619
Central-nervous-system methyl-group metabolism in children with neurological complications of HIV infection
To
methyl-group metabolism
in the in infection with system human immunodeficiency virus (HIV), levels of and methionine, 5-methyltetrahydrofolate, S-adenosylmethionine were measured by highperformance liquid chromatography in cerebrospinal fluid (CSF) from six children with congenital HIV infection and neurological complications. Total neopterins were also measured, as a marker of macrophage activation. In all six children concentrations of one or more methyl-group carriers were lower than those in a reference population of children, and all of the five in whom CSF neopterins were measured had higher than normal levels. Defective methylation may play a part in the neurological damage caused by HIV infection. assess
central
nervous
Introduction
Neurological complications may develop in up to 90% of children with human immunodeficiency virus (HIV) infection,l and, in the majority, are due to the direct infection of the central nervous system by the virus.2 Demyelination is a prominent feature and may affect both the subcortical white matter and the long tracts of the spinal cord.3 In addition, there may be microvascular calcification in the basal ganglia with extension into the white matter and junctional area of the cortex.4 The lesions, neuroradiologically and at necropsy, bear a striking resemblance to those found in children with defective folate metabolism;5-9 the spinal cord lesions in adults (vacuolar myelopathy) have been likened to those of subacute combined degeneration due to deficiency of vitamin B12 (cobalamin). 10 However, in HIV encephalitis the lesions are characterised by infiltrates of mononuclear cells and the presence of multinucleated giant cells which are of histiocytic origin and contain HIV.11,12 We have previously reported low cerebrospinal fluid (CSF) folate concentrations and high concentrations of total neopterin (dihydroneopterin plus fully oxidised neopterin) in two children with congenital HIV infection.13 This finding, together with the similarity in the neuropathological lesions and the known links between folate and pterin metabolism,9 suggested to us that the neurological damage in HIV infection could be due to inhibition of folate metabolism resulting from neopterin accumulation secondary to chronic stimulation of the macrophage system.13,14 We have now examined CSF concentrations of 5-methyltetrahydrofolate and total neopterins in four more children with HIV infection, and
CSF concentrations of two other methyl-group carriers, methionine and S-adenosylmethionine. The links between methionine and folate metabolism are summarised in fig 1. S-adenosylmethionine is the body’s main methyl-group donor. A relation between the neurological damage in HIV infection and defective methyl-group transfer could have important implications for therapy.
Patients and methods Six children, aged 1 -4—29 years, who were seropositive for HIV by enzyme-linked immunosorbent assay and whose mothers had risk factors for HIV infection, underwent lumbar puncture to exclude infection or because the diagnosis was unclear; this gave us an opportunity to undertake biochemical analysis of the CSF. Patient details are given in table I; patients 2 and 5 have been described previously. 13 Five children had neurological symptoms. Five children, including the symptom-free patient, underwent
computed tomography (CT) or magnetic resonance imaging (MRI) of the brain; the scans were reviewed by one observer (Dr B. Kendall, Hospital for Sick Children, London). None of the children were treated with zidovudine. At the time of investigation patient 6 was taking vitamin supplements which included folic acid. methylS-ADENOSYLMETHIONINE 2
S-ADENOSYLHOMOCYSTEINE
dimethylglycine betame
METHIONINE
HOMOCYSTEINE
&dar ;
THF
formyl-
B12
t
METHYL-THF
METHYLENE-THF THE
Fig 1-Folate-dependent methyl-group transfer. THF=tetrahydrofolate; B12=cobalamin, 1 =5, 10-methylenetetrahydrofolate reductase; 2 = methyltransferases CSF was taken from the lumbar sac, frozen at the bedside on dry - 70°C. The first millilitre was stored; the second millilitre was collected into tubes containing dithioerythritol and diethylenetriamine penta-acetic acid and used for measurement of total neopterin concentrations; the third millilitre was collected into plain tubes and used for measurement of S-adenosylmethionine, methionine, and 5-methyltetrahydrofolate concentrations.
ice, and stored at
ADDRESS: Department of Child Health, Institute of Child Health, 30 Guilford Street, London WC1 N 1 EH, UK (R Surtees, MRCP, K. Hyland, PhD, I. Smith, FRCP). Correspondence to Dr R. Surtees.
