Type I
Type I citrullinemia (Online Mendelian Inheritance in Man (OMIM): 215700, also known as classic citrullinemia) usually becomes evident in the first few days of life. Affected infants typically appear normal at birth, but as ammonia builds up in the body, they develop a lack of energy (lethargy), poor feeding, vomiting, seizures, and loss of consciousness. These medical problems can be life-threatening in many cases. A milder form of type I citrullinemia is less common in childhood or adulthood. Some people with gene mutations that cause type I citrullinemia never experience signs and symptoms of the disorder. Diagnosis of citrullinemia type I is elevated citrulline in the blood. [2]
Type I citrullinemia is the most common form of the disorder, affecting about one in 57,000 births worldwide. Mutations in the ASS gene cause type I citrullinemia. The enzyme made by this gene, argininosuccinate synthetase (EC 6.3.4.5), is responsible for one step of the urea cycle. Mutations in the ASS gene reduce the activity of the enzyme, which disrupts the urea cycle and prevents the body from processing nitrogen effectively. Excess nitrogen, in the form of ammonia, and other byproducts of the urea cycle, accumulate in the bloodstream, leading to the characteristic features of type I citrullinemia. [2]
Adolescent and adult citrin deficiency (AACD), formerly known as type II citrullinemia (Online Mendelian Inheritance in Man (OMIM): 605814 and Online Mendelian Inheritance in Man (OMIM): 603471) is a clinical phenotype of citrin deficiency, caused by mutations in the SLC25A13 gene. AACD may appear in citrin deficiency patients during adolescence or adulthood and represents the most severe form of the condition. [3] Clinical symptoms may include strong food preference for protein/fat-rich foods, aversion to carbohydrates, sweets, and alcohol, hyperlipidemia, fatty liver, and hyperammonemia, with the latter resulting in neuropsychiatric symptoms (such as aggression, irritability, and hyperactivity), seizures, and coma. Diagnosis of AACD includes biochemical measurements such as raised blood ammonia and citrulline levels, liver function markers, and history of food preference. Genetic testing for SLC25A13 mutations remains the gold standard for confirmatory diagnosis. Known triggers of AACD onset include certain medications, serious infections, and high carbohydrate, sugar or alcohol intake. [3]
AACD occurs in an estimated one in 100,000 to 230,000 individuals, while the estimated incidence rate of citrin deficiency in Japan is one in 17,000 individuals, suggesting that not all citrin deficiency patients will develop this phenotype. AACD has also been reported in people from East Asian, Middle Eastern, South Asian, and Caucasian populations. Mutations in the SLC25A13 gene are responsible for AACD. This gene makes a protein called citrin, which normally shuttles certain molecules in and out of mitochondria. These molecules are essential for the urea cycle and are also involved in making proteins and nucleotides. Mutations in SLC25A13 typically prevent the production of 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 AACD.
