Summary
In humans, subacute combined degeneration of the spinal cord and brain, a primary demyelinating disease, is caused by cobalamin or methyltetrahydrofolate deficiency. Experimental studies into its pathogenesis suggest that dysfunction of the methyl-transfer pathway may be the cause. Compelling evidence for this comes from the study of inborn errors of cobalamin metabolism where deficiency of methylcobalamin, but not deoxyadenosylcobalamin, is associated with demyelination. Recent studies have focused upon inborn errors of the methyl-transfer pathway. Cerebrospinal fluid concentrations of metabolites of the methyl-transfer pathway have been measured in humans with sequential errors of the pathway and correlated with demyelination demonstrated on magnetic resonance imaging of the brain. This has provided new data suggesting that deficiency ofS-adenosylmethionine is critical to the development of demyelination in cobalamin deficiency.
Similar content being viewed by others
References
Adams RD, Kubik CS (1944) Subacute degeneration of the brain in pernicious anemia.N Engl J Med 231: 1–9.
Amur SG, Shanker G, Cochran JM, Ved HS, Pieringer RA (1986) Correlation between inhibition of myelin basic protein (arginine) methyltransferase by sinefungin and lack of compact myelin formation in cultures of cerebral cells from embryonic mice.J Neurosci Res 16: 367–376.
Auletta A, Gery A, Parmar A, Davis J, Mishra L, Mead J (1974) The effect of folate and folate analogues upon dihydrofolate reductase and DNA synthesis in kidneys of normal mice.Life Sci 14: 1541–1553.
Beckman DR, Hoganson G, Berlow S, Gilbert EF (1987) Pathological findings in 5,10-methylenetetrahydrofolate deficiency.Birth Defects 23: 47–64.
Billings F (1902) The changes in the spinal cord and medulla in pernicious anemia.Boston Med Surg J 147: 225–233, 257–263.
Blackley R (1969)The Biochemistry of Folic Acid and Related Pteridines. Amsterdam: North-Holland.
Cantoni GL (1975) Biological methylation: selected aspects.Annu Rev Biochem 44: 435–451.
Carmel R, Watkins D, Goodman SL, Rosenblatt DS (1988) Hereditary defect of cobalamin metabolism (Cbl G mutation) presenting as a neurological disorder in adulthood.N Engl J Med 318: 1738–1741.
Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ (1986) Subacute combined degeneration of the cord, dementia and Parkinsonism due to an inborn error of folate metabolism.J Neurol Neurosurg Psychiatr 49: 920–927.
Crang AJ, Jacobson W (1980) The methylation in vitro of myelin basic protein by arginine methylase from mouse spinal cord.Biochem Soc Trans 8: 611–612.
Dayan AD, Ramsey RB (1974) An inborn error of vitamin B12 metabolism associated with cellular deficiency of coenzyme forms of the vitamin. Pathological and neurochemical findings in one case.J Neurol Sci 23: 117–128.
Deacon R, Purkiss P, Green R, Perry J, Chanarin I (1986) Vitamin B12 neuropathy is not due to failure to methylate myelin basic protein.J Neurol Sci 72: 113–117.
Frenkel EP (1971) Studies on the mechanism of the neural lesion of pernicious anemia.J Clin Invest 30: 33a-34a.
Ghosh SK, Syed SK, Jung S, Paik WK, Kim S (1990) Substrate specificity for myelin basic protein-specific protein methylase I.Biochim Biophys Acta 1039: 142–148.
Hoffman DR, Marion DW, Cornatzer WE, Duerre JA (1980)S-adenosylmethionine andS-adenosylhomocysteine metabolism in isolated rat liver. Effects ofl-methionine,l-homocysteine and adenosine.J Biol Chem 255: 10822–10827.
Hyland K, Smith I, Bottiglieri T et al (1988) Demyelination and decreasedS-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency.Neurology 38: 459–462.
Israëls MCG, Wilkinson JF (1949) Risk of neurological complications in pernicious anaemia treated with folic acid.Br Med J 2: 1072–1075.
Layzer RB, Fishman RA, Schaffer JA (1978) Neuropathy following abuse of nitrous oxide.Neurology 28: 504–506.
Lee C-C, Surtees R, Duchen L (1992) Distal motor axonopathy and central nervous system vacuolation caused by cycloleucine, an inhibitor of methionine adenosyltransferase.Brain 115: 935–955.
Lever EG, Elwes RDC, Williams A, Reynolds EH (1986) Subacute combined degeneration of the cord due to folate deficiency: response to methyl-folate treatment.J Neurol Neurosurg Psychiatr 49: 1203–1207.
Levitt M, Nixon P, Pincus J, Bertino J (1971) Transport characteristics of folate in cerebrospinal fluid; a study utilising doubly labelled 5-methyltetrahydrofolate and 5-formyltetrahydrofolate.J Clin Invest 50: 1301–1308.
Metz J (1992) Cobalamin deficiency and the pathogenesis of nervous system disease.Annu Rev Nutr 12: 59–79.
