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Hyperhomocysteinaemia; with reference to its neuroradiological aspects

  • Paediatric Neuroradiology
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Abstract

Severe or even mild hyperhomocysteinaemia can cause a wide range of neurological problems. In recent years its vascular complications, including cerebral stroke, in children and young adults have gained special interest, because hyperhomocysteinaemia is treatable and recurrence of vascular incidents may be preventable. Current knowledge about biochemical mechanisms leading to hyperhomocysteinaemia, the pathogenesis of vascular pathology and neurological disfunction, and the various patterns of cerebral damage are reviewed. The significance of MRI in diagnosis, follow-up and research on hyperhomocysteinaemia is discussed.

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References

  1. Carson NAJ, Neill DW (1962) Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child 37: 505–513

    Google Scholar 

  2. Natowicz M, Kelley RI (1987) Mendelian etiologies of stroke. Ann Neurol 22:175–192

    Google Scholar 

  3. Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GHJ, Bromberg IL, Cerone R, Fowler B, Gröbe H, Schmidt H, Schweitzer L (1985) The natural history of homocystinuria due to cystathionine β-synthase deficiency. Am J Hum Genet 37:1–31

    Google Scholar 

  4. Mudd SH, Levy HL, Skovby F (1989) Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 693–734

    Google Scholar 

  5. Rosenblatt DS (1989) Inherited disorders of folate transport and metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 2049–2064

    Google Scholar 

  6. Fenton WA, Rosenberg LE (1989) Inherited disorders of cobalamin transport and metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 2065–2082

    Google Scholar 

  7. Tada K, Tateda H, Arashima S, Sakai K, Kitagawa T, Aoki K, Suwa S, Kawamura M, Oura T, Takesada M, Kuroda Y, Yamashita F, Matsuda I, Naruse H (1984) Follow-up study of a nation-wide neonatal metabolic screening program in Japan. Eur J Pediatr 142: 204–207

    Google Scholar 

  8. Skovby F, Krassikoff N, Francke U (1984) Assignment of the gene for cystathionine β-synthase to human chromosome 21 in somatic cell hybrids. Hum Genet 65:291–294

    Google Scholar 

  9. Watkins D, Rosenblatt DS (1988) Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups, cblE and cblG. J Clin Invest 81:1690–1694

    Google Scholar 

  10. Fenton WA, Rosenberg LE (1978) Genetic and biochemical analyses of human cobalamin mutants in cell culture. Ann Rev Genet 12:223–248

    Google Scholar 

  11. Coull BM, Malinow MR, Beamer N, Sexton G, Nordt F, deGarmo P (1990) Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke. Stroke 21:572–576

    Google Scholar 

  12. Mölgaard J, Malinow MR, Lassvik C, Holm AC, Upson B, Olsson AG (1992) Hyperhomocyst(e)inaemia: an independent risk factor for intermittent claudication. J Int Med 231:273–279

    Google Scholar 

  13. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH (1992) A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 268: 877–881

    Google Scholar 

  14. Boers GHJ, Smals AGH, Trijbels FJM, Fowler B, Bakkeren JAJM, Schoonderwaldt HC, Kleijer WJ, Kloppenborg PWC (1985) Heterozygosity of homocytinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 313:709–715

    Google Scholar 

  15. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I (1991) Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 324:1149–1155

    Google Scholar 

  16. Brattström L, Lindgren A (1992) Hyperhomocysteinemia as a risk factor for stroke. Neur Res 14:81–84

    Google Scholar 

  17. Franken DG, Boers GHJ, Blom HJ, Trijbels JMF, Kloppenborg PWC (1994) Treatment of mild hyperhomocysteinemia in vascular patients. Arterioscler Thromb 14:465–470

    Google Scholar 

  18. Ueland PM, Refsum H, Brattström L (1992) Plasma homocysteine and cardiovascular disease. In: Francis RB Jr (ed) Artherosclerotic cardiovascular disease, hemostasis, and endothelial function. Marcel Dekker, New York, pp 183–236

    Google Scholar 

  19. Boers GHJ, Fowler B, Smals AGH, Trijbels JMF, Leermakers AL, Kleijer WJ, Kloppenborg PWC (1985) Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts. Hum Genet 69:164–169

    Google Scholar 

  20. Kang SS, Wong PKW, Bock HG, Horwitz A, Grix A (1991) Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations. Am J Hum Genet 48:546–551

    Google Scholar 

  21. Kang SS, Wong PKW, Susmano A, Sora J, Norusis M, Ruggie N (1991) Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet 48:536–545

