid supplements (21%). Author-reported clinical improvement was documented for 26% of patients, 15% deteriorated, and 19% had limited or no change; notably, no indication of clinical outcome was reported for 40% cases.
UNASSIGNED: This review illustrates a significant burden of disease and highlights a considerable unmet need for clinically effective treatment options for patients with ARG1-D.