- Email: [email protected]
p53 polymorphism and cervical cancer
pretation and good communication between the referring clinician and the radiologist should be maintained to prevent unnecessary therapeutic interventions and to manage future outbreaks. *Giovanni Battista Orsi, Gaetano Maria Fara Institute of Hygiene, University “La Sapienza”, Piazzale Aldo Moro 5, 00185 Rome, Italy 1
Lev MH, Rhea JT, Bramson RT. Avoidance of variability and error in radiology. Lancet 1999; 354: 272. 2 Faix RG, Adams JT. Neonatal necrotizing enterocolitis: current concepