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608 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 609

Hereditary Folate Malabsorption OTHER CAUSES OF MEGALOBLASTIC ANEMIA
Hereditary folate malabsorption is a rare inherited disorder in which Congenital Dyserythropoietic Anemia
patients cannot absorb folate from the gastrointestinal tract or trans- The congenital dyserythropoietic anemias are lifelong anemias. They
port it across the choroid plexus and into the cerebrospinal fluid. 29,30 often are mild, showing dysplastic changes affecting the red cell line
The molecular basis for this disorder is caused by abnormalities in the only, most typically multinuclearity of the normoblasts. They appear to
PCFT. Patients present with severe megaloblastic anemia, seizures, result from defects in glycosylation of polylactosaminoglycans linked
29
mental retardation, and other CNS findings. Folate levels are low in to membrane proteins and ceramides. Of the three types, two (type I
412
419
the serum and nil in the cerebrospinal fluid. Folate given parenterally usually and type III occasionally ) show megaloblastic red cell pre-
420
421
has corrected the anemia and seizures in some patients but has had no cursors (Chap. 39).
effect on other CNS symptoms or on the cerebrospinal fluid folate level.
Treatment with daily folinic acid by injection maintains the spinal fluid Refractory Megaloblastic Anemia
level and can lead to normal development. 389
Refractory megaloblastic anemia is regarded as a manifestation of some
Dihydrofolate Reductase Deficiency sideroblastic anemias (Chap. 59) and myelodysplastic disorders (Chap.
422
Dihydrofolate reductase deficiency may present isolated megaloblastic 87). The megaloblastic changes are atypical. Dysplastic features are
anemia within days or weeks after birth. The anemia responds to folinic confined to the erythroid series. Giant metamyelocytes and bands are
acid but not to folic acid. 413 absent from the marrow. A few patients with refractory megaloblastic
anemia respond to pharmacologic doses of pyridoxine (200 mg/day),
423
5
N -Methyltetrahydrofolate–Homocysteine Methyltransferase perhaps because of an effect on serine transformylase, which requires
Deficiency both pyridoxine and folate.
Decreased methyltransferase activity was described in a liver biopsy
from a child with megaloblastic anemia and mental retardation. The Acute Erythroid Leukemia
anemia failed to respond to folate, cobalamin, or pyridoxal phosphate. In acute erythroid leukemia, a variety of acute myelogenous leukemia
414
424
The phenotype of this disorder resembles the inborn errors of cobal- (Chap. 89) nucleated red cells appear on the blood film, there is usu-
amin metabolism affecting the methionine synthesis reaction and has ally marked anisocytosis and anisochromia, and macrocytes are usually
not been well characterized as a distinct entity at the molecular level. present. The marrow shows pronounced erythroid hyperplasia involv-
ing very bizarre looking megaloblast-like red cell precursors, often con-
Methylene Tetrahydrofolate Reductase Deficiency taining multiple nuclei or nuclear fragments (see Chap. 88, Fig. 88–1)
In this rare autosomal recessive disorder there is a severe hyperhomo- together with increased numbers of blasts. The megaloblastoid ery-
cysteinemia and homocystinuria with low plasma methionine. Patients throid precursors frequently appear vacuolated.
have neurologic and vascular complications but no megaloblastic Consideration of the rarer causes of megaloblastic anemia is
anemia or methylmalonic aciduria. The polymorphic variations in important when the common and correctable causes resulting from
389
MTHFR have been discussed earlier as well as their influence on dis- folate or cobalamin deficiencies have been excluded. This is particularly
ease susceptibility and the influence of the enzyme on the distribution important in the pediatric age group, but also in patients who are refrac-
of major folate species toward either methylation or DNA synthetic tory to treatment with either folate or cobalamin.
pathways.
REFERENCES
OTHER INBORN ERRORS 1. Butterworth CJ, Santini RJ, Frommeyer WJ: The pteroylglutamate components of
Hereditary Orotic Aciduria American diets as determined by chromatographic fractionation. J Clin Invest 42:1929–
1939, 1963.
Hereditary orotic aciduria is an autosomal recessive disorder of pyrim- 2. Stover PJ, Field MS: Trafficking of intracellular folates. Adv Nutr 2(4):325–331, 2011.
idine metabolism characterized by megaloblastic anemia, growth 3. Institute of Medicine: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin
415
impairment, and excretion of orotic acid in the urine. Cobalamin and B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. The National Academies
Press, Washington, DC, 2000.
folate levels are normal. 4. von der Porten AE, Gregory JF 3rd, Toth JP, et al: In vivo folate kinetics during
chronic supplementation of human subjects with deuterium-labeled folic acid. J Nutr
Lesch-Nyhan Syndrome 122(6):1293–1299, 1992.
The Lesch-Nyhan syndrome is an X-linked disorder of purine metabo- 5. Herbert V: Experimental nutritional folate deficiency in man. Trans Assoc Am Physi-
cians 75:307–320, 1962.
lism characterized by hyperuricemia, hyperuricosuria, and a neurologic 6. Halsted C: Folate deficiency in alcoholism. Am J Clin Nutr 33(12):2736–2740, 1980.
disease with self-mutilation. It is caused by a hypoxanthine–guanine 7. Alperin J, Hutchinson H, Levin W: Studies of folic acid requirements in megaloblastic
phosphoribosyltransferase deficiency. One patient described had meg- anemia of pregnancy. Arch Intern Med 117(5):681–688, 1966.
aloblastic anemia. 416 8. Schwarz R, Johnston RJ: Folic acid supplementation—When and how. Obstet Gynecol
88(5):886–887, 1996.
9. Ulevitch R, Kallen R: Purification and characterization of pyridoxal 5′-phosphate
Thiamine-Responsive Megaloblastic Anemia dependent serine hydroxymethylase from lamb liver and its action upon beta-
Seven children with severe megaloblastic anemia, sensorineural deaf- phenylserines. Biochemistry 16(24):5342–5350, 1977.
ness, and diabetes mellitus, all beginning in infancy, have been reported. 10. Anderson DD, Stover PJ: SHMT1 and SHMT2 are functionally redundant in nuclear de
novo thymidylate biosynthesis. PLoS One 4(6): E5839, 2009.
The anemia responded to thiamine (25 to 100 mg/day). The marrow 11. Deacon R, Chanarin I, Perry J, Lumb M: Marrow cells from patients with untreated per-
was reported as myelodysplastic in two patients with the disorder. nicious anaemia cannot use tetrahydrofolate normally. Br J Haematol 46(4):523–528,
417
The gene for this puzzling disorder has been mapped to the long arm 2009.
of chromosome 1, and the underlying biochemical defect is caused by 12. Wahba A, Friedkin M: The enzymatic synthesis of thymidylate. I. Early steps in the
purification of thymidylate synthetase of Escherichia coli. J Biol Chem 237:3794–3801,
reduced nucleic acid production through impairment of the thiamine 1962.
dependent pentose cycle enzyme transketolase that results in cell-cycle 13. Fenech M: The role of folic acid and vitamin B12 in genomic stability of human cells.
Mutat Res 475(1–2):57–67, 2001.
arrest and the megaloblastic phenotype. This condition is also dis- 14. Huennekens F: Folic acid coenzymes in the biosynthesis of purines and pyrimidines.
418
cussed in Chap. 44. Vitam Horm 26:375–394, 1968.

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