    Google Scholar 

  22. Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J (1988) Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 81:466–474

    Google Scholar 

  23. Wilcken DEL, Dudman NPB, Tyrrell PA, Robertson MR (1988) Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: possible implications for prevention of vascular disease. Metabolism 37:697–701

    Google Scholar 

  24. Hultberg B, Agardh E, Andersson A, Brattström L, Isaksson A, Israelsson B, Agardh CD (1991) Increased levels of plasma homocysteine are associated with nephropathy, but not severe retinopathy in type I diabetes mellitus. Scand J Clin Lab Invest 51:277–282

    Google Scholar 

  25. Ueland PM, Refsum H (1989) Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease and drug therapy. J Lab Clin Med 114: 473–501

    Google Scholar 

  26. Skovby F (1985) Homocystinuria: Clinical, biochemical and genetic aspects of cystathionine β-synthase and its deficiency in man. Acta Paediatr Scand (Suppl) 321:1–21

    Google Scholar 

  27. Brett EM (1966) Homocystinuria with epilepsy. Proc Roy Soc Med 59:484–487

    Google Scholar 

  28. Grieco AJ (1977) Homocystinuria: pathogenetic mechanism. Am J Med Sci 273:120–132

    Google Scholar 

  29. Abbott MH, Folstein SE, Abbey H, Pyeritz RE (1987) Psychiatric manifestations of homocystinuria due to cystathionine β-synthase deficiency: prevalence, natural history, and relationship to neurological impairment and vitamin B6-responsiveness. Am J Med Genet 26:959–969

    Google Scholar 

  30. Davous P, Rondot P (1983) Homocystinuria and dystonia (letter). J Neurol Neurosurg Psychiatry 46:283

    Google Scholar 

  31. Kempster PA, Brenton DP, Gale AN, Stern GM (1988) Dystonia in homocystinuria. J Neurol Neurosurg Psychiatry 51:859–862

    Google Scholar 

  32. Shih VE, Salam MZ, Mudd SH, Uhlendorf BW, Adams RD (1972) A new form of homocystinuria due to N5N10-methylenetetrahydrofolate reductase deficiency (abstract). Pediatr Res 6: 395/135

    Google Scholar 

  33. Mudd SH, Uhlendorf BW, Freeman JM, Finkelstein JD, Shih VE (1972) Homocystinuria associated with decreased methylenetetrahydrofolate reductase activity. Biochem Biophys Res Commun 46:905–912

    Google Scholar 

  34. Christensen E, Brandt NJ (1985) Prenatal diagnosis of 5,10-methylenetetrahydrofolate reductase deficiency (letter) N Engl J Med 313:50–51

    Google Scholar 

  35. Visy JM, LeCoz P, Chadefaux B, Fressinaud C, Woimant F, Marquet J, Zittoun J, Visy J, Vallat JM, Haguenau M (1991) Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency revealed by stroke in adult siblings. Neurology 41:1313–1315

    Google Scholar 

  36. Cochran FB, Packman S (1992) Homocystinuria presenting as sagittal sinus thrombosis. Eur Neurol 32:1–3

    Google Scholar 

  37. Nishimura M, Yoshino K, Tomita Y, Takashima S, Tanaka J, Narisawa K, Kurobane I (1985) Central and peripheral nervous system pathology of homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency. Pediat Neurol 1:375–378

    Google Scholar 

  38. Haworth JC, Dilling LA, Surtees RAH, Seargeant LE, Lue-Shing H, Cooper BA, Rosenblatt DS (1993) Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers. Am J Med Genet 45:572–576

    Google Scholar 

  39. Cooper BA, Rosenblatt DS (1987) Inherited defects of vitamin B12 metabolism. Ann Rev Nutr 7:291–320

    Google Scholar 

  40. Carmel R, Watkins D, Goodman SI, Rosenblatt DS (1988) Hereditary defect of cobalamin metabolism (cblG mutation) presenting as a neurologic disorder in adulthood. N Engl J Med 318:17380–1741

    Google Scholar 

  41. Mitchell GA, Watkins D, Melançon SB, Rosenblatt DS, Geoffroy G, Orquin J, Barsoum Homsy M, Dallaire L (1986) Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria. J Pediatrics 108:410–415

    Google Scholar 

  42. Shinnar S, Singer HS (1984) Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence: a treatable cause of dementia and myelopathy. N Engl J Med 311: 451–454

