Overview of the disease
Autosomal recessive urea cycle disorders are characterized by hyperammonemia resulting in feeding difficulties, vomiting, lethargy, convulsions, coma, etc. Symptomatic treatments such as dietary modification, medication, dialysis, etc., are the mainstay of treatment, and liver transplantation is not yet a cure for those who are eligible, and failure to detect and treat the disease in time may result in death and disability.
Definition
Citrullinemia is a rare autosomal recessive metabolic disorder.
The disease is caused by a genetic defect that results in an impairment of the urea cycle and an increase in the concentration of citrulline in the blood, which prevents the liver from converting excess nitrogen to urea, resulting in liver and brain damage due to elevated blood ammonia, and then a series of clinical symptoms [1-2].
Citrullinemia can lead to feeding difficulties, nausea, vomiting, headache, drowsiness, convulsions, and coma.
Early screening for the disease and maintaining blood ammonia at low levels are the main ways to improve the prognosis of affected children.
Classification
Classification according to etiology
Citrullinemia type I
Caused by a mutation in the gene for argininosuccinate synthetase.
Most common in newborns and infants, the main symptoms include feeding difficulties, vomiting, drowsiness, convulsions and loss of consciousness.
Citrullinemia type II
Caused by mutations in the SLC25A13 gene (localized at 7q21.3) encoding Citrin protein.
The main manifestations of adult onset are mental abnormalities, convulsions, and coma, while newborns may have jaundice, abnormal bleeding, and developmental delay.
Causes
Causes
Citrullinemia is caused by gene mutation. The causative gene for citrullinemia type I is the arginine succinate synthetase gene.
The causative gene for citrullinemia type II is the SLC25A13 gene (localized at 7q21.3), which encodes Citrin.
The risk of the disease is increased in children with close parental marriage or an immediate family member with citrullinemia.
Pathogenesis
The gene defect results in impaired urea cycling, increased citrulline concentrations in the blood, and accumulation of ammonia and precursor metabolites, causing a range of symptoms due to necrosis and edema in the liver and brain.
Symptoms
Main Symptoms
The clinical manifestations of different types of citrullinemia are highly variable and differ between children and adults.
Citrullinemia type I
Usually manifests as feeding difficulties, convulsions, dystonia (stiff neck, tilt back), vomiting, coma, etc. in early neonates. Due to the rapid onset of the disease and the difficulty in diagnosis, the mortality rate is extremely high. Severe neurological damage and liver damage are predominant.
Patients with late-onset citrullinemia type I have a later onset of the disease, and the clinical manifestations are milder than those of neonates, with periodic vomiting, lethargy, and convulsions.
Some female patients develop the disease during pregnancy or postpartum, and may have apathy, severe headache, convulsions, coma or even death [4].
Although some patients are diagnosed as citrullinemia type I by genetic analysis, they have no obvious symptoms, such as SLC25A13 variant gene carriers who do not develop the disease for life.
Citrullinemia type II
Neonatal intrahepatic cholestatic hepatitis
The onset of the disease occurs from birth to several months of age, most often within 2 months of age and rarely later than 5 months of age.
The main manifestations are persistent jaundice that does not subside, light-colored stools, feeding difficulties, growth retardation, and diarrhea.
Some patients are relieved by dietary modification and medication, and a small number of them develop adult-onset citrullinemia type II after puberty.
Adult-onset citrullinemia type II
Patients tend to be thin, and most of them have obvious dietary preferences, preferring high-protein and high-fat foods, such as beans and meat products, but hating high-sugar foods.
Most of them develop in adulthood, usually after ingesting sweets, drinking alcohol, taking certain drugs or infections suddenly appear memory impairment, confusion and other mental abnormalities, and in severe cases, the disease develops rapidly, and the lack of proper treatment can be life-threatening [5].
Complications
Intellectual disability: if not treated in time, the brain can be damaged causing intellectual developmental disorders, unable to study, work and live normally [6].
Cerebral palsy: related to the brain damage caused by hyperammonemia, which can be manifested as movement disorders and postural abnormalities.
Medical treatment
Department of Medicine
Pediatric internal medicine
Prompt medical consultation is recommended if the pediatric patient has symptoms such as periodic vomiting, lethargy, and convulsions.
Neurology
Adults with symptoms such as memory disorders, confusion, and convulsions are advised to seek prompt medical attention.
Emergency Medicine
If an adult or a pediatric patient develops symptoms such as abnormal muscle tone, convulsions, drowsiness, coma, etc., it is recommended to visit the Emergency Department promptly.
Preparation for medical treatment
Preparing for your visit: registering, preparing your documents, and frequently asked questions.
Tips for seeking medical treatment
Family members or patients should record whether there are any obvious triggers for the onset of symptoms.
Record the time of onset, duration and severity of symptoms for the doctor’s reference.
