NeurometPlus

Incidence

An autosomal recessive mode of inheritance has been demonstrated in two separate kindreds. Of the 13 paediatric cases, 12 have been of Dutch origin. The defect has also been identified in an adolescent and four adults, and in three of the latter it was the metabolic basis for drug-induced toxicity during 5'-FU therapy, suggesting this defect may not be as rare as previously thought.

Clinical Characteristics

There is considerable genetic heterogeneity in clinical expression. Great phenotypic variability had been observed with DPD deficiency, with convulsive disorders, motor retardation, and mental retardation being the most frequent manifestations. The defect has been described in children and adults. The paediatric patients so far reported have not exhibited a characteristic clinical picture. Microcephaly has been a consistent finding. The hallmarks of the more severe form appear to be developmental retardation, epilepsy and muscular hypotonia, this neurological picture being associated with NMR evidence of severe delay in myelination of the brain parenchyma. In the majority, psychomotor development is normal initially, but speech retardation, developmental delay and behavioural changes, with varying degrees of involvement, may develop subsequently. Four cases have had atypical epileptic seizures of late onset.

Precipitants

Patients with DHPD deficiency should not be given 5'-FU.

Provocation Tests

Oral loading with uracil or thymine, resulting in the recovery of more than 70% of the load in urine, may also be used to confirm the defect.

Diagnostic Procedures

High levels of thymine and uracil are found in the urine by GC-MS or HPLC. Plasma ammonia, plasma and urinary amino acids and other routine clinical chemistry are normal. DHPD deficiency may be confirmed by demonstrating the enzyme defect in cultured fibroblasts and leucocytes.