Argininemia, also known as arginase deficiency, or hyperargininemia, is a relatively rare form of urea cycle abnormality. The urea cycle is the main metabolic pathway for ammonia removal in the body, mainly in the liver, where ammonia is converted into non-toxic urea through a series of enzymatic reactions and excreted by the kidneys. Defects in any of the six enzymes involved in the urea cycle (carbamoylphosphate synthase I, ornithine carbamoyltransferase, argininosuccinate synthase, arginase, N-acetylglutamate synthase) can cause disorders of the urea cycle. Arginase is the last step in the urea cycle as a hydrolase that hydrolyzes arginine to ornithine and urea. Arginase has two isomers. Arginase-1 (AI) and Arginase-2 (AII). AI is found mainly in the cytoplasm of hepatocytes and is also expressed in erythrocytes, where it plays a major role in the urea cycle; A11 is most abundant in the kidney and prostate and is located in the mitochondrial matrix. AI deficiency can lead to argininemia, which is autosomal recessive. argininemia is one of the rare types of urea cycle disorders, with an estimated Compared to the remaining urea cycle disorders, argininemia has a relatively late age of onset, a relatively mild clinical presentation, and a rare acute hyperammonemia. The molecular pathology, clinical manifestations and progress of diagnosis and treatment of argininemia are reviewed. 1, the molecular pathology of argininemia The arginase gene is located at 6q23.2, and its cDNAHl was first cloned in 1987. arginase gene is about 11.1 kb long, contains 8 exons, and encodes a protein with a relative molecular mass of 347000 containing 322 amino acids. Arginase is an Mn”-dependent hydrolase that contains two Mn2+ binding centers, the enzyme activity centers. So far, 29 pathogenic mutations have been reported in the human gene mutation database, including 16 missense mutations, 5 small fragment deletions, 4 shearing abnormalities, 1 large fragment deletion, 1 small fragment deletion and 1 large fragment insertion each. 2. Clinical manifestations and diagnosis The main clinical manifestations of argininemia are cognitive and motor deterioration, progressive spastic paralysis, and short stature. The disease differs from the rest of urea cycle disorders in that hyperammonemia is less common, and occasionally hyperammonemic coma is seen. Argininemia rarely develops in the neonatal period, and most children have psychomotor degeneration as the first symptom between 3 months and 4 years of age. Infants mainly present with symptoms of chronic hyperammonemia such as irritability, feeding difficulties, vomiting, and lethargy after the introduction of milk or the addition of protein-rich supplements. In infants, the main symptoms are nausea, recurrent vomiting, clumsy movements, and easy falling. If the disease is not diagnosed and treated in time, the symptoms will worsen and spastic paralysis, mental retardation, coma, convulsions and growth arrest will occur, and the convulsions are often generalized clonic seizures. Argininemia in the neonatal period and early onset (<3 months) is characterized by severe neurodegenerative symptoms with biliary jaundice and hepatomegaly. Physical examination may reveal short stature, microcephaly, spastic light paraplegia, hyperactive tendon reflexes, and toe gait in half of the patients. Pyramidal signs such as ataxia, involuntary movements (tardive dyskinesia and chorea-like movements), and tremor may also be present, but are relatively uncommon. Neurological imaging in argininemia is characterized by the following features: diffuse brain atrophy following severe cerebral edema, infarct-like lesions, regional ischemic injury, and also reversible symmetric involvement of the temporal lobe, cingulate gyrus, and insula cortex. Patients may have cerebellar atrophy or multicystic cerebral softening. The EEG is often nonspecific, with focal, multifocal, and diffuse spikes and abnormal slow waves possible, and more than 50% of patients show slowed background activity and epileptogenic waves. Peripheral nerve testing is generally uneventful, hearing and vision are generally unimpaired, and severe spasticity may cause skeletal deformities. Laboratory tests reveal that plasma arginine levels can rise to 5-10 times or more than normal, and cerebrospinal fluid arginine levels can rise up to 10 times the normal level. Argininemia can cause liver damage, increased plasma transaminases, and prolonged clotting time. Blood urea nitrogen levels may be reduced, but to a lesser extent than other urea cycle disorders, possibly related to the compensatory effects of AII. In patients with argininemia, ammonia levels are generally lower than in other urea cycle disorders, and acute hyperammonemic episodes have been reported occasionally and are less common. Some patients with argininemia may have persistent mild elevations of blood ammonia. Patients may have whealateuria, which may be related to the activation of N-acetylglutamate synthase by elevated arginine in the body leading to activation of carbamoyl phosphate synthase I, resulting in increased carbamoyl phosphate and whealate production. The patient's erythrocyte arginase activity is significantly reduced, and the diagnosis is confirmed by the combination of clinical symptoms. The recent development and application of tandem mass spectrometry for neonatal screening has contributed to early diagnosis and treatment. 200,000 newborns in Massachusetts, USA were screened by Marsden and one case of argininemia was identified. 