    Google Scholar 

  43. Brattström L, Lindgren A, Israelsson B, Malinow MR, Norrving B, Upson B, Hamfelt A (1992) Hyperhomocysteinaemia in stroke: prevalence, cause, and relationship to type of stroke and stroke risk factors. Eur J Clin Invest 22: 214–221

    Google Scholar 

  44. White HH, Rowland LP, Araki S, Thompson HL, Cowen D (1965) Homocystinuria. Arch Neurol 13:455–470

    Google Scholar 

  45. Carson NAJ, Dent CE, Field CMB, Gaull GE (1965) Homocystinuria: clinical and pathological review of ten cases. J Pediatr 66:565–583

    Google Scholar 

  46. Schoonderwaldt HC, Boers GHJ, Gruysberg JRM, Schulte BPM, Slooff JL, Thijssen HOM (1981) Neurological manifestations of homocystinuria. Clin Neurol Neurosurg 83:153–162

    Google Scholar 

  47. Chou SM, Waisman HA (1965) Spongy degeneration of the central nervous system. Arch Pathol 79:357–363

    Google Scholar 

  48. Dunn HG, Perry TL, Dolman CL (1966) Homocystinuria. A recently discovered cause of mental defect and cerebrovascular thrombosis. Neurology 16:407–420

    Google Scholar 

  49. Kanwar YS, Manaligod JR, Wong PKW (1976) Morphologic studies in a patient with homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency. Pediatr Res 10:598–609

    Google Scholar 

  50. Wong PKW, Justice P, Hruby M, Weiss EB, Diamond E (1977) Folic acid nonresponsive homocystinuria due to methylenetetrahydrofolate reductase deficiency. Pediatrics 59:749–756

    Google Scholar 

  51. Baumgartner ER, Wick H, Ohnacker H, Probst A, Mauer R (1980) Vascular lesions in two patients with congenital homocystinuria due to different defects of remethylation. J Inher Metabl Dis 3: 101–103

    Google Scholar 

  52. Beckman DR, Hoganson G, Berlow S, Gilbert EF (1987) Pathological findings in 5,10-methylenetetrahydrofolate reductase deficiency. Birth Defects 23: 47–64

    Google Scholar 

  53. 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 Psychiatry 49:920–927

    Google Scholar 

  54. Dillon MJ, England JM, Gompertz D, Goodey PA, Grant DB, Hussein HAA, Linnell JC, Matthews DM, Mudd SH, Newns GH, Seakins JWT, Uhlendorf BW, Wise IJ (1974) Mental retardation, megaloblastic anaemia, methylmalonic aciduria and abnormal homocysteine metabolism due to an error in vitamin B12 metabolism. Clin Sci Mol Med 47:43–61

    Google Scholar 

  55. Erbe RW (1986) Inborn errors of folate metabolism. In: Blakeley RL, Whitehead VM (eds) Folates and pterins: nutritional, pharmalogical and physiological aspects. Vol 3. John Wiley and Sons, New York, pp 413–465

    Google Scholar 

  56. 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

    Google Scholar 

  57. Duchen LW, Jacobs JM (1992) Nutritional deficiencies and metabolic disorders. In: Adams JH, Duchen LW (eds) Greenfield's neuropathology. 5th edn. Edward Arnold, London, pp 820–834

    Google Scholar 

  58. Ludolph AC, Ullrich K, Bick U, Fahrendorf G, Przyrembel H (1991) Functional and morphological deficits in late-treated patients with homocystinuria: a clinical, electrophysiologic and MRI study. Acta Neurol Scand 83: 161–165

    Google Scholar 

  59. Mirowitz SA, Sartor K, Prensky AJ, Gado M, Hodges III FJ (1991) Neurodegenerative diseases of childhood: MR and CT evaluation. J Comput Assist Tomogr 15:210–222

    Google Scholar 

  60. Arbour L, Rosenblatt B, Clow C, Wilson GN (1988) Postoperative dystonia in a female patient with homocystinuria. J Pediatr 113:863–864

    Google Scholar 

  61. Berardelli A, Thompson PD, Zaccagnini M, Giardini O, D'Eufemia P, Massoud R, Manfredi M (1991) Two sisters with generalized dystonia associated with homocystinuria. Mov Dis 6:163–165

    Google Scholar 

  62. Rutledge JN, Hilal SK, Silver AJ, Defendini R, Fahn S (1987) Study of movement disorders and brain iron by MR. AJNR 8:397–411

