Citrullinemia is a urea cycle disorder and type I citrullinemia is the classic form of the disease. It is characterized by the accumulation of ammonia and other toxic nitrogenous substances in the body and defects in the ASS1 gene. The ASS1 gene encodes argininosuccinate synthetase 1 enzyme, one of the enzymes involved in the urea cycle. Defects in the enzyme disrupt the urea cycle, causing the accumulation of several nitrogenous toxic compounds, including ammonia, causing the characteristic signs and symptoms of type I citrullinemia.
Type I citrullinemia itself can be of a common severe form and a less common milder form. The former manifests itself in the very first days of an affected infant's life in the form of severe lethargy, poor feeding, seizures and loss of consciousness. The milder form has its onset in childhood or early adulthood and is characterized by intense headaches, lethargy, ataxia, and balance and vision problems. Classic citrullinemia is estimated to affect about 1 in every 57,000 live births worldwide.
A diagnosis of classical citrullinemia can be confirmed upon the following: hyperammonimia, reduced plasma argininosuccinic acid and increased plasma citrulline levels, and reduced tissue assay of arginiosuccinate synthetase enzyme activity. Mutation analysis of the ASS1 gene is also available for a one-step detection. Management strategies include going on a high calorie-low protein diet, supplementation of arginine, and administration of sodium phenylbutyrate and L-carnitine. Hemodialysis is frequently used in times of emergency. Liver transplantation may also be required. It is important to limit exposure to infectious diseases.
Yadav and Reavey (1988) conducted a quantitative amino acid analysis in 800 subjects over a three-year period in Al-Sabah Hospital. Thirty-five patients with aminoacidopathy were identified, all but two of whom were the offspring of first-degree consanguineous marriages. Among the patients, four had citrullinemia.
Three citrullinemic sibs from a Kuwaiti Bedouin family were reported and discussed by Mady (1994). The family also included a discordant identical twin. [Mady SA. Citrullinemia: report of three Bedouin sibs and review. Med Princ Pract. 1994; 4(3):154-8.]
Vilaseca et al. (2001) conducted a molecular analysis of five Mediterranean patients with citrullinemia. Mutational analysis revealed that two Moroccan siblings were homozygous for G390R.
Joshi et al. (2002) carried out a retrospective analysis of all patients born with inborn errors of metabolism in Oman between June 1998 and December 2000. Among 82 patients, three were diagnosed with citrullinemia [CTGA Database Editor's note: Computed annual incidence rate is 2.4/100,000].
Al-Riyami et al (2012) reported on the types and patterns of IEMs encountered in a sample of 1100 high-risk neonates referred to SQU Hospital in Oman over a 10-year period (1998-2002). MS/MS was used to analyze blood samples from heel pricks. A total of 119 of these neonates were found to test positive for an IEM. Citrullinemia was detected in three neonates (two males, one female), belonging to three families. Two of the patients had a family history of the condition, while all three had consanguineous parents.
In 2003, the Hamad Medical Corporation, in partnership with the University Children's Hospital of Heidelberg built a comprehensive newborn screening program. Between December 2003 and July 2006, Lindner et al. (2007) investigated 25,214 neonates born in Qatar for inborn errors of metabolism and endocrine disorders. One neonate was diagnosed with citrullineaemia, type I. The screening result was received 9-days of age, and treatment was started at 10-days. However, the treatment was discontinued after 3-months because the phenotype was very mild.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Urea cycle disorders were diagnosed in 12 out of 248 cases. Among them, 6 cases from two families were found to have citrullinemia. The diagnosis was made based on the presence of hyperammonemia and the typical plasma amino acids profiles. The estimated incidence of this condition is 4 in 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
Al-Shamsi et al. (2014) undertook a study to calculate the birth prevalence of IEMs among Emiratis in the UAE by taking into consideration all neonates born with an inherited metabolic condition at Tawam Hospital between 1995 and 2012. A total of 37 distinct IEMs were found in Emirati neonates in this study, providing an estimated IEM birth prevalence of 75.24 per 100,000 live births. Citrullimemia, Type 1 was found to have a birth prevalence of less than 0.98 per 100,000. A single mutation in the ASS1 gene was identified in the affected patient(s).