Abstract：
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.
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.
摘要：
背景：精氨酸酶1缺乏症（ARG1-D）是一种罕见的，进步,代谢紊乱，其特征是由血浆精氨酸水平升高引起的破坏性表现。它通常在儿童早期出现痉挛（主要影响下肢），流动性障碍，癫痫发作,发育迟缓,智力残疾。本系统综述旨在确定和描述已发表的概述流行病学的证据，诊断方法,疾病进展的措施，临床管理，和ARG1-D患者的结局。
方法：跨多个数据库（如MEDLINE，Embase,根据PRISMA指南,于2020年4月20日对ClinicalTrials.gov中的临床研究进行了回顾(报告了结果),没有日期限制.使用预定义的资格标准来识别具有ARG1-D患者特定数据的研究。两名独立的审阅者筛选记录并从纳入的研究中提取数据。使用改良的纽卡斯尔-渥太华量表进行非比较研究评估质量。
结果：总体而言，55条记录报告40项已完成的研究和3项正在进行的研究被纳入。10项研究报告了一般人群中ARG1-D的患病率，中位数为1/1,000,000。经常报道的诊断方法包括基因检测，血浆精氨酸水平，和红细胞精氨酸酶活性。然而,常规新生儿筛查并非普遍可用，缺乏疾病意识可能会阻止早期诊断或导致误诊，因为这种疾病与其他疾病有重叠的症状，比如脑瘫。在诊断和评估疾病进展时报告的常见表现包括痉挛（主要影响下肢）。流动性障碍，发育迟缓,智力残疾,和癫痫发作。严重的饮食蛋白质限制，必需氨基酸补充，和氮清除剂给药是ARG1-D患者中最常见的治疗方法。只有少数研究报告了这些干预措施对智力障碍有意义的临床结果，运动功能和适应性行为评估，住院治疗,或死亡。根据纽卡斯尔-渥太华量表，纳入研究的总体质量被评估为良好。
结论：尽管ARG1-D是一种罕见的疾病，已发表的证据表明，患者的疾病负担很高。当前的护理标准在预防疾病进展方面无效。显然仍然需要新的治疗选择，以及改善诊断和疾病意识，以便在临床表现发作之前发现和开始治疗，从而有可能实现更正常的发展。改善症状学，或预防疾病进展。
方法：跨多个数据库（如MEDLINE，Embase,根据PRISMA指南,于2020年4月20日对ClinicalTrials.gov中的临床研究进行了回顾(报告了结果),没有日期限制.使用预定义的资格标准来识别具有ARG1-D患者特定数据的研究。两名独立的审阅者筛选记录并从纳入的研究中提取数据。使用改良的纽卡斯尔-渥太华量表进行非比较研究评估质量。
结果：总体而言，55条记录报告40项已完成的研究和3项正在进行的研究被纳入。10项研究报告了一般人群中ARG1-D的患病率，中位数为1/1,000,000。经常报道的诊断方法包括基因检测，血浆精氨酸水平，和红细胞精氨酸酶活性。然而,常规新生儿筛查并非普遍可用，缺乏疾病意识可能会阻止早期诊断或导致误诊，因为这种疾病与其他疾病有重叠的症状，比如脑瘫。在诊断和评估疾病进展时报告的常见表现包括痉挛（主要影响下肢）。流动性障碍，发育迟缓,智力残疾,和癫痫发作。严重的饮食蛋白质限制，必需氨基酸补充，和氮清除剂给药是ARG1-D患者中最常见的治疗方法。只有少数研究报告了这些干预措施对智力障碍有意义的临床结果，运动功能和适应性行为评估，住院治疗,或死亡。根据纽卡斯尔-渥太华量表，纳入研究的总体质量被评估为良好。
结论：尽管ARG1-D是一种罕见的疾病，已发表的证据表明，患者的疾病负担很高。当前的护理标准在预防疾病进展方面无效。显然仍然需要新的治疗选择，以及改善诊断和疾病意识，以便在临床表现发作之前发现和开始治疗，从而有可能实现更正常的发展。改善症状学，或预防疾病进展。
