CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families.

The cblE type of homocystinuria is a rare autosomal recessive disorder, which manifests with megaloblastic anaemia and developmental delay in early childhood. This disease is caused by a defect in reductive activation of methionine synthase (MTR). Our study was directed at clinical, biochemical, enzymatic and molecular characterization of two Czech patients with the cblE type of homocystinuria. Case 1 involves a 20-year-old mentally retarded patient who presented with megaloblastic anaemia at 10 weeks of age. She was treated with folates and vitamin B12, and subsequent attempts to cease administration of folates led to recurrence of megaloblastic anaemia. Biochemical features included severe hyperhomocysteinaemia and hypomethioninaemia and in fibroblasts defective formation of methionine from formate, and no complementation with cblE cells. Subsequent molecular analysis of the methionine synthase reductase (MTRR) gene revealed compound heterozygosity for a transition c.1459G>A (G487R) and a 2bp insertion (c.1623-1624insTA). Case 2 involves an 8-year-old girl with nystagmus and developmental delay in whom megaloblastic anaemia was detected at 11 weeks of age. Severe hyperhomocysteinaemia with normal methionine levels was found and enzymatic and complementation studies confirmed the cblE defect. This patient is homozygous for a 140 bp insertion (c.903-904ins140). The insertion is caused by a T>C transition within intron 6 of the MTRR gene, which presumably leads to activation of an exon splicing enhancer. In the families of both patients, enzymatic and mutation analyses were successfully used for prenatal diagnosis. Our study expands the knowledge of the phenotypic and genotypic variability of the cblE type of homocystinuria and supports the concept that this disorder is caused by mutations in the MTRR gene.