Megaloblastic Anemia Due To Dihydrofolate Reductase Deficiency

A number sign (#) is used with this entry because megaloblastic anemia due to dihydrofolate reductase deficiency is caused by homozygous mutation in the dihydrofolate reductase gene (DHFR; 126060) on chromosome 5q.

Description

Dihydrofolate reductase deficiency is an autosomal recessive metabolic disorder characterized by the hematologic findings of megaloblastic anemia and variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy (Banka et al., 2011) to childhood absence epilepsy with learning difficulties to lack of symptoms (Cario et al., 2011). Treatment with folinic acid can ameliorate some of the symptoms.

Clinical Features

Banka et al. (2011) reported a boy, born of first-cousin British Pakistani parents, who presented at age 4 months with megaloblastic anemia and acquired microcephaly. He showed poor feeding, pallor, and soon developed pancytopenia and refractory seizures. Brain MRI showed severe cerebral and cerebellar atrophy. Laboratory studies showed normal serum folate, vitamin B12, and ferritin levels, but the CSF showed markedly decreased 5-methyltetrahydrofolate (5-MTHF) and low tetrahydrobiopterin (BH4). There was no methylmalonic aciduria, and plasma homocysteine was normal. Oral folinic acid improved the anemia and seizures, but the CSF BH4 levels continued to drop. At age 19 months, he was profoundly delayed with central hypotonia, poor head control, and inability to fix and follow. An older sib died at 28 weeks of age with a history of anemia and intractable seizures of undefined cause. Postmortem examination showed a small brain, with ventricular dilatation and white matter atrophy of the cerebrum. There was neuronal loss in the cerebellar folia and neuronal and vascular calcifications in the basal ganglia and subcortical white matter, respectively. Banka et al. (2011) also reported a second unrelated child of Pakistani descent with the disorder. He presented at age 10 weeks with poor feeding, icterus, hepatomegaly, and megaloblastic anemia. Brain MRI showed hypoplasia of the cerebellar vermis and delayed myelination. At age 5 years, he was microcephalic with severe developmental delay and ataxia.

Cario et al. (2011) reported 3 sibs, born of distantly related parents of European descent, with DHFR deficiency and a comparatively milder phenotype than that reported by Banka et al. (2011). The oldest sib had no clinical symptoms at age 11 years and had red cell macrocytosis, but no anemia. The second sib presented at age 5 years with megaloblastic anemia and normal serum folate. He was treated with folic acid, which resolved the anemia, but he later developed learning disabilities and absence epilepsy with eyelid myoclonia at age 8. The third sib had a complicated febrile seizure at age 2 years. Laboratory studies showed macrocytosis without anemia, and she had normal development. At age 5, she developed absence seizures with eyelid myoclonia and was treated with folic acid. The CSF showed low or absent 5-MTHF, which responded to folinic acid in 2 patients studied. Irregular treatment resulted in seizure onset.

Molecular Genetics

In 6 patients with megaloblastic anemia and DHFR deficiency, Banka et al. (2011) and Cario et al. (2011) simultaneously and independently identified homozygous mutations in the DHFR gene (L80F; 126060.0001 and D153V; 126060.0002, respectively). The phenotypes were different: the 3 patients reported by Banka et al. (2011) had severely delayed psychomotor development, generalized seizures, and cerebral and cerebellar atrophy, whereas the 3 sibs reported by Cario et al. (2011) were either asymptomatic or had childhood absence epilepsy with eyelid myoclonus and mild learning disabilities. Treatment with folinic acid ameliorated the hematologic and seizure phenotypes. The phenotype was caused by decreased cerebral levels of methyltetrahydrofolate.

History

Walters (1967) described an infant with megaloblastic anemia who responded to parenteral administration of 100 micrograms of N(5)-formyltetra hydrofolate but not to the same dose of folic acid. These findings suggested an abnormality in dihydrofolate reductase activity, which was supported by findings of hepatic biopsy. Erbe (1975) reported follow-up of the patient. At age 19, he manifested mild mental retardation and sociopathic behavior leading to repeated incarcerations. However, no deficiency of dihydrofolate reductase could be shown in cultured skin fibroblasts.

Tauro et al. (1976) described 2 unrelated families, in each of which 2 sibs had severe megaloblastic anemia from birth. Deficiency of dihydrofolate reductase prevented conversion of folic acid to tetrahydrofolic acid. The 2 patients so treated responded to parenteral 5-formyltetrahydrofolic acid. The abnormality of dihydrofolate reductase differed in the 2 families. In the first family, liver enzyme activity was at first undetectable but was restored to normal by high cation concentration in the assay. In the second, the enzyme measured one-quarter normal in liver and was restored to only half-normal by high cation concentration. However, Banka et al. (2011) stated that the first patient was later found to have methionine synthase reductase deficiency (236270) and the second patient was later found by Hoffbrand et al. (1984) to have transcobalamin II deficiency (275350).