Vol 9, Issue 4, 2021 ISSN - 2321-4406 Review Article EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND HINDRANCE OF UREA CYCLE ERROR OF METABOLISM VENKATA VASAVI KAVITAPU1, BINDU MADHAVA S2, SAMEER SHARMA3* 1School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India. 2Department of Biochemistry, Kuvempu University, Shimoga, Karnataka, India. 3Department of Bioinformatics, BioNome Private Limited, Bengaluru, Karnataka, India. Email: [email protected] Received: 31 May 2021, Revised and Accepted: 29 June 2021 ABSTRACT Inborn errors of metabolism (IEMs) are a class of genetic disorders that are rare individually, but collectively they occur in common terms exhibiting an average prevalence of 1 in 1000 individuals. One of the most commonly occurring IEMs is the urea cycle disorders (UCDs), which are a group of unusual disorders that have an effect on the urea cycle, a sequence of metabolic processes through which nitrogen is transformed into urea and expelled from the body by the urine. These diseases are the primary cause of hereditary hyperammonemia, and they can result in developmental disabilities, epilepsy, loss of psychomotor control, and death. UCDs are most commonly diagnosed during infancy, although certain infants do not exhibit symptoms until they are in their early childhood. IEMs are precisely diagnosed and recorded through tandem mass spectroscopy-based newborn screening. Recent advances in IEMs include new therapies based on dietary modification, enzyme replacement therapy, development of novel compounds, and diagnosis involving untargeted metabolomics and whole-exome sequencing are also widely being used in new disease discovery. Modern improvements in diagnosis and care have increased the prognosis significantly for a lot of children with IEM. It has been suggested that expanded access to awareness of IEMs is the most significant change leading to better treatment. The purpose of this review is to provide an overview on IEM and present in-depth knowledge about the UCDs including their subtypes. Keywords: Inborn errors of metabolism, Urea cycle disorders, Urea cycle disorders classification, Management of urea cycle disorders. © 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijms.2021v9i4.42246. Journal homepage: https://innovareacademics.in/journals/index.php/ijms INTRODUCTION Of the most significant laboratory outcomes associated with inborn metabolic errors, urea cycle defects [8], and certain organic acidemias Given the existence of conventional biochemical technologies in are at the top. the 20th century, the inborn metabolic errors originally identified were usually diseases of intoxication manifesting in the central UCDs are a type of inborn error in hepatic metabolism [9] caused by nervous system or different end-organ consequences [1]. Inborn the lack of enzymatic activities that control the transfer of nitrogen errors of metabolism (IEM) are inherited single gene defects caused from ammonia to urea. With an average prevalence of at least 1 in by a malfunction or abnormality in a transporter, an enzyme or its 2500, these conditions often lead to lethal hyperglutaminemia and cofactor, leading to substrate aggregation or the product deficiency. Sir hyperammonemia [10,11]. The manifestations of UCDs vary with Archibald Garrod described these diseases for the first time in 1908 and independent of the age, although they are most probably to appear submitted his study titled “Inborn Errors in Metabolism” to the Royal during the late infancy, neonatal stage, and at the time of puberty. College of Physicians as the Croonian Lectures [2-4]. More than 700 Early signs are generally nonspecific, so it is crucial to regularly IEMs were known till date [5]. IEM is rare, but their overall occurrence screen for hyperammonemia to determine a diagnosis rapidly and is greater than 1:1000 and is responsible for a considerable portion of avoid complications. A disorder known as transient hyperammonemia disability and deaths during childhood [6]. Most of the IEM disorders of the newborn is of the differential diagnosis in neonates, while are autosomal recessive type, but X-linked and autosomal dominant in older infants the defects of fatty acid oxidation may be taken into disorders are also existent. Since neonates with IEMs typically present consideration [12,13]. The toxic ammonia is eliminated by the urea with nonspecific symptoms [7], a high note of suspicion is critical cycle through renal excretion which is generated by the amino acid for early detection of IEMs. Hence, any previous records of paternal deamination by transforming it into nontoxic urea. If the urea cycle fails affiliation or a formerly infected