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Folic acid, pernicious anaemia, and prevention of neural tube defects
COMMENTARY
Folic acid, pernicious anaemia, and prevention of neural tube defects know that an increase in folic acid consumption can prevent neural tube defects. A randomised trial of folic acid supplementation before conception showed that 4 mg a day prevented nearly three-quarters of such abnormalities.’ Other evidence suggests that most of this protective effect can be achieved by taking about one tenth of this amount-an extra 0-4 mg a day.2 This, then, is a reasonable public health target. Women planning a pregnancy are advised to take one 0.4 mg tablet a day, obtainable over the counter from pharmacies and health food stores as folic acid on its own.3 However, the fact that so many pregnancies are unplanned means that this method of prevention will inevitably have its limitations. In Britain, dietary intake of folate, consumed as derivatives of pure folic acid with lower bioavailability, averages about 0-2 mg per day. Consequently, selection of unfortified foods that can deliver at least three times the current intake of folate would require a big change in the national diet. The only practical way of ensuring that all women of childbearing age increase their intake of folic acid is by fortification of staple foods. For these reasons the UK and US governments have recommended that cereals be fortified with folic acid (bread and breakfast cereals in Britain and flour and other cereal grains in the USA). 3,4 This approach will also help to prevent folate deficiency anaemia, a particular problem in elderly people on poor diets. Although the strategy seems complete, there is a concern. Addition of even a vitamin to a staple food requires a high assurance of safety. Folic acid is widely thought to be non-toxic, even when consumed in large quantities (it is a water soluble vitamin and is rapidly excreted in the urine). However, about 45 years ago clinicians noticed that, in pernicious anaemia, large doses of folic acid (usually 5 mg or more) sometimes improved the haematological disorder but did not improve the neuropathy, and may even have brought it on sooner. This prompted the fear that the diagnosis of pernicious anaemia might be delayed by administration of folic acid, with progression of the neuropathy, perhaps irreversibly. Concern that this sequence of events might occur, albeit to a lesser extent, with lower amounts of folic acid led to the fortification recommendations being limited to a level that may add, on average, only about 0-1mg folic acid a day, a quarter of the target level.5 We believe that it is a mistake to regard this effect-the correction of the blood abnormality in pernicious anaemia by folic acid-as a masking of the disease or as a toxic effect of the vitamin. Currently about 12% of patients with pernicious anaemia present with neuropathy alone.6 An increase in dietary folic acid might increase this percentage while reducing the proportion of patients presenting with anaemia. The neuropathy is reversible with timely presentation and prompt treatment with vitamin B12. It is not necessary to "preserve" the anaemia to achieve an earlier diagnosis. Moreover, it is unreasonable to extra encourage haematological to make the which in any case morbidity help diagnosis, should be based on assessment of B12 status. Concern over the presence or absence of an We
< -
now
accompanying macrocytosis or anaemia is misplaced; and, the extent that this might limit public health measures designed to prevent neural tube defects, it represents an error of judgment. The haematological effect of folic acid in pernicious anaemia should not be used as a reason for failure to implement adequate folic-acid fortification for prevention of neural tube defects. to
Nicholas J Wald, Carol Bower Wolfson Institute of Preventive Medicine, Medical Hospital, London, UK
1 2
3 4
5
6
College of St Bartholomew’s
MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the MRC Vitamin Study. Lancet 1991; 338: 132-37. Wald NJ. Folic acid and neural tube defects: the current evidence and implications for prevention. In: Neural tube defects (CIBA Foundation symposium 181). Chichester: Wiley, 1994: 192-211. Report from an Expert Advisory Group. Folic acid and the prevention of neural tube defects. London: Department of Health, 1992. Department of Health and Human Services, Public Health Service. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR 1992; 41/RR-14: 1-7. US campaign for women to take folic acid to prevent birth defects.
BMJ 1994; 208: 223. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988; 318: 1720-728.