620
TABLE I-NEUROLOGICAL FEATURES OF STUDY CHILDREN
Concentrations of all metabolites
were
measured
by
means
high-performance liquid chromatography.15,17 Reference ranges were based on the analysis of CSF from groups of children with various neurological and metabolic disorders who underwent diagnostic lumbar puncture and in whom no disturbance of methyl-group or pterin metabolism was expected. Children
with
0
of
central-nervous-system infections and those
receiving anticonvulsants were excluded. Because CSF levels of S-adenosylmethionine fall sharply during the first year of life and remain stable thereafter (unpublished), its reference range was based on CSF from children aged between 1 and 5 years; no age-related change is apparent for the other metabolites and their reference ranges were based on CSF from subjects aged 1 week to 19 years.
Differences between the group with HIV infection and the reference populations were assessed by comparison of mean values with the approximate t statistic of Welch.
Results Five of the six patients had symptoms consistent with subacute HIV encephalitis, and four of the five investigated neuroradiologically had scans consistent with this diagnosis; the symptom-free patient had evidence of early centralnervous-system involvement on CT scan of the brain (table I). In all six patients CSF concentrations of one or more components of the methyl-group transfer pathway were below the reference range--S-adenosylinethionine in five patients, 5-methyltetrahydrofolate in four, and methionine in one patient (table II). One of the two patients with normal CSF 5-methyltetrahydrofolate levels (patient 6) was taking folic acid at the time of lumbar puncture. CSF neopterin levels were high in all five patients studied. By comparison with the reference population, the mean CSF levels of S-adenosylmethionine and 5-methyltetrahydrofolate were TABLE II-BIOCHEMICAL FINDINGS
0
SAM=S-adenosytmethion!ne,
Met=methionine,
MTH F = 5-methyltetraerror
of mean, C!=95%
100
150
200
250
I 300
S-adenosylmethionine (nmol/I)
Fig 2-Relation between CSF S-adenosylmethionine methionine concentrations in HIV-infected patients.
and
significantly lower in the HIV group; the difference in methionine levels was not significant (table II). In the reference population for whom both metabolites were measured, there was no relation between CSF methionine and CSF
S-adenosylmethionine (not shown).
However, in the children with HIV infection, although the numbers were small, there seemed to be a linear relation between the levels of the two metabolites (fig 2). The two children with the lowest CSF neopterin levels had the highest (including the only normal) CSF 5methyltetrahydrofolate concentrations.
Discussion A reduction in
myelination of the corticospinal tracts with preservation of axons is a frequent finding in children dying of HIV infection.18 The vacuolar myelopathy seen in adults,1O although less common, also occurs.1,18 Foci of demyelination surround the infected cells of the monocyte macrophage lineage in the brain and spinal cord, and in the brain microvascular calcifications may accompany the demyelination.3 The mechanisms by which the infection causes the neurological lesions are not known,19 but the virtual absence of infected neurons, astrocytes, and oligodendrocytes is consistent with a metabolic caused Our finding that children with HIV infection may have low CSF concentrations of key metabolites in the methyl-group pathway (fig 1) may provide a clue to the mechanisms of
neurological damage. Single carbon groups enter the folate cycle mainly as formyl groups and are bound to tetrahydrofolate, which is then
hydrofolate ; Neo=total neoptenns, SEM standard confidence Interval. N D not done
50 CSF
reduced
in
