Citrullinemia

The watermelon Citrullis vulgaris contains abundant citrulline, which gives the disease its name. Source: CT State Dept. of Education

Other Names

Citrullinemia is also known as CIT, citrullinuria, argininosuccinate synthetase deficiency, and ASS deficiency. The name refers to the very high concentrations of the amino acid citrulline that are found in serum, cerebrospinal fluid, and urine of patients with the disease. Citrulline, in turn, gets its name from the watermelon, whose Latin name is Citrullis vulgaris; citrulline is found in abundance in watermelons.

Types

Citrullinemia is classified into two types: type I and type II. Type I citrullinemia (also called classic citrullinemia) usually becomes evident in the first few days of life and can become life-threatening. Less commonly, a milder form of type I citrullinemia can develop later in childhood or adulthood. Type II citrullinemia is characterized by potentially life-threatening neurological symptoms that can occur in childhood or adults (adult-onset). Often adult-onset type II citrullinemia is triggered by an injury, such as infection. The features of adult-onset type II citrullinemia may also develop in people who as infants had a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). This liver condition is also known as neonatal-onset type II citrullinemia. NICCD blocks the flow of bile (a digestive fluid produced by the liver) and prevents the body from processing certain nutrients properly.

Symptoms

Infants with type I citrullinemia typically appear normal at birth, but symptoms develop as ammonia builds up in their bodies:^[1]

• Lack of energy
• Vomiting
• Poor feeding
• Seizures
• Loss of consciousness

The late-onset form of type I citrullinemia that occurs in adults is associated with the following symptoms:

• Intense headaches
• Vision loss
• Problems with balance and muscle coordination
• Decreased energy

Some people with type I citrullinemia never manifest symptoms.

Type II citrullinemia chiefly causes neurological symptoms:

• Confusion
• Restlessness
• Memory loss
• Abnormal behaviors (such as aggression, irritability, and hyperactivity)
• Seizures
• Coma

Causes

Citrullinemia belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of chemical reactions that takes place in liver cells. These reactions process excess nitrogen that is generated when protein is used by the body. The excess nitrogen is used to make a compound called urea, which is excreted in urine.

Mutations in the ASS1 and SLC25A13 genes cause citrullinemia. Type I is caused by alterations in the ASS1 gene; adult-onset type II, the SLC25A13 gene.^[2]

The ASS1 gene encodes an enzyme called argininosuccinate synthetase 1. This enzyme controls one of the steps in the urea cycle. Mutations in the ASS1 gene reduce the activity of the enzyme, which disrupts the urea cycle and prevents the body from processing nitrogen effectively.

The SLC25A13 gene encodes a protein called citrin. Within cells, citrin helps transport molecules used in the production and breakdown of simple sugars, the production of proteins, and the urea cycle. Molecules transported by citrin are also involved in making nucleotides, which are the building blocks of DNA and its chemical cousin, RNA. Mutations in the SLC25A13 gene typically prevent cells from making any functional citrin, which inhibits the urea cycle and disrupts the production of proteins and nucleotides. The resulting buildup of ammonia and other toxic substances leads to the symptoms of adult-onset type II citrullinemia.

Citrullinemia is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene without displaying symptoms themselves.

Diagnosis

Infants who inherit type I citrullinemia typically show symptoms within the first several days of life. Symptoms of type II usually appear in adulthood.

Diagnosis is based on symptoms, a family history, measurement of ammonia in the blood, and amino acid excretion in urine. A diagnosis can also be made by measuring the amount of argininosuccinate synthetase 1 in cells obtained from the skin.

Treatment

People with citrullinemia need to restrict their intake of protein. Blood ammonia levels can be reduced by treatment with sodium benzoate, sodium phenylacetate, and arginine, which are given intravenously (IV).^[3] Hemodialysis may be needed in severe cases to rid the blood of toxic compounds. For long-term treatment, sodium phenylbutyrate and arginine can be taken by mouth.

Clinical Trials

• A list of of ongoing, U.S.-based clinical trials.

Risk Factors

The symptoms of adult-onset type II citrullinemia are known to be triggered by certain medications, infections, surgery, and alcohol intake.

Epidemiology

Type I citrullinemia is the most common form of the disorder, affecting about 1 in 57,000 people worldwide. Type II citrullinemia is found primarily in the Japanese population, where it occurs in an estimated 1 in 100,000 to 230,000 individuals. Type II also has been reported in other populations, including people from East Asia and the Middle East.

References

1. ↑ Mohyuddin F, Rathbun JC, McMurray WC. Studies on amino acid metabolism in citrullinuria. Am J Dis Child. 1967 Jan;113(1):152-6. Citation
2. ↑ Kobayashi K, Jackson MJ, Tick DB, O'Brien WE, Beaudet AL. Heterogeneity of mutations in argininosuccinate synthetase causing human citrullinemia. J Biol Chem. 1990 Jul 5;265(19):11361-7. Abstract | PDF
3. ↑ Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. 2007 May 31;356(22):2282-92. Abstract | PDF

External Links

• Gene Review: Citrin Deficiency
• Gene Review: Citrullinemia Type I
• Gene Review: Urea Cycle Disorders Overview