160,000 New England newborns were screened by Zytkovicz and others. In our laboratory, we screened over 500,000 newborns in Shanghai by tandem mass spectrometry and detected only one case of argininemia, suggesting that the disease is rare. 3. Pathogenesis of argininemia Arginine deficiency leads to the inability to hydrolyze arginine into ornithine and urea, thus ammonia cannot be excreted as urea, and arginine, the substrate of the enzyme, and the metabolites of arginine accumulate in the body. Arginine is metabolized in various pathways and is a precursor substance for the synthesis of nitrogen dioxide, creatine, polyamines, and guanabutamine. The relatively mild degree of hyperammonemia in patients with argininemia compared to other urea cycle disorders may be related to the compensatory effect of AII, the tautomer of AI, and Picker et al. demonstrated a significant upregulation of mitochondrial arginase activity in AI-deficient patients. The pathogenesis of neurological symptoms in patients with argininemia is so far unclear, but it may be related to the following mechanisms: ① Chronic hyperammonemia: Since the neurological symptoms of patients are significantly different from the manifestations of other urea cycle disorders, and patients can develop more severe neurological symptoms without a significant increase in blood ammonia levels, it is thought that hyperammonemia may not be the main cause of neurological symptoms in argininemia . ② accumulation of guanidinium-based compounds: previous studies found elevated levels of guanidinium-based compounds in the blood and cerebrospinal fluid of patients. It is now believed that guanidinium-based compounds such as hyperarginine, N-acetylarginine, α-keto-δ-guanidinovaleric acid (α-K-δ-GVA), etc. are closely related to the neurological damage in argininemia. Some guanidino compounds can inhibit the activity of transketolase, which leads to demyelination changes and manifests as upper motor neuron signs; d-K-8-GVA and others can inhibit the action of neurotransmitter γ-aminobutylamine and promote the occurrence of convulsions; in animal experiments, N-acetylarginine and hyperarginine were found to significantly inhibit the Na+-K+-ATPase of mouse neuronal cell membranes, and Na+-K+- ATPase plays an important role in maintaining nerve cell excitability and cell membrane fluidity, and can induce epileptogenesis when inhibited; arginine and hyperarginine N-acetylarginine can induce the generation of free radicals, and also reduce the antioxidant capacity of nerve cells by inhibiting the activities of catalase, superoxide dismutase and glutathione peroxidase. (iii) Arginine accumulation: Arginine is a substrate for the synthesis of citrulline in the central nervous system, a reaction catalyzed by nitric oxide synthase, which produces nitric oxide in the production of citrulline. Significantly elevated levels of arginine in the cerebrospinal fluid of patients with argininemia may indirectly lead to an increase in nitric oxide, which has been shown to have neurotoxic effects and to play an inhibitory role in the proliferation and differentiation of the nervous system. 4, Treatment Argininemia is one of the better treated types of urea cycle disorders, and its treatment consists of three main aspects: restricting protein intake; supplementing essential amino acids; and increasing the bypass metabolism of waste nitrogen. ① Diet therapy: Diet therapy plays a central role in the treatment of argininemia and is the key to treating argininemia. Protein intake should be limited on the basis of ensuring energy supply, and a low-arginine diet is advocated, with appropriate supplementation of special amino acid powder (25% to 50%) and natural protein (50% to 70%) that does not contain arginine and is rich in branched-chain amino acids. The special amino acid powder is generally 0.7 g/(kg-d). Recommended protein intake for children with urea cycle disorders: 1.36 to 1.77 g/(kg-d) for 1 to 3 months of age, 1.31 to 1.36/(kg-d) for 3 to 6 months of age, 1.14 to 1.31 g/(kg-d) for 6 to 12 months of age, 0.97/(kg-d) for 2 years of age, 0.9 g/(kg-d) for 3 years of age, and 0.87 g/(kg-d) for 4 to 6 years of age /(kg-d) heart 1l. Diet therapy can maintain the blood arginine level at normal level, delay and stop the disease progression, and improve the neurological symptoms of the children. ②Promote the bypass metabolism of nitrogen: When the blood ammonia of the children is high, sodium benzoate and sodium phenylbutyrate can be applied to promote the excretion of nitrogen from urine in the form of mare's uric acid and phenylacetylglutamine amide, thus promoting the excretion of nitrogen. The dosage of sodium benzoate is 250 me/(kg-d) and sodium phenylacetate is 500 mg/(kg-d), and the blood ammonia level should be controlled below 60 umol/L. Acute hyperammonemia is rare and is usually caused by fasting, infection, protein load, anesthesia or surgery, etc. Once it occurs, it should be treated actively to prevent the occurrence of hyperammonemic encephalopathy by taking measures such as protein prohibition, continuous supplementation of high calorie diet, and promotion of nitrogen excretion, etc. Those whose blood ammonia reaches 500 umol/L without improvement after taking the above treatment measures should undergo hemodialysis. Prasad et al. found that 54% of patients had improved cognitive ability, 45% had increased height, 64% had spastic paralysis with varying degrees of relief, and 19% had uncontrolled or even died after treatment with dietary therapy and ammonia excretory drugs in 27 patients with argininemia. The disease could not be controlled or even died. 6, prenatal diagnosis Argininemia can be diagnosed prenatally by the following two methods: ① gene mutation detection: in the case of clear prevalent arginase gene mutation, amniotic fluid or chorionic villus specimens are taken and DNA is extracted for fetal arginase gene detection; ② detection of arginase activity: although arginase is not expressed in amniotic fluid and chorionic villus cells, the arginase activity in fetal erythrocytes in the middle and late stages of pregnancy has reached postnatal level III. Although arginase is not expressed in amniotic fluid and chorionic villus cells, the activity of arginase in fetal erythrocytes in the middle and late stages of pregnancy has reached postnatal level IIIJ, therefore, umbilical cord puncture is feasible at 18-24 weeks of middle and late pregnancy to obtain fetal erythrocytes for prenatal diagnosis by measuring erythrocyte arginase activity. Argininemia is a treatable congenital metabolic disorder, which can be diagnosed early by tandem mass spectrometry and other tests, thus enabling early intervention in affected children and controlling the progression of the disease through dietary therapy and medication, and even achieving asymptomatic survival.