Megaloblastic anemia resistant to treatment is seen with

Ans. c (Orotic aciduria) (Ref. Harrison's Principles of Internal Medicine 17th ed., 651, 2449)Paragraph from Harrison's medicine 17th/p. 2449Orotic Aciduria# Hereditary orotic aciduria is caused by mutations in a bifunctional enzyme, uridine-S'-monophosphate (UMP) synthase, which converts orotic acid to UMP in the de novo synthesis pathway.# It is characterized by: hypochromic megaloblastic anemia that is unresponsive to vitamin B12 and folic acid, growth retardation, and neurologic abnormalities.# Increased excretion of orotic acid causes crystalluria and obstructive uropathy.# Replacement of uridine (100-200 mg/kg per day) corrects the anemia, reduces orotic acid excretion, and improves the other sequelae of the disorder.OROTIC ACIDURIA# It is a rare disorder of pyrimidine metabolism.# Two enzymatic functions are defective in this disorder:- Orotidine-5-prime-pyrophosphorylase and- Decarboxylase for orotidine-5-prime-phosphate.# Characterised by- Hypochromic anemia with megaloblastic changes in bone marrow not responding to folic acid or vit.BI2,- Leukopenia,- Retarded growth, and- Urinary excretion of orotic acid# The phenotypic features of orotic aciduria:# Megaloblastic anemia that is unresponsive to vitamin B12 and folic acid.# Hypochromic, microcytic circulating erythrocytes that persist with administration of iron or pyridoxine.# Large amounts of orotic acid in the urine.# Correction of anemia and i in orotic acid excretion on uridylic acid and cytidylic acid administration.MEGALOBLASTIC ANEMIA: TREATMENTTreatment of Cobalamin Deficiency# Lifelong regular cobalamin injections.# Cobalamin should be given routinely to all patients who have had a total gastrectomy or ileal resection.# Patients who have undergone gastric reduction for control of obesity or who are receiving long-term treatment with proton pump inhibitors should be screened and, if necessary, given cobalamin replacement.# Replenishment of body stores should be complete with six lOOOmg IM inj of hydroxocobalamin at 3-7 day intervals.# For maintenance therapy, 1000 mg hydroxocobalamin IM once every 3 months is satisfactory.# Sublingual therapy has also been proposed for those in whom injections are difficult.Treatment of Folate Deficiency# Oral doses of 5-15 mg folic acid daily for about 4 months# Before large doses of folic acid are given, cobalamin deficiency must be excluded and, if present, corrected, other- wise cobalamin neuropathy may develop, despite a response of the anemia of cobalamin deficiency to folate therapy.# Long-term folic acid therapy is required in chronic dialysis or hemolytic anemias, in gluten-induced enteropathy.