Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation

Abstract

Objective-Adult onset type II citrullinemia is an inherited disorder of amino acid metabolism caused by a deficiency of liver specific argininosuccinate synthetase activity. Most of the patients with this disease were reported in Japan and therefore, this disease has not been well recognised outside this country. The detailed clinical pictures of the patients with type II citrullinaemia are reported and their outcomes after liver transplantation referred to. Methods-Ten patients with this disease were evaluated. Seven of them underwent liver transplants using a graft obtained from a healthy family member. Results-There were six men and four women; the age of onset of encephalopathy ranged from 17 to 51 years. The initial symptom in nine patients was sudden onset disturbance of consciousness, and one patient had long been regarded as having a chronic progressive psychotic illness. High concentrations of plasma citrulline and ammonia were commonly seen on admission. Although brain CT or MRI lacked any consistent findings, the EEG was abnormal in all patients, showing diVuse slow waves. Additionally, in five patients chronic pancreatitis preceded the onset of encephalopathy. After liver transplantation the metabolic abnormalities, including abnormal plasma concentrations of citrulline and ammonia, were immediately corrected and all neuropsychic symptoms soon disappeared, except for impaired cognitive function in one patient. Six out of these seven patients returned to their previous social lives, including work. Conclusions-The clinical concept of adult onset type II citrullinaemia coincides well with the range of hepatic encephalopathy, and liver transplantation is a very promising therapeutic approach.

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

“…Patients diagnosed were from 11 to 79 years old with a mean age of 34.4 Ϯ 12.6 (n ϭ 102) Yasuda et al 2000). Although the prognosis is bad, liver transplantation is remarkably effective (Todo et al 1992;Yazaki et al 1996;Kawamoto et al 1997;Onuki et al 2000;Takenaka et al 2000;Kasahara et al 2001;Ikeda et al 2001). Symptoms are often provoked after medication, infection, or alcohol intake.…”

“…Most patients are thin, more than 90% showing a body mass index less than 20, and about 40% show an index less than 17. Pancreatitis, hyperlipidemia, and hepatoma are the major complications of CTLN2 Ikeda et al 2001;Tsujii et al 1976). …”

“…On the other hand, liver transplantation has been shown to be very effective. Following two cases of orthotopic liver transplantation performed at Pittsburgh in 1988 (Todo et al 1992) and at Brisbane in 1993 (Kawamoto et al 1997), 20 cases of CTLN2 in Japan have been treated with livingrelated partial liver transplantation (Yazaki et al 1996;Onuki et al 2000;Takenaka et al 2000;Kasahara et al 2001;Ikeda et al 2001). Liver transplantation normalizes most of the metabolic disturbances and symptoms, except those from brain atrophy already occurred.…”

“…These phenomena are useful for diagnosis of CTLN2 Tsuboi et al 2001;Ikeda et al 2001;Maruyama et al 2001;Oshiro et al 2002) and to determine the prognosis of the patients (Yagi et al 1988), and may be related to the finding that about 10% of the patients with CTLN2 suffer from hepatoma without liver cirrhosis at relatively young ages (Tsujii et al 1976;Kobayashi et al 2000).…”

Early Detection and Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency Missed by Newborn Screening Using Tandem Mass Spectrometry

“…Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) is another recognized stage of the disease that is characterized by retarded growth and fatty liver in childhood [9]. In the second or later decades, some individuals with citrin deficiency develop CTLN2 with liver dysfunction that is severe enough to require a liver transplantation [10]. The variety of symptoms associated with a lifelong citrin deficiency suggests a need for early diagnosis and treatment to prevent morbidity [11,12].…”