several to form 5steps This is essential for the methyltetrahydrofolate. compound transfer of methyl groups to cobalamin and then to homocysteine, to form methionine. The recycling of homocysteine to methionine is required to maintain homoeostasis in methyl-group metabolism. Methionine is the precursor of S-adenosylmethionine, the body’s main methyl-group donor. Methylation is important in many biochemical pathways in the brain21 and, in particular, it has a vital role in the maintenance of the myelin sheath.22,23 Experimental evidence suggests that defective turnover of S-adenosylmethionine may lead to demyelination and that it can be corrected by increasing the supply of methionine.2124 Work in children with inborn errors of metabolism supports the view that defective methyl-group metabolism causes demyelination. In two disorders leading to a deficiency of 5-methyltetrahydrofolate (deficiencies of 5,10methylenetetrahydrofolate reductase and dihydropteridine
621
reductase) demyelination and microvascular calcification frequent findings.9,22 In 5,10-methylenetetrahydrofolate
are
CSF reductase S-adenosylmethionine deficiency concentrations are low and the pattern of demyelination is indistinguishable from that seen in cobalamin deficiency ;22 the demyelination can be ameliorated by administration of large doses of a methyl-group donor, betaine, which can transfer methyl groups to homocysteine directly without the need for folate or cobalamin (fig 1).22 In the children with HIV infection described here, the cause of the low levels of S-adenosylmethionine and 5-methyltetrahydrofolate in the CSF has still to be determined. However, the changes were of similar magnitude to those seen in the inborn errors of metabolism, consistent with the possibility that low S-adenosylmethionine concentrations have a role in the demyelinating process. The direct, and apparently linear, relation between CSF concentrations of S-adenosylmethionine and methionine (found only in the HIV-infected patients) suggests that the availability of methionine may be limiting the production of S-adenosylmethionine. This might be explained by deficiency of 5-methyltetrahydrofolate. We have suggested previously that neopterins might inhibit folate metabolism.14 Dihydroneopterin is released from macrophages after stimulation by interferon gamma.25 Hence, the high neopterin levels in the patients’ CSF reflect activation of macrophages within the central nervous system. In addition to neopterin release, macrophages respond in various ways which are potentially toxic to the host tissues. An important response is the production of oxygen free radicals,25 which change the biophysical properties of membranes and reduce fluidity.26 Membrane fluidity can be restored by phospholipid methyltransferases, which use S-adenosylmethionine as the methyl-group donor.27 Especially in the areas surrounding the infected cells of the macrophage/monocyte lineage, and in the presence of a reduced supply of 5-methyltetrahydrofolate, such repair of damaged membranes could cause excessive consumption of methyl groups, perhaps thereby leading to a deficiency of S-adenosylmethionine. Treatment with methyl-group donors such as betaine and methionine has been effective in children with inborn errors of metabolism,22,28 and could be useful in HIV infection if the role of defective methyl-group metabolism is confirmed. Further studies are required to establish the frequency of such changes in HIV infection and to elucidate the mechanisms involved.
We thank Dr B. Kendall, for reviewing the neuroradiological studies on the patients, and Prof R. Levinsky, Dr S. Strobel, Dr E. Brett, Dr J. Wilson, and Dr M. Levine, for referring patients for investigation. This study was supported by grants from the Wellcome Trust (R. S.), Action Research for the Crippled Child (K. H.), and the Medical Research Council (I. S.).
REFERENCES 1. Belman AL, Diamond G, Dickson DW,
et
al. Pediatric
acquired
immunodeficiency syndrome: neurological syndromes. Am J Dis Child 1988; 142: 29-35.
2. Epstein LG, Sharer LR, Goudsmit J. Neurological and neuropathological features of human immunodeficiency virus infection in children. Ann Neurol 1988; 23 (suppl): S19-23.
3.
