Citrullinemia Type 1

 Citrullinemia Type 1

DISEASE OVERVIEW

Citrullinemia type I (CTLN1) is a rare autosomal recessive genetic disorder that includes a neonatal acute (classic) form, a milder late-onset form, a form that begins during or after pregnancy and an asymptomatic form.

CTLN1 is caused by deficiency or absence of the enzyme argininosuccinate synthetase (ASS). ASS is one of six enzymes that play a role in the removal of nitrogen from the body, a process known as the urea cycle. The lack of this enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia) in the blood and all body fluids.

Infants with the classic form may experience vomiting, refusal to eat, progressive lethargy and show signs of increased intracranial pressure. Prompt treatment can prolong survival, but neurologic deficits are usually present. The course of the late-onset form is sometimes milder but episodes of hyperammonemia are similar to the classic form.

SIGNS & SYMPTOMS

The severity of CTLN1 varies from patient to patient. The classic form, characterized by profound lack of ASS enzyme activity, displays symptoms shortly after birth (neonatal period). A milder form of the disorder, which is characterized by partial lack of the ASS enzyme, affects some infants later during infancy or childhood.

The symptoms of CTLN1 are caused by the accumulation of ammonia in the blood and cerebrospinal fluid (CSF). The classic form occurs within 24-72 hours after birth, usually following a protein feeding and is initially characterized by refusal to eat, lethargy, lack of appetite, vomiting and irritability. Affected infants may also experience seizures, diminished muscle tone (hypotonia), respiratory distress, accumulation of fluid in the brain (cerebral edema) and liver failure.

If untreated, CTLN1 may progress to coma due to high levels of ammonia in the CSF (hyperammonemic coma). Neurological abnormalities including developmental delays, intellectual disability and cerebral palsy may occur and are more severe in infants who are in hyperammonemic coma for more than three days. Increased intracranial pressure can result in increased muscle tone, spasticity, abnormal reflex movements of the foot (ankle clonus) and seizures. If left untreated, the disorder will result in life-threatening complications.

In some patients, including those with partial enzyme deficiency, onset of the disorder may not occur until later during infancy or childhood. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), avoidance of high-protein foods from the diet, inability to coordinate voluntary movements (ataxia), progressive lethargy and vomiting. Infants with the mild form may alternate between periods of wellness and hyperammonemia. Infants and children with this form of CTLN1 may also develop hyperammonemic coma and life-threatening complications.

Another form of CTLN1 occurs during and after pregnancy. Affected women may experience migraine headaches, repeated episodes of vomiting, lethargy, seizures, confusion, hallucinations and potentially coma. Behavioral changes may also occur including manic episodes and psychosis. Affected women may also have accumulation of fluid in the brain (cerebral edema).

Some individuals with CTLN1 do not experience symptoms or hyperammonemia. The basis for these milder variants is not established.

CAUSES

CTLN1 is caused by changes (mutations or pathogenic variants) in the ASS1 gene that is responsible for production of the argininosuccinate synthetase (ASS) enzyme. The symptoms of CTLN1 develop due to deficiency of this enzyme, which is needed to detoxify ammonia in the body. Failure to properly remove ammonia via synthesis of urea leads to the abnormal accumulation of ammonia in the blood (hyperammonemia).

CTLN1 is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

DISORDERS WITH SIMILAR SYMPTOMS

Symptoms of the following disorders may be similar to those of citrullinemia type 1. Comparisons may be useful for a differential diagnosis:

The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which waste nitrogen is converted into urea and removed from the body through the urine. Ammonia is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, intolerance to protein and/or coma. The liver may be abnormally enlarged (hepatomegaly) in some patients. In severe cases, life-threatening complications often result. In addition to citrullinemia, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinic acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)

Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to break down (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy and seizures. They also develop metabolic acidosis (too much acid in the blood). If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon.

Citrullinemia type II is caused by pathogenic variants in the SLC25A13 gene resulting in a deficiency of the citrin protein. In infants, this can cause a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) characterized by a block in the flow of bile that prevents the body from processing certain nutrients properly. NICCD often resolves within a year, but those affected can later develop features of adult-onset citrullinemia type II. Symptoms of the adult-onset form include confusion, restlessness, memory loss, aggression, irritability and hyperactivity, seizures, and coma.

DIAGNOSIS

A diagnosis of citrullinemia can be confirmed by a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Excessive amounts of ammonia and citrulline in the blood strongly suggests the diagnosis of CTLN1. Molecular genetic testing for detection of pathogenic variants in the ASS1 gene is available to confirm the diagnosis.

CTLN1 may also be diagnosed through newborn screening programs. Citrulline can be measured on the newborn blood spot by tandem mass spectroscopy. Every state in the U.S. screens every newborn for CTLN1. Early detection is important because prompt identification and treatment may prevent the hyperammonemia that causes brain damage.

Carrier testing and prenatal diagnosis are available if the specific pathogenic variant has been identified in the family.

Siblings of an affected child should be tested immediately after birth and those with elevated ammonia or citrulline should receive a low protein diet.

Treatment

Treatment of an individual with CTLN1 requires the coordinated efforts of a team of specialists. Biochemical geneticists, pediatricians, neurologists and dieticians are needed to work together to ensure a comprehensive approach to treatment. Management involves prompt diagnosis, control of hyperammonemia and control of intracranial pressure.

Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some patients, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.

The treatment of CTLN1 is aimed at preventing excessive ammonia from being formed or for removing excessive ammonia during a hyperammonemic episode. Medications that assist in the removal of nitrogen from the body by providing an alternative means of waste nitrogen removal are employed. Available medications are Buphenyl, Ammonul, and Raviciti, as well as arginine.

Dietary restrictions are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants are placed a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula, and a calorie supplement without protein is often used.

Multiple vitamins and calcium supplements may also be used.

Aggressive treatment including hospitalization and protein restriction is needed in hyperammonemic

episodes that have progressed to vomiting and increased lethargy. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose.

In patients where there is no improvement or in patients where hyperammonemic coma develops, the removal of ammonia by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children and adults who are first diagnosed with CTLN1 during hyperammonemic coma.

Affected children should be monitored to prevent increased intracranial pressure and to anticipate the onset of a hyperammonemic episode. Warning signs include mood changes, headaches, lethargy, nausea, vomiting, refusal to eat and ankle clonus. Affected individuals should receive periodic blood tests to determine the level of ammonia in the blood and to determine the concentration of plasma amino acids to assist in the management of the protein restricted diet. Detection of elevated levels of ammonia may allow treatment before clinical symptoms appear.

Liver transplantation has been reported to improve quality of life and prolong survival in some patients

TYPE DOCTOR AND DEPARTMENT: NEUROLOGY SPECIALIST CAN DIAGNOSE THIS DISEASE.