Citrullinaemia and isolated sulphite oxidase deficiency in two siblings.

Abstract

Isolated sulphite oxidase deficiency (McKusick 272300), is a rare autosomal recessive metabolic disorder (Irreverre 1967) but its association with citrullinaemia in the same family and in the same patient is surely exceptional. We report the third (patient 1) and fourth (patient 2) children of a healthy consanguineous Portuguese couple. Two older siblings died in the neonatal period with 'intraventricular haemorrhage' and 'sepsis', respectively. Patient 1, a girl, presented at the first day of life with poor feeding, hypotonia, irritability, and later pedalling movements and coma. Diagnosis of citrullinaemia was made on day 4, based on the plasma ammonia (280 #mol/L; normal 15-40), eitrulline (634 #tool/L; normal 15-30) and undetectable arginine (normal 22-88 pmol/L). Other routine biochemical tests such as sulphite test, orotic and organic acids, were normal. A deficiency of argininosuccinate synthetase (ASS) was confirmed in a fibroblast culture (ASS activity 0.008 nmol/h per mg protein; controls 0.12-0.81). After peritoneal dialysis, a restricted-protein diet with arginine supplementation and sodium benzoate was instituted. Despite an early diagnosis and good metabolic control the child showed an unexplained progressive neurological deterioration and died at 8 months of age with meningitis. Prenatal diagnosis for ASS deficiency was carried out on the next pregnancy, revealing an unaffected female fetus (patient 2). This child, now 31⁄2 years old, became symptomatic at day 2 with seizures, hypotonia and hyporeactivity. Citrullinaemia was excluded by normal ASS activity in fibroblast culture (1.44#mol/min per mg protein; controls 1.01). Other systematic routine biochemical tests, including plasma uric acid and sulphite test, were normal. Re-evaluation at 2 years of age showed a spastic quadriparesis, head lag, microcephaly and optic atrophy without dislocated lenses. CT scans revealed cortical and subcortical atrophy. A diagnosis of isolated sulphite oxidase deficiency was suspected on the basis of an abnormal amino acid profile: S-sulphocysteine in plasma (20 #mol/L), S-sulphocysteine in urine (896/~mol/mmol creatinine), high taurine and low cyst(e)ine concentration in plasma. The sulphite test was then positive. Urinary excretion of xanthine and hypoxanthine was normal and plasma uric acid was always normal. Sulphite oxidase activity in fibroblasts was totally absent. All these results are in agreement with an isolated sulphite oxidase deficiency. Thereafter we re-established the fibroblast culture of the citrullinaemic case (patient 1) and here, too, sulphite oxidase activity was not detectable (controls 2.1/~kat/kg protein).