Gray F, Gherardi R, Scaravilli F. The neuropathology of the acquired immunodeficiency syndrome (AIDS). A review. Brain 1988; 111:
245-66. 4. Belman AL, Lantos G, Horoupian D, et al. AIDS: calcification of the basal ganglia in infants and children. Neurology 1986; 36: 1192-99. 5. Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ. Subacute combined degeneration of the cord, dementia and Parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatr 1986; 49: 920-27. 6. Beckman DR, Hoganson G, Berlow S, Gilbert EF. Pathological findings in 5, 10-methylene tetrahydrofolate reductase deficiency. Birth Defects
1987; 23: 47-64. 7. Devivo DC, Malas D, Nelson JS, Land VJ. Leukoencephalopathy in childhood leukaemia. Neurology 1984; 27: 609-13. 8. Lund E, Hamborg-Pederson B. Computed tomography of the brain following prophylactic treatment with irradiation therapy and intraspinal methotrexate in children with acute lymphoblastic leukaemia. Neuroradiology 1984; 26: 351-58. 9. Smith I, Hyland K, Kendall B, Leeming R. Clinical role of pteridine therapy in tetrahydrobiopterin deficiency. J Inherit Metab Dis 1985; 8 (suppl 1): 39-45. 10. Petito CK, Navia BA, Cho E-S, Jordan BD, George DC, Price RW. Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med 1985; 312: 874-79. 11. Budka H. Multinucleated giant cells in brain: a hallmark of the acquired immunodeficiency syndrome (AIDS). Acta Neuropathol 1986; 69: 253-58. 12. Koenig S, Gendelman HE, Orenstein JM, et al. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 1986; 233: 1089-93. 13. Habibi P, Strobel S, Smith I, et al. Neurodevelopmental delay and focal seizures as presenting symptoms of human deficiency virus 1 infection. Eur J Pediatr 1989; 148: 315-17. 14. Smith I, Howells DW, Kendall B, Levinsky R, Hyland K. Folate deficiency and demyelination in AIDS. Lancet 1987; ii: 215. 15. Howells DW, Smith I, Hyland K. Estimation of tetrahydrobiopterin and other pterins in cerebrospinal fluid using reversed-phase highperformance liquid chromatography with electrochemical and fluorescence detection. J Chromatogr 1986; 381: 285-94. 16. Surtees R, Hyland K. A method for the measurement of Sadenosylmethionine in small volume samples of cerebrospinal fluid or brain using high performance liquid chromatographyelectrochemistry. Anal Biochem 1989; 181: 331-35. 17. Surtees R, Hyland K. L-3, 4-dihydroxyphenylalanine causes a fall in central nervous system S-adenosylmethionine concentrations in man. J Neurol Neurosurg Psychiatr (in press). 18. Dickson DW, Belman AL, Kim TS, Horoupian DS Rubinstein A. Spinal cord pathology in pediatric acquired immunodeficiency syndrome. Neurology 1989; 39: 227-35. 19. Price RW, Brew B, Sidtis J, Rosenblum M, Scheck AC, Cleary P. The brain in AIDS: central nervous system HIV-1 infection and AIDSdementia complex. Science 1988; 239: 586-92. 20. Walker DG, Itagaki S, Berry K, McGeer PL. Examination of brains of AIDS cases for human immunodeficiency virus and human cytomegalovirus nucleic acids. J Neurol Neurosurg Psychiatr 1989; 52: 583-90. 21. Zappia V, Salvatore F, Porcelli M, Cacciapuoti G. Novel aspects in the biochemistry of adenosylmethionine and related sulfur compounds. In: Zappia V, Usdin E, Salvatore F, eds. Biochemical and pharmacological roles of adenosylmethionine and the central nervous system. Oxford: Pergamon Press, 1979: 2-6. 22. Hyland K, Smith I, Bottiglieri T, et al. Demyelination and decreased S-adenosylmethionine in 5, 10-methylenetetrahydrofolate reductase deficiency. Neurology 1988; 38: 459-62. 23. Weir DG, Keating S, Molloy A, et al. Methylation deficiency causes vitamin B12-associated neuropathy in the pig. J Neurochem 1988; 51: 1949-52. 24. Scott JM, Dinn JJ, Wilson P, Weir DG. Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet 1981; ii: 334-37. 25. Nathan CR. Peroxide and pteridine: an hypothesis on the regulation of macrophage antimicrobial activity by interferon gamma. Interferon 1986; 7: 125-43. 26. Richter C. Biophysical consequences of lipid peroxidation in membranes. Chem Phys Lipids 1987; 44: 175-89. 27. Hirata F, Axelrod J. Phospholipid methylation and biological signal transmission. Science 1980; 209: 1082-90. 28. Bartholomew DW, Batshaw ML, Allen RH, et al. Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria. J Pediatr 1988; 112: 32-39.