Preparation Checklist
Symptom Checklist
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Does the child have convulsions, drowsiness, etc.?
Does the child have symptoms such as periodic vomiting, drowsiness, convulsions, etc.?
Does the child have symptoms such as persistent jaundice, light-colored stools, feeding difficulties, growth retardation, diarrhea, etc.?
Are there any symptoms such as apathy, severe headaches, convulsions, etc.?
List of medical history
Has anyone in the relatives had this condition?
Are the parents inbred?
Have medications been taken recently? What medications were taken?
Checklist
Test results of the last 1 month, which can be brought to the doctor’s office
Laboratory tests: blood ammonia test, liver function test, blood amino acid analysis, etc.
Imaging tests: Cranial MRI, etc.
Diagnosis
Diagnosis based on
Medical history
Parents are consanguineous.
Relatives, especially parents, suffer from citrullinemia.
Clinical manifestations
The patient has convulsions, lethargy, jaundice that does not subside, light-colored stools, feeding difficulties, growth retardation, and diarrhea.
Periodic vomiting, lethargy, and convulsions occur during the growth of the child.
Female patients develop symptoms such as apathy, severe headache, convulsions during pregnancy or after delivery.
Symptoms such as memory impairment and confusion occur after drinking alcohol, taking drugs, illness and other stimuli.
Laboratory Tests
Blood ammonia test
Blood ammonia test should be performed when patients present with unexplained nausea, vomiting, convulsions, convulsions, lethargy, coma, etc. It is one of the key tests for the diagnosis and management of citrullinemia.
Blood ammonia may be significantly elevated in patients with early-onset citrullinemia, and some late-onset blood ammonia levels may be normal.
Liver function tests
Serum levels of total bilirubin, direct bilirubin, and transaminases are elevated.
Combined with the fact that the patient’s jaundice does not subside and the blood ammonia is elevated, the possibility of citrullinemia should be considered.
Blood Amino Acid Analysis
Citrulline may be significantly elevated in patients with citrullinemia.
Enzymatic analysis
Argininosuccinate synthetase activity is deficient in all tissues of the body in classic patients.
Late-onset patients have decreased hepatic argininosuccinate synthetase activity.
Genetic testing
Detection of gene mutation sites aids in diagnosis and differential diagnosis.
Detection of pathogenic variants in both alleles ASS1 or SLC25A13 confirms the diagnosis of the disease [1].
Histopathologic examination of the liver
Patients with citrullinemia have cholestasis in the hepatocytes and small bile ducts, fatty deposits in the hepatocytes, varying degrees of inflammation and fibrosis.
Magnetic Resonance Imaging
Helps to assess brain development and brain damage in patients.
Diffuse cerebral edema, basal ganglia injury, and, in severe cases, cerebral herniation and cerebral infarction are common in the acute phase of citrullinemia. Chronic hyperammonemia often has demyelinating lesions and brain atrophy.
Differential diagnosis
Neonatal sepsis
Similarities: Neonatal sepsis and citrullinemia type I may both present with symptoms such as shortness of breath, failure to raise body temperature, refusal of breastfeeding, poor response, progressive impaired consciousness in a short period of time, and convulsions [7].
Differences: Inflammatory indexes such as blood routine, C-reactive protein, calcitoninogen and so on may be no abnormality in citrullinemia type I, but blood ammonia level is elevated, abnormalities can be seen in cranial MRI, and genetic testing can make a definite diagnosis.
Progressive familial intrahepatic cholestasis
Similarities: Jaundice that does not go away, light-colored or even clay-colored stools, feeding difficulties, lethargy, irritability, agitation, convulsions, etc.
Differences: progressive familial intrahepatic cholestasis does not usually present with amino acid abnormalities, hypoglycemia, and lowered serum proteins, and the disease is characterized by normal levels of type I and type II glutamyl transpeptidase, and genetic testing can make a definitive diagnosis [2].
Alagille syndrome
Similarities: Both present with persistent jaundice and hepatomegaly, and growth retardation.
Differences: Alagille syndrome is characterized by a triangular face with a wide forehead and a pointed chin, two deep, widely spaced eyes, and an elongated nose, while citrullinemia does not have these features, and the diagnosis can be confirmed by genetic testing.
Congenital bile acid synthesis disorder
Similarities: Both may present with jaundice, convulsions, diarrhea, and developmental delay.
Differences: Congenital bile acid synthesis disorder has normal blood glucose, alpha-fetoprotein, serum protein, and amino acid metabolism, unlike citrullinemia. Normal or very low serum bile acid levels as well as bile acid composition analysis and genetic testing can differentiate.
Treatment
Aims of treatment: to reduce the blood ammonia level, to avoid intracranial hypertension and cerebral edema caused by persistently high blood ammonia, to reduce the probability of death or disability, and to improve the quality of life.