    Google Scholar 

  63. Drayer BP, Olanow W, Burger P, Johnson GA, Herfkens R, Riederer S (1986) Parkinson plus syndrome: diagnosis using high field MR imaging of brain iron. Radiology 159:494–498

    Google Scholar 

  64. Surtees R, Leonard J, Austin S (1991) Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 338: 1550–1554

    Google Scholar 

  65. Bellini C, Cerone R, Bonacci W, Caruso U, Magliano CP, Serra G, Fowler B, Romano C (1992) Biochemical diagnosis and outcome of 2 years treatment in a patient with combined methylmalonic aciduria and homocystinuria. Eur J Pediatr 151:818–820

    Google Scholar 

  66. van Diemen-Steenvoorde R, van Nieuwenhuizen O, de Klerk JBC, Duran M (1990) Quasi-moyamoya disease and heterozygosity for homocystinuria in a five-year-old girl. Neuropediatr 21: 110–112

    Google Scholar 

  67. Harker LA, Harlan JM, Ross R (1983) Effect of sulfinpyrazone on homocysteine-induced endothelial injury and arteriosclerosis in baboons. Circ Res 53: 731–739

    Google Scholar 

  68. Starkebaum G, Harlan JM (1986) Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 77: 1370–1376

    Google Scholar 

  69. Scott JM, Weir DG (1981) The methyl folate trap. Lancet ii:337–340

    Google Scholar 

  70. Scott JM, Dinn JJ, Wilson P, Weir DG (1981) Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet ii:334–337

    Google Scholar 

  71. Hyland K, Smith I, Bottiglieri T, Perry J, Wendel U, Clayton PT, Leonard JV (1988) Demyelination and decreased S-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency. Neurology 38:459–462

    Google Scholar 

  72. Wwir DG, Keating S, Molloy A, McPartlin J, Kennedy S, Blanchflower J, Kennedy DG, Rice D, Scott JM (1988) Methylation deficiency causes vitamin B12-associated neuropathy in the pig. J Neurochem 51:1949–1952

    Google Scholar 

  73. Schatz RA, Wilens TE, Sellinger OT (1981) Decreased transmethylation of biogenic amines after in vivo elevation of brain S-Adenosyl-l-homocysteine. J Neurochem 36:1739–1748

    Google Scholar 

  74. Fregnan GB, Biagi G (1988) Proconvulsive and convulsive properties of methionine, homocysteine and related compounds in mice. Acta Therapeutica 14:31–43

    Google Scholar 

  75. Olney JW (1974) Toxic effects of glutamate and related aminoacids on the developing central nervous system. In: Nyhan WL (ed) Heritable disorders of amino acid metabolism. John Wiley, London, pp 501–512

    Google Scholar 

  76. Hyland K, Smith I, Howells DW, Clayton PT, Leonard JV (1985) The determination of pterins, biogenic amine metabolites and aromatic amino acids in cerebrospinal fluid using isocratic reverse phase liquid chromatography with in series dual cell coulometric electrochemical and fluorescence detection: use in a study of inborn errors of dihydropteridine reductase and 5,10-methylenetetrahydrofolate reductase. In: Wachter H, Curtius HC, Pfleiderer W (eds) Biochemical and clinical aspects of pteridins, vol 4. Walter de Gruyter, Berlin, pp 85–99

    Google Scholar 

  77. Wendel U, Bremer HJ (1984) Betaine in the treatment of homocystinuria due to 5,10 methylenetetrahydrofolate reductase deficiency. Eur J Pediatr 142: 147–150

    Google Scholar 

  78. Holme E, Kjellman B, Ronge E (1989) Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency. Arch Dis Child 64:1061–1064

    Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Division of Vascular Surgery, Free University Hospital, P.O. Box 7057, NL-1007 MB, Amsterdam, The Netherlands

    M. van den Berg & J. A. Rauwerda

  2. Department of Child Neurology, Free University Hospital, Amsterdam, The Netherlands

    M. S. van der Knaap

  3. Department of Internal Medicine, Division of Endocrinology, University Hospital, Nijmegen, The Netherlands

    G. H. J. Boers

  4. Department of Internal Medicine, Free University Hospital, Amsterdam, The Netherlands

    C. D. A. Stehouwer

  5. Department of Radiology, Free University Hospital, Amsterdam, The Netherlands

    J. Valk

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  1. M. van den Berg
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van den Berg, M., van der Knaap, M.S., Boers, G.H.J. et al. Hyperhomocysteinaemia; with reference to its neuroradiological aspects. Neuroradiology 37, 403–411 (1995). https://doi.org/10.1007/BF00588024

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