Central-nervous-system methyl-group metabolism in children with neurological complications of HIV infection
To
methyl-group metabolism
in the in infection with system human immunodeficiency virus (HIV), levels of and methionine, 5-methyltetrahydrofolate, S-adenosylmethionine were measured by highperformance liquid chromatography in cerebrospinal fluid (CSF) from six children with congenital HIV infection and neurological complications. Total neopterins were also measured, as a marker of macrophage activation. In all six children concentrations of one or more methyl-group carriers were lower than those in a reference population of children, and all of the five in whom CSF neopterins were measured had higher than normal levels. Defective methylation may play a part in the neurological damage caused by HIV infection. assess
central
nervous
Introduction
Neurological complications may develop in up to 90% of children with human immunodeficiency virus (HIV) infection,l and, in the majority, are due to the direct infection of the central nervous system by the virus.2 Demyelination is a prominent feature and may affect both the subcortical white matter and the long tracts of the spinal cord.3 In addition, there may be microvascular calcification in the basal ganglia with extension into the white matter and junctional area of the cortex.4 The lesions, neuroradiologically and at necropsy, bear a striking resemblance to those found in children with defective folate metabolism;5-9 the spinal cord lesions in adults (vacuolar myelopathy) have been likened to those of subacute combined degeneration due to deficiency of vitamin B12 (cobalamin). 10 However, in HIV encephalitis the lesions are characterised by infiltrates of mononuclear cells and the presence of multinucleated giant cells which are of histiocytic origin and contain HIV.11,12 We have previously reported low cerebrospinal fluid (CSF) folate concentrations and high concentrations of total neopterin (dihydroneopterin plus fully oxidised neopterin) in two children with congenital HIV infection.13 This finding, together with the similarity in the neuropathological lesions and the known links between folate and pterin metabolism,9 suggested to us that the neurological damage in HIV infection could be due to inhibition of folate metabolism resulting from neopterin accumulation secondary to chronic stimulation of the macrophage system.13,14 We have now examined CSF concentrations of 5-methyltetrahydrofolate and total neopterins in four more children with HIV infection, and
CSF concentrations of two other methyl-group carriers, methionine and S-adenosylmethionine. The links between methionine and folate metabolism are summarised in fig 1. S-adenosylmethionine is the body’s main methyl-group donor. A relation between the neurological damage in HIV infection and defective methyl-group transfer could have important implications for therapy.
Patients and methods Six children, aged 1 -4—29 years, who were seropositive for HIV by enzyme-linked immunosorbent assay and whose mothers had risk factors for HIV infection, underwent lumbar puncture to exclude infection or because the diagnosis was unclear; this gave us an opportunity to undertake biochemical analysis of the CSF. Patient details are given in table I; patients 2 and 5 have been described previously. 13 Five children had neurological symptoms. Five children, including the symptom-free patient, underwent
computed tomography (CT) or magnetic resonance imaging (MRI) of the brain; the scans were reviewed by one observer (Dr B. Kendall, Hospital for Sick Children, London). None of the children were treated with zidovudine. At the time of investigation patient 6 was taking vitamin supplements which included folic acid. methylS-ADENOSYLMETHIONINE 2
S-ADENOSYLHOMOCYSTEINE
dimethylglycine betame
METHIONINE
HOMOCYSTEINE
&dar ;
THF
formyl-
B12
t
METHYL-THF
METHYLENE-THF THE
Fig 1-Folate-dependent methyl-group transfer. THF=tetrahydrofolate; B12=cobalamin, 1 =5, 10-methylenetetrahydrofolate reductase; 2 = methyltransferases CSF was taken from the lumbar sac, frozen at the bedside on dry - 70°C. The first millilitre was stored; the second millilitre was collected into tubes containing dithioerythritol and diethylenetriamine penta-acetic acid and used for measurement of total neopterin concentrations; the third millilitre was collected into plain tubes and used for measurement of S-adenosylmethionine, methionine, and 5-methyltetrahydrofolate concentrations.
ice, and stored at
ADDRESS: Department of Child Health, Institute of Child Health, 30 Guilford Street, London WC1 N 1 EH, UK (R Surtees, MRCP, K. Hyland, PhD, I. Smith, FRCP). Correspondence to Dr R. Surtees.