Flip tip inversion and haemophilia
A
See page 329
unique inversion of the tip of the X chromosome is now to be responsible for about half of all cases of severe haemophilia A (factor VIII deficiency).’,2 The
A
known
inversion mechanism involves an intronless gene of unknown function, designated F8A, two copies of which are located near the tip of the X chromosome while one is present within intron 22 of the factor VIII gene itself. (The latter copy was the first example of an intronic gene to be found in a vertebrate genome.) Either of the two telomeric copies can cross over with the intronic copy of F8A, thus dividing the factor VIII gene into two halves facing in opposite directions and separated by 500 kb; the locus is thereby comprehensively disabled (figure). Crossover is much commoner with the distal F8A copy than with the proximal copy, but the fine details of the mechanism have not yet been revealed by sequencing through the breakpoints of such inversions. In this issue, Goodeve and colleagues confirm the frequency of this remarkable genetic lesion in haemophilia A and show its usefulness in providing clinical diagnostic information. Female relatives of haemophiliacs require genetic counselling, hitherto largely provided by linkage analysis with several polymorphic markers within and near the factor VIII gene. This approach fails when the level of the mutation is unknown, as is often the case in a disorder with a high rate of new mutations, or when polymorphic markers are uninformative. In such cases, mutationspecific diagnosis provides the only hope for definitive tracking of a mutant gene in a family, although measurement of the factor VIII concentration in putative carriers can help in a few favourable cases. The very high mutational heterogeneity in haemophilia A and the large size and complexity of the factor VIII gene have until now prohibited routine use of mutation-specific diagnosis. Since the inversion occurs in half the severe cases and can be detected by a simple Southern blotting procedure, this
307
Folic acid, pernicious anaemia, and prevention of neural tube defects know that an increase in folic acid consumption can prevent neural tube defects. A randomised trial of folic acid supplementation before conception showed that 4 mg a day prevented nearly three-quarters of such abnormalities.’ Other evidence suggests that most of this protective effect can be achieved by taking about one tenth of this amount-an extra 0-4 mg a day.2 This, then, is a reasonable public health target. Women planning a pregnancy are advised to take one 0.4 mg tablet a day, obtainable over the counter from pharmacies and health food stores as folic acid on its own.3 However, the fact that so many pregnancies are unplanned means that this method of prevention will inevitably have its limitations. In Britain, dietary intake of folate, consumed as derivatives of pure folic acid with lower bioavailability, averages about 0-2 mg per day. Consequently, selection of unfortified foods that can deliver at least three times the current intake of folate would require a big change in the national diet. The only practical way of ensuring that all women of childbearing age increase their intake of folic acid is by fortification of staple foods. For these reasons the UK and US governments have recommended that cereals be fortified with folic acid (bread and breakfast cereals in Britain and flour and other cereal grains in the USA). 3,4 This approach will also help to prevent folate deficiency anaemia, a particular problem in elderly people on poor diets. Although the strategy seems complete, there is a concern. Addition of even a vitamin to a staple food requires a high assurance of safety. Folic acid is widely thought to be non-toxic, even when consumed in large quantities (it is a water soluble vitamin and is rapidly excreted in the urine). However, about 45 years ago clinicians noticed that, in pernicious anaemia, large doses of folic acid (usually 5 mg or more) sometimes improved the haematological disorder but did not improve the neuropathy, and may even have brought it on sooner. This prompted the fear that the diagnosis of pernicious anaemia might be delayed by administration of folic acid, with progression of the neuropathy, perhaps irreversibly. Concern that this sequence of events might occur, albeit to a lesser extent, with lower amounts of folic acid led to the fortification recommendations being limited to a level that may add, on average, only about 0-1mg folic acid a day, a quarter of the target level.5 We believe that it is a mistake to regard this effect-the correction of the blood abnormality in pernicious anaemia by folic acid-as a masking of the disease or as a toxic effect of the vitamin. Currently about 12% of patients with pernicious anaemia present with neuropathy alone.6 An increase in dietary folic acid might increase this percentage while reducing the proportion of patients presenting with anaemia. The neuropathy is reversible with timely presentation and prompt treatment with vitamin B12. It is not necessary to "preserve" the anaemia to achieve an earlier diagnosis. Moreover, it is unreasonable to extra encourage haematological to make the which in any case morbidity help diagnosis, should be based on assessment of B12 status. Concern over the presence or absence of an We
< -
now
accompanying macrocytosis or anaemia is misplaced; and, the extent that this might limit public health measures designed to prevent neural tube defects, it represents an error of judgment. The haematological effect of folic acid in pernicious anaemia should not be used as a reason for failure to implement adequate folic-acid fortification for prevention of neural tube defects. to
Nicholas J Wald, Carol Bower Wolfson Institute of Preventive Medicine, Medical Hospital, London, UK
1 2
3 4
5
6
College of St Bartholomew’s
MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the MRC Vitamin Study. Lancet 1991; 338: 132-37. Wald NJ. Folic acid and neural tube defects: the current evidence and implications for prevention. In: Neural tube defects (CIBA Foundation symposium 181). Chichester: Wiley, 1994: 192-211. Report from an Expert Advisory Group. Folic acid and the prevention of neural tube defects. London: Department of Health, 1992. Department of Health and Human Services, Public Health Service. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR 1992; 41/RR-14: 1-7. US campaign for women to take folic acid to prevent birth defects.
BMJ 1994; 208: 223. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988; 318: 1720-728.
Flip tip inversion and haemophilia
A
See page 329
unique inversion of the tip of the X chromosome is now to be responsible for about half of all cases of severe haemophilia A (factor VIII deficiency).’,2 The
A
known
inversion mechanism involves an intronless gene of unknown function, designated F8A, two copies of which are located near the tip of the X chromosome while one is present within intron 22 of the factor VIII gene itself. (The latter copy was the first example of an intronic gene to be found in a vertebrate genome.) Either of the two telomeric copies can cross over with the intronic copy of F8A, thus dividing the factor VIII gene into two halves facing in opposite directions and separated by 500 kb; the locus is thereby comprehensively disabled (figure). Crossover is much commoner with the distal F8A copy than with the proximal copy, but the fine details of the mechanism have not yet been revealed by sequencing through the breakpoints of such inversions. In this issue, Goodeve and colleagues confirm the frequency of this remarkable genetic lesion in haemophilia A and show its usefulness in providing clinical diagnostic information. Female relatives of haemophiliacs require genetic counselling, hitherto largely provided by linkage analysis with several polymorphic markers within and near the factor VIII gene. This approach fails when the level of the mutation is unknown, as is often the case in a disorder with a high rate of new mutations, or when polymorphic markers are uninformative. In such cases, mutationspecific diagnosis provides the only hope for definitive tracking of a mutant gene in a family, although measurement of the factor VIII concentration in putative carriers can help in a few favourable cases. The very high mutational heterogeneity in haemophilia A and the large size and complexity of the factor VIII gene have until now prohibited routine use of mutation-specific diagnosis. Since the inversion occurs in half the severe cases and can be detected by a simple Southern blotting procedure, this
307