Orotic aciduria type I. Hereditary orotic aciduria (UMP synthase deficiency)
Incidence
Autosomal recessive. This is an extremely rare disorder and has been identified in 14 cases widely distributed geographically, including caucasians, orientals, Polynesians, American Indians and negroes.
Clinical Characteristics
The onset of symptoms has usually occurred in the first few months of life. All patients have had a macrocytic hypochromic megaloblastic anaemia unresponsive to the usual forms of therapy (iron, folic acid and B12), and sometimes leucopenia. Failure to thrive, developmental retardation, cardiac malformations, bilateral strabismus, sparse hair, inability to sit unaided, and gross crystalluria, occasionally with ureteric obstruction, have been general findings. Renal function is generally normal. Infections have occurred in some instances, associated with abnormalities of immune function. Heterozygotes show mild orotic aciduria but are otherwise unaffected. The enzyme defect is inherited in an autosomal recessive fashion and has been confirmed in liver, fibroblasts, lymphoblasts, erythrocytes and leucocytes from affected individuals.
Precipitants
No.
Provocation Tests
No.
Diagnostic Procedures
Homozygotes may be detected by the severe refractory megaloblastic anaemia and the high levels of orotic acid in the urine of up to 10 mmol (2g)/24 h, compared with normal values of less than 10 µmol (2 mg)/24 h. Urinary orotic acid may be measured colorimetrically, but blanks must be included since falsely raised values can be produced by histidine, septrin etc.HPLC methods specific for orotic acid measurement in plasma and urine are available and plasma orotic acid concentrations of 40 µmol/l, compared to the normal of less than 0.1 µmol/l, have been reported. The fractional clearance of orotic acid exceeds the GFR which indicates active secretion and explains why plasma levels are not raised unless accumulation is excessive. The defect may be confirmed by the low-to-undetectable levels of OPRT and ODC in lysed erythrocytes. The majority of patients have low but detectable activity of both OPRT and ODC in fibroblasts.