620
TABLE I-NEUROLOGICAL FEATURES OF STUDY CHILDREN
Concentrations of all metabolites
were
measured
by
means
high-performance liquid chromatography.15,17 Reference ranges were based on the analysis of CSF from groups of children with various neurological and metabolic disorders who underwent diagnostic lumbar puncture and in whom no disturbance of methyl-group or pterin metabolism was expected. Children
with
0
of
central-nervous-system infections and those
receiving anticonvulsants were excluded. Because CSF levels of S-adenosylmethionine fall sharply during the first year of life and remain stable thereafter (unpublished), its reference range was based on CSF from children aged between 1 and 5 years; no age-related change is apparent for the other metabolites and their reference ranges were based on CSF from subjects aged 1 week to 19 years.
Differences between the group with HIV infection and the reference populations were assessed by comparison of mean values with the approximate t statistic of Welch.
Results Five of the six patients had symptoms consistent with subacute HIV encephalitis, and four of the five investigated neuroradiologically had scans consistent with this diagnosis; the symptom-free patient had evidence of early centralnervous-system involvement on CT scan of the brain (table I). In all six patients CSF concentrations of one or more components of the methyl-group transfer pathway were below the reference range--S-adenosylinethionine in five patients, 5-methyltetrahydrofolate in four, and methionine in one patient (table II). One of the two patients with normal CSF 5-methyltetrahydrofolate levels (patient 6) was taking folic acid at the time of lumbar puncture. CSF neopterin levels were high in all five patients studied. By comparison with the reference population, the mean CSF levels of S-adenosylmethionine and 5-methyltetrahydrofolate were TABLE II-BIOCHEMICAL FINDINGS
0
SAM=S-adenosytmethion!ne,
Met=methionine,
MTH F = 5-methyltetraerror
of mean, C!=95%
100
150
200
250
I 300
S-adenosylmethionine (nmol/I)
Fig 2-Relation between CSF S-adenosylmethionine methionine concentrations in HIV-infected patients.
and
significantly lower in the HIV group; the difference in methionine levels was not significant (table II). In the reference population for whom both metabolites were measured, there was no relation between CSF methionine and CSF
S-adenosylmethionine (not shown).
However, in the children with HIV infection, although the numbers were small, there seemed to be a linear relation between the levels of the two metabolites (fig 2). The two children with the lowest CSF neopterin levels had the highest (including the only normal) CSF 5methyltetrahydrofolate concentrations.
Discussion A reduction in
myelination of the corticospinal tracts with preservation of axons is a frequent finding in children dying of HIV infection.18 The vacuolar myelopathy seen in adults,1O although less common, also occurs.1,18 Foci of demyelination surround the infected cells of the monocyte macrophage lineage in the brain and spinal cord, and in the brain microvascular calcifications may accompany the demyelination.3 The mechanisms by which the infection causes the neurological lesions are not known,19 but the virtual absence of infected neurons, astrocytes, and oligodendrocytes is consistent with a metabolic caused Our finding that children with HIV infection may have low CSF concentrations of key metabolites in the methyl-group pathway (fig 1) may provide a clue to the mechanisms of
neurological damage. Single carbon groups enter the folate cycle mainly as formyl groups and are bound to tetrahydrofolate, which is then
hydrofolate ; Neo=total neoptenns, SEM standard confidence Interval. N D not done
50 CSF
reduced
in
several to form 5steps This is essential for the methyltetrahydrofolate. compound transfer of methyl groups to cobalamin and then to homocysteine, to form methionine. The recycling of homocysteine to methionine is required to maintain homoeostasis in methyl-group metabolism. Methionine is the precursor of S-adenosylmethionine, the body’s main methyl-group donor. Methylation is important in many biochemical pathways in the brain21 and, in particular, it has a vital role in the maintenance of the myelin sheath.22,23 Experimental evidence suggests that defective turnover of S-adenosylmethionine may lead to demyelination and that it can be corrected by increasing the supply of methionine.2124 Work in children with inborn errors of metabolism supports the view that defective methyl-group metabolism causes demyelination. In two disorders leading to a deficiency of 5-methyltetrahydrofolate (deficiencies of 5,10methylenetetrahydrofolate reductase and dihydropteridine
