Citrin deficiency is an inherited metabolic disorder that primarily affects the liver. It stems from mutations in the SLC25A13 gene, which holds the instructions for making a protein called citrin. This condition presents with symptoms that differ depending on the individual’s age. The disorder’s effects are tied to the protein’s role in cellular energy and waste removal, leading to distinct clinical phases throughout a person’s life.
The Genetic Basis of Citrin Deficiency
Citrin deficiency is caused by flaws in the SLC25A13 gene, which produces the citrin protein. This protein is a transporter, mainly active in the liver, that moves molecules across the membrane of mitochondria, the energy-producing centers of cells. Citrin helps shuttle a molecule called aspartate out of the mitochondria, a necessary step for the urea cycle to function correctly.
The urea cycle is a sequence of reactions in liver cells that processes excess nitrogen from protein use. It converts this nitrogen into urea, which the body safely excretes in urine. When the citrin protein is dysfunctional, the urea cycle is impaired, leading to a toxic buildup of ammonia. This disruption also affects carbohydrate metabolism and the production of proteins and nucleotides.
The condition is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the mutated SLC25A13 gene, one from each parent, to develop the disorder. Individuals who inherit only one mutated copy are considered carriers; they do not show symptoms but can pass the gene to their children.
Clinical Manifestations and Symptoms
The presentation of citrin deficiency varies with age and is categorized into three main phases. The first is Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD). In newborns, this condition appears as prolonged jaundice, poor growth, and liver dysfunction, including fatty liver, low blood protein levels, and blood clotting problems. While many infants with NICCD see their symptoms resolve within the first year, a small number may experience progressive liver failure.
After NICCD resolves, individuals may enter a quiet period during childhood where they appear asymptomatic. During this time, they develop distinct dietary preferences, a condition known as Failure to Thrive and Dyslipidemia caused by Citrin Deficiency (FTTDCD). These individuals show a strong aversion to carbohydrate-rich foods and a preference for protein and fat-rich foods. This behavior is believed to be a subconscious metabolic adaptation.
The most severe form is Adult-onset Type II Citrullinemia (CTLN2), which can manifest suddenly in adulthood between ages 20 and 50. CTLN2 is characterized by neurological symptoms due to high blood ammonia levels. Symptoms can include sudden confusion, disorientation, restlessness, irritability, and seizures. Episodes are triggered by events such as consuming alcohol or a high-carbohydrate meal.
Diagnostic Process
The diagnosis of citrin deficiency begins with newborn screening programs that identify certain blood abnormalities. These initial results prompt more specific follow-up testing to confirm the condition.
Biochemical tests are used to identify the metabolic signatures of the deficiency. These tests measure substances in the blood, including ammonia and specific amino acids. Elevated levels of citrulline and arginine are common findings.
While biochemical tests provide strong evidence, a definitive diagnosis is achieved through genetic testing. This involves analyzing the SLC25A13 gene to identify the mutations responsible for the disorder. Identifying two disease-causing mutations confirms the diagnosis and allows for genetic counseling for the family.
Management and Treatment Approaches
Management of citrin deficiency centers on dietary modifications. Unlike many other urea cycle disorders that require protein restriction, the recommended diet is low in carbohydrates and high in protein and fat. This approach helps bypass the metabolic block and provides alternative energy sources, which can prevent symptoms associated with FTTDCD and CTLN2.
Dietary therapy is supplemented with products to support metabolic function. Medium-chain triglyceride (MCT) oil is used as it provides a readily available energy source that does not rely on impaired metabolic pathways. Because the condition can affect nutrient absorption, supplements of fat-soluble vitamins may also be recommended to prevent deficiencies.
For individuals who develop the neurological symptoms of CTLN2, dietary management alone may not be sufficient. In these cases, liver transplantation is the only curative treatment. Replacing the patient’s liver with a healthy one provides a new organ with a functional citrin protein, which resolves the dangerous hyperammonemia.