Lichtheim (1887) Zur kenntnis der perniciösen Anämie.Verhandl d Cong f Innere Med 6: 84–96.
Pallis CA, Lewis PD (1974)The Neurology of Gastrointestinal Disease. London: Saunders, 30.
Ramsey RB, Fischer VW (1978) Effect of 1-aminocyclopentane-1-carboxylic acid (cycloleucine) on developing rat central nervous system phospholipids.J Neurochem 30: 447–457.
Rosenberg LE, Fenton WA (1989) Disorders of propionate and methylmalonate metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds.The Metabolic Basis of Inherited Disease, 6th edn. New York: McGraw-Hill, 821–844.
Russell JSR, Batten FE, Collier J (1900) Subacute combined degeneration of the spinal cord.Brain 23: 39–110.
Schatz RA, Wilens TE, Sellinger OZ (1981) Decreased transmethylation of biogenic amines after in vivo elevation of brainS-adenosyl-l-homocysteine.J Neurochem 36: 1739–1748.
Scott JM, Dinn J, Wilson P, Weir DG (1981) Pathogenesis of subacute combined degeneration: a result of methyl group deficiency.Lancet 2: 334–337.
Small DH, Carnegie PR (1982) In vivo methylation of an arginine in chicken myelin basic protein.J Neurochem 38: 184–190.
Small DH, Carnegie PR, Anderson RMcD (1981) Cycloleucine-induced vacuolation of myelin is associated with inhibition of protein methylation.Neurosci Lett 21: 287–292.
Smith I, Hyland K, Kendall B, Leeming R (1985) Clinical role of pteridine therapy in tetrahydrobiopterin deficiency.J Inher Metab Dis 8 (Suppl 1): 39–45.
Surtees R (1992)S-Adenosylmethionine deficiency and demyelination. A study of the metabolites of the methyl-transfer pathway in cerebrospinal fluid. PhD thesis, University of London.
Surtees R, Hyland K (1990a) Cerebrospinal fluid concentrations ofS-adenosylmethione, methionine and 5-methyltetrahydrofolate in a reference population: cerebrospinal fluidS-adenosylmethionine declines with age in humans.Biochem Med Metab Biol 44: 192–199.
Surtees R, Hyland K (1990b)l-3,4-Dihydroxyphenylalanine (levodopa) lowers central nervous systemS-adenosylmethionine concentrations in humans.J Neurol Neurosurg Psychiatr 53: 569–572.
Surtees R, Leonard J, Austin S (1991) Association of demyelination with deficiency of cerebrospinal fluidS-adenosylmethionine in inborn errors of methyl-transfer pathway.Lancet 338: 1550–1554.
Tabor CW, Tabor H (1976) 1,4-Diaminobutane (putrescine), spermidine and spermine.Annu Rev Biochem 45: 285–306.
Ungley C (1949) Subacute combined degeneration of the cord. I. Response to liver extracts. II. Trials with vitamin B12.Brain 72: 382–427.
van der Westhuyzen J, Fernandes-Costa F, Metz J (1982) Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats: protection by methionine and aggravation by folates.Life Sci 31: 2001–2010.
van der Westhuyzen J, Metz J (1983) TissueS-adenosyl-methionine levels in fruit bats (Rousettus aegyptiacus) with nitrous oxide-induced neuropathy.Br J Nutr 50: 325–330.
Vieira-Makings E, Metz J, van der Westhuyzen J, Bottiglieri T, Chanarin I (1990) Cobalamin neuropathy. IsS-adenosylhomocysteine toxicity a factor?Biochem J 266: 707–711.
Vivaqua RJ, Myerson RM, Prescott DJ, Rabinowitz JL (1966) Abnormal propionic-methyl malonic-succinic acid metabolism in vitamin B12 deficiency and its possible relationship to the neurologic syndrome of pernicious anaemia.Am J Med Sci 251: 507–515.
Weir DG, Keating S, Molloy A et al (1988) Methylation deficiency causes vitamin B12-associated neuropathy in the pig.J Neurochem 51: 1949–1952.
Weir DG, Molloy AM, Keating JN et al (1992) Correlation of the ratio ofS-adenosyl-l-methionine toS-adenosyl-l-homocysteine in the brain and cerebrospinal fluid of the pig: implications for the determination of this methylation ratio in human brain.Clin Sci 82: 93–97.
Woltman HW (1918) Brain changes associated with pernicious anaemia.Arch Int Med 21: 791–843.
Zappia V, Salvatore F, Porcelli M, Cacciapuoti G (1979) Novel aspects in the biochemistry of adenosylmethionine and related sulphur compounds. In Zappia V, Usdin E, Salvatore F, eds.Biochemical and Pharmacological Roles of Adenosylmethionine and the Central Nervous System. Oxford: Pergamon Press, 1–16.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Surtees, R. Biochemical pathogenesis of subacute combined degeneration of the spinal cord and brain. J Inherit Metab Dis 16, 762–770 (1993). https://doi.org/10.1007/BF00711908
Issue Date:
DOI: https://doi.org/10.1007/BF00711908