621
reductase) demyelination and microvascular calcification frequent findings.9,22 In 5,10-methylenetetrahydrofolate
are
CSF reductase S-adenosylmethionine deficiency concentrations are low and the pattern of demyelination is indistinguishable from that seen in cobalamin deficiency ;22 the demyelination can be ameliorated by administration of large doses of a methyl-group donor, betaine, which can transfer methyl groups to homocysteine directly without the need for folate or cobalamin (fig 1).22 In the children with HIV infection described here, the cause of the low levels of S-adenosylmethionine and 5-methyltetrahydrofolate in the CSF has still to be determined. However, the changes were of similar magnitude to those seen in the inborn errors of metabolism, consistent with the possibility that low S-adenosylmethionine concentrations have a role in the demyelinating process. The direct, and apparently linear, relation between CSF concentrations of S-adenosylmethionine and methionine (found only in the HIV-infected patients) suggests that the availability of methionine may be limiting the production of S-adenosylmethionine. This might be explained by deficiency of 5-methyltetrahydrofolate. We have suggested previously that neopterins might inhibit folate metabolism.14 Dihydroneopterin is released from macrophages after stimulation by interferon gamma.25 Hence, the high neopterin levels in the patients’ CSF reflect activation of macrophages within the central nervous system. In addition to neopterin release, macrophages respond in various ways which are potentially toxic to the host tissues. An important response is the production of oxygen free radicals,25 which change the biophysical properties of membranes and reduce fluidity.26 Membrane fluidity can be restored by phospholipid methyltransferases, which use S-adenosylmethionine as the methyl-group donor.27 Especially in the areas surrounding the infected cells of the macrophage/monocyte lineage, and in the presence of a reduced supply of 5-methyltetrahydrofolate, such repair of damaged membranes could cause excessive consumption of methyl groups, perhaps thereby leading to a deficiency of S-adenosylmethionine. Treatment with methyl-group donors such as betaine and methionine has been effective in children with inborn errors of metabolism,22,28 and could be useful in HIV infection if the role of defective methyl-group metabolism is confirmed. Further studies are required to establish the frequency of such changes in HIV infection and to elucidate the mechanisms involved.
We thank Dr B. Kendall, for reviewing the neuroradiological studies on the patients, and Prof R. Levinsky, Dr S. Strobel, Dr E. Brett, Dr J. Wilson, and Dr M. Levine, for referring patients for investigation. This study was supported by grants from the Wellcome Trust (R. S.), Action Research for the Crippled Child (K. H.), and the Medical Research Council (I. S.).
REFERENCES 1. Belman AL, Diamond G, Dickson DW,
et
al. Pediatric
acquired
immunodeficiency syndrome: neurological syndromes. Am J Dis Child 1988; 142: 29-35.
2. Epstein LG, Sharer LR, Goudsmit J. Neurological and neuropathological features of human immunodeficiency virus infection in children. Ann Neurol 1988; 23 (suppl): S19-23.
3.
Gray F, Gherardi R, Scaravilli F. The neuropathology of the acquired immunodeficiency syndrome (AIDS). A review. Brain 1988; 111:
245-66. 4. Belman AL, Lantos G, Horoupian D, et al. AIDS: calcification of the basal ganglia in infants and children. Neurology 1986; 36: 1192-99. 5. Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ. Subacute combined degeneration of the cord, dementia and Parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatr 1986; 49: 920-27. 6. Beckman DR, Hoganson G, Berlow S, Gilbert EF. Pathological findings in 5, 10-methylene tetrahydrofolate reductase deficiency. Birth Defects
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