Treatment principle: Dietary adjustment, drug therapy, dialysis, and liver transplantation if the indications are met.
General treatment
When hyperammonemia is suspected or has been diagnosed, protein intake should be stopped immediately for 24-48 hours.
Intravenous infusion of a 10% glucose solution containing electrolytes and a fat solution to provide adequate calories, hydration, and electrolytes.
For infants, a special milk formula that is lactose-free and enriched with medium-chain fats is available.
Children and adults should reduce the proportion of sugars in their total daily calories, increase the proportion of proteins and lipids, and control protein intake in those with markedly elevated blood ammonia.
Medication
Essential amino acids
Commonly used drugs include arginine.
Hyperammonemia is ameliorated by supplementing the substrate or activating enzymes in the urea cycle metabolism so that ammonia is excreted through the urea cycle.
It can be given intravenously during acute hyperammonemia, or orally on a daily basis, and needs to be taken for life, with the dosage adjusted with age.
Drugs for ammonia removal
Commonly used drugs include sodium benzoate, sodium phenylacetate (or sodium phenylbutyrate).
These drugs remove nitrogen through bypass metabolism.
Choleretic drugs
Ursodeoxycholic acid is commonly used.
It may cause adverse reactions such as constipation, allergy, itching, headache and dizziness during application [2].
Vitamins.
Supplementation of fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, and vitamin K during treatment.
Hemodialysis
Hemodialysis should be started as soon as possible after admission of patients with severe hyperammonemia. Indications for hemodialysis include a rapid increase in ammonia, acute hyperammonemia resistant to initial drug therapy, and/or ammonia persistently above 350 to 400 μmol/L.
Ammonia concentrations are tested hourly during dialysis, and hemodialysis is discontinued when ammonia concentrations fall below 200 μmol/L.
Surgical treatment
The risk of death and neurologic complications associated with citrullinemia is high enough to consider undergoing liver transplantation.
Liver transplantation can prevent the associated encephalopathy due to hyperammonemia, correct metabolic disorders, and improve the dietary habits of high protein addiction [8].
Prognosis
Cure.
Citrullinemia is a rare autosomal recessive inherited metabolic disease, which cannot be cured yet, but if it can be detected in time and treated reasonably for a long period of time, the symptoms can be relieved and the morbidity can be controlled, and the prognosis is good.
If it is not detected in time or severe brain or liver damage occurs, the prognosis is poor.
Harmfulness
Citrullinemia can cause extensive localized necrosis and edema of brain tissue, and patients who fail to receive timely treatment may develop mental retardation, cerebral palsy or even death.
Patients usually need to control their diet, which has some adverse effects on daily life.
Daily
Daily Management
Dietary management
After a definitive diagnosis of intrahepatic cholestasis in newborns, it is necessary to stop breastfeeding and lactose-containing formulas, and switch to lactose-free formulas rich in medium-chain triglycerides.
Foods rich in fat-soluble vitamins, such as carrots and tomatoes, should be increased appropriately [9].
Adult patients with episodes of citrullinemia type II need to appropriately reduce the proportion of sugars in total calories and appropriately increase the proportion of proteins and lipids; protein intake needs to be controlled if blood ammonia is significantly elevated.
Adult patients should avoid alcohol and alcoholic foods.
Life management
Infection or fever may induce hyperammonemia; efforts should be made to avoid infection, especially during the 1st year.
Patients should be vaccinated on time to prevent various infections that may induce hyperammonemia.
Psychological support
Parents should patiently explain the necessity of long-term medication and strengthen the patient’s medication compliance. When symptoms are severe, patients should be comforted to reduce the psychological burden.
Follow-up
Regular follow-up helps to monitor the growth and development of the child and the psychological condition, and to adjust the dosage of drugs or take other interventions in time.
Long-term monitoring of ammonia and plasma amino acids, total serum protein, albumin, and prealbumin concentrations is needed to assess the adequacy of protein intake over weeks to months.
In stable patients, neonates and infants less than 2 years of age are evaluated every 1 to 3 months, children 2 to 12 years of age are evaluated 2 to 3 times per year, and adolescents and adults are evaluated annually [10].
Prevention
Citrullinemia is an inherited metabolic disorder for which there are no effective preventive measures, but the probability of its occurrence can be reduced by the following methods.
Avoiding consanguineous marriages.
Couples with a positive family history of citrullinemia are advised to undergo genetic counseling in preparation for pregnancy, and prenatal diagnosis of the fetus should be performed if pregnancy has already occurred.
During pregnancy, female patients should have their blood ammonia and liver function monitored, and their nutrition should be balanced, and protein intake should be limited if the blood ammonia is too high.
Newborns with risk factors should be screened for citrullinemia after birth to help detect the disease early and intervene in a timely manner.