Maria Luís Cardoso

Clinical, biochemical and molecular characterization of Cystinuria in a cohort of 12 patients

Barbosa M, Lopes A, Mota C, Martins E, Oliveira J, Alves S, De Bonis P, do Céu Mota M, Dias C, Rodrigues‐Santos P, Fortuna AM, Quelhas D, Lacerda L, Bisceglia L, Cardoso ML. Clinical, biochemical and molecular characterization of Cystinuria in a cohort of 12 patients.

Liver transplantation in a case of argininaemia

De¢ciency of arginase (EC 3.5.3.1), which converts arginine to urea and ornithine, is a rare autosomal recessive disease (McKusick 207800) caused by mutations in the ARG1 gene on chromosome 6q23. Onset is usually in childhood and clinical manifestations include progressive spastic paraparesis and mental slowing. In contrast to other urea cycle disorders (UCDs), liver involvement is less frequent and usually not as severe as, for instance, that observed in ornithine carbamyltransferase de¢ciency or in citrullinaemia. Moreover, while patients with other UCDs are at risk for intercurrent hyperammonaemic episodes even when they are on aggressive nutritional and dietary management, recurrent hyperammonaemia is not a primary feature of argininaemia (Colombo 1992). Consistently, patients with argininaemia are scarcely considered as candidate for liver transplantation. However, the rationale for orthotopic liver transplantation (OLT) still stands in this condition, because it would replace a de¢cient enzyme with an active hepatic arginase. We report a successful OLT in a patient with arginase de¢ciency in whom severe liver involvement was the only clinical manifestation. The proposita had an uneventful perinatal and neonatal period. At birth, she weighed 3050 g (P25), her height was 50 cm (P50) and her head circumference was 33.5 cm (P10). At age 2 months, cholestatic jaundice and hepatosplenomegaly were detected. Laboratory investigations showed total serum bilirubin of 186 mmol/L (normal < 17), conjugated serum bilirubin 161 mmol/L (normal < 3:5), SGOT 186UI/L (normal < 56), SGPT 530 UI/L (normal < 39), gGT 85UI/L (normal < 45), total cholesterol 7.1 mmol/L (normal 3.4^4.8), thromboplastin time 55.3 s (normal 35 s), prothrombin time 33.9 s (normal 14 s). Plasma arginine concentrations were elevated (1756 mmol/L). A liver biopsy revealed porta-porta septa, canalicular cholestasis, ductular proliferation and mononuclear portal in¢ltrates. The di¡erential diagnosis included extrahepatic biliary atresia, choledocal cyst, a1-antitrypsin de¢ciency and infectious diseases (TORCH, syphilis, B hepatitis), all ruled out by appropriate testing. De¢ciency of arginase A1 activity was con¢rmed in blood red cells. Molecular genetic analyses detected the homozygous R21X mutation in the ARG1 gene. She was put on a low-protein, J. Inherit. Metab. Dis. 24 (2001) 885^887 # SSIEM and Kluwer Academic Publishers. Printed in the Netherlands.

Liver Transplantation Prevents Progressive Neurological Impairment in Argininemia

Argininemia is a rare hereditary disease due to a deficiency of hepatic arginase, which is the last enzyme of the urea cycle and hydrolyzes arginine to ornithine and urea. The onset of the disease is usually in childhood, and clinical manifestations include progressive spastic paraparesis and mental retardation. Liver involvement is less frequent and usually not as severe as observed in other UCDs. For this reason, and because usually there is a major neurological disease at diagnosis, patients with argininemia are rarely considered as candidates for OLT despite its capacity to replace the deficient enzyme by an active one. We report on long-term follow-up of two patients with argininemia. Patient 1 was diagnosed by the age of 20 months and despite appropriate conventional treatment progressed to spastic paraparesis with marked limp. OLT was performed at 10 years of age with normalization of plasmatic arginine levels and guanidino compounds. Ten years post-OLT, under free diet, there is no progression of neurological lesions. The second patient (previously reported by our group) was diagnosed at 2 months of age, during a neonatal cholestasis workup study. OLT was performed at the age of 7 years, due to liver cirrhosis with portal hypertension, in the absence of neurological lesions and an almost-normal brain MRI. After OLT, under free diet, there was normalization of plasmatic arginine levels and guanidino compounds. Twelve years post-OLT, she presents a normal neurological examination. We conclude that OLT prevents progressive neurological impairment in argininemia and should be considered when appropriate conventional treatment fails.

Current Issues Regarding Prenatal Diagnosis of Inborn Errors of Cholesterol Biosynthesis

Maria Luis Cardoso1,2, Mafalda Barbosa3,4, Ana Maria Fortuna3 and Franklim Marques1,2 1Faculty of Pharmacy, University of Porto, Porto 2Institute for Molecular and Cell Biology, University of Porto, Porto 3Medical Genetics Centre Jacinto Magalhaes, National Health Institute Ricardo Jorge Porto 4Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga Portugal