sibling may indicate the possibility of to function, ammonia builds up in the blood and thus causes impaired IEMs. mental state, fatigue, cerebral edema, lethargy, and eventually, coma, and death [14]. The IEMs can be classified into two categories: Those caused by abnormalities in energy sources metabolism such as proteins, The metabolic condition hyperammonemia is characterized by carbohydrates, or lipids and those caused by disruption in pathways increased ammonia levels, a potent neurotoxin. Hyperammonemia is occurring within cell organelles such as peroxisome, mitochondria, most often represented by neurological signs and symptoms, which and lysosome. Urea cycle disorders (UCDs), chemical acidemias, and can be acute or chronic, based on the repressed abnormality [15]. To amino acidopathies are examples of metabolic disorders affected by avoid permanent neurological damage, hyperammonemia should be protein metabolism disorder. Defects of fatty acid b-oxidation and the detected early and treated promptly. Aside from ammonia, urinary carnitine shuttle are examples of lipid metabolism disorders. Among organic acids and plasma amino acids are necessary to determine the the carbohydrate diseases are galactosemia and glycogen storage form of UCD [16]. It should be recognized that metabolic disorders disorders. The storage disorders of lysosomes are caused by disability can be variable and inconsistent. Hence, to validate the diagnosis, to digest or recycling of complex large macromolecules and might enzymatic, or molecular analyses are required. In IEMs, early diagnosis manifest with a variety of symptoms, based on the enzymatic block. and administration of adequate therapy are needed to avoid mortality Kavitapu et al. Innovare Journal of Medical Science, Vol 9, Issue 4, 2021, 12-17 and reduce complications [17]. In the case of suspected IEMs, the urea cycle proximal portion. It catalyses the conversion of carbamoyl management should be initiated before the birth [18]. A number of phosphate and ornithine into citrulline. OTC deficiency is a hereditary IEM-related conditions are detectable by current newborn screening condition that induces excess amounts of ammonia to accumulate in (NBS) programs. NBS allows for the detection of an IEM during an the blood [33]. The prevalence of OTC deficiency has been estimated asymptomatic period and the performance of medical treatments to be 1 in 14,000 to 1 in 77,000 individuals. The degree of onset of that change the disease’s natural history. A few IEM can be treated, OTC deficiency differs from one person to another, often within the and as a result, many are incorporated in NBS services in different family [34-38]. countries [19-21]. Argininosuccinate synthetase deficiency OVERVIEW OF UCDS This deficiency is also called as Citrullinemia. It is a UCD of autosomal recessive type. Citrullinemia leads to accumulation of toxic compounds The urea cycle is the primary mechanism for removing nitrogen waste and ammonia in the blood [39]. Argininosuccinate synthetase deficiency produced by the breakdown of proteins and other molecules containing is of two types, that is, Type I citrullinemia (citrullinemia) and Type II nitrogen by converting the ammonia to urea. The urea cycle comprises citrullinemia. The reason for the deficiency is due to mutations in genes five catalytic enzymes (CPS1, OTC, ASL, ARG1, and ASS1), two amino which differ for both the types and clinical manifestations are also acid transporters which are Ornithine translocase and Citrin [22,23]. different [40-42]. The most common type of Citrullinemia is Type I Besides this, it consists of N-acetyl glutamate synthetase (NAGS), a co- citrullinemia exhibiting overall incidence more than 1 in 57,000 of factor producing enzyme. UCDs are inborn metabolic errors caused by global population. Type II citrullinemia shows prevalence of one in defects in the waste product’s metabolism that is generated during the 100,000 to 230,000 people and is found majorly in the population of breakdown of protein and other nitrogenous substances [24]. UCDs Japan. are caused by deficiencies that are inherited in either of the urea cycle pathway’s 6 enzymes or 2 transporters (CPS1, OTC, ASS1, ASL, ARG1, Argininosuccinic aciduria (ASA) NAGS, ORNT1, or citrin). The abnormal protein’s role in the pathway, ASA is a genetic disorder that occurs due to the partial or complete as well as the seriousness of the defect, influences the severity of the deficiency of argininosuccinate lyase (ASL) enzyme and it is the second UCD. As a consequence, urea excretion is compromised, resulting in the most common type of UCD. This deficiency leads to the argininosuccinic ammonia