Abnormal Fatty Acid Metabolism in Peripheral Nerves of Patients with Pernicious Anemia

Abstract

A B S T R A C T Fatty acid synthesis from radiopropionate was evaluated. in sural nerve biopsy slices from five normal controls and nine patients with pernicious anemia.The nerves were incubated in ["4C]propionate, the lipids were extracted, and the fatty acid methyl esters were chromatographed by gas-liquid chromatography. In the normal nerves the radiolabel was found primarily in short chain (C12 and C14) fatty acids. The nerves from pernicious anemia patients showed two fatty acids peaks that were not discernible in the normal nerves, and these fatty acids had retention times intermediate to those of myristic (C14.0) and palmitic (C160) acids and palmitoleic (C16 1) and stearic (C18 0) acids, respectively. These two peaks (a C15 and C17 fatty acid) contained the bulk of the radioactivity recovered in the fatty acid fraction after incubation with ['4C]propionate. Catalytic reduction and rechromatography failed to alter the retention time of these compounds suggesting that they are not unsaturated fatty acids. The nerves from the pernicious anemia patients had a decrease in the mean content of normal fatty acids when compared with the nerves from control patients as well as a decrease in the mean synthesis of normal fatty acids as estimated by isotope incorporation after incubation with ["C]propionate or 'H20. Analysis of myelin isolated from the nerves indicated that the changes at least in part were in that fraction.A portion of this material was presented at the 63rd An- (Fig. 1) (4). The source of folate in this reaction is the storage form of folate, N -methyltetrahydrofolic acid. The clinical expression of vitamin B12 deficiency, via interference with this pathway, is based upon the need of B12 as a coenzyme for the methyltransferase reaction. Thus B12 deficiency results in a "trapping" of this storage folate reducing available active folate coenzyme forms. Since active folate is required in the conversion of deoxyuridylic acid to thymidylic acid, deprivation interferes with the pyrimidine biosynthetic pathway of deoxyribonucleic acid producing the classic megaloblastic changes seen in B12 deficiency (5-7). As would be anticipated folic acid bypasses this alteration and effectively repairs the defect even in the continued absence of vitamin B12 (Fig. 1).The second biochemical pathway that is affected by vitamin B12 deficiency is that responsible for the metabo-1,-1bbrcviations used in this tapier: GLC, gas-li(quid chromatograplly; PA, pernicious anemia.

Severe encephalopathy with epilepsy in an infant caused by subclinical maternal pernicious anaemia: case report and review of the literature

“…Furthermore, a secondary elevation of guanidinoacetate, which is known to be neurotoxic [23], may contribute to the pathogenesis of the encephalopathy in vitamin B 12 deficiency. On the other hand, reduced methylmalonyl-CoA breakdown results in an excess of the precursor propionyl-CoA which leads to odd-chain fatty acid synthesis and incorporation in nerve sheets with altered neural functions [2].…”

Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry.

“…Some investigators have favored a defect in L-methylmalonyl-CoA mutase as the cause and have suggested that the neuropsychiatric abnormalities are due to a buildup in propionyl-CoA and a resultant increase in odd number carbon fatty acids in peripheral nerves and the central nervous system (44)(45)(46) neuropsychiatric abnormalities in patients with Cbl deficiency. Our finding that serum methionine is not decreased in patients with Cbl deficiency would appear to argue against a mechanism involving a lack of methionine as the cause of the neuropsychiatric abnormalities, but it should be emphasized that levels of methionine in serum may not reflect levels of methionine in peripheral nerves and the central nervous system.…”

Nitrous oxide-induced B12 deficiency myelopathy: Perspectives on the clinical biochemistry of vitamin B12

“…This, in turn, has been shown to lead to the formation of abnormal fatty acids [12,[18][19][20][21]. In fact, the accumulation of propionyl-CoA leads to increased odd chain fatty acids, while an increase in methylmalonyl-CoA leads to an increase in branched chain fatty acids [19,20,23,24]. There are, in fact, several lines of experimental evidence which would seem to support this hypothesis, both from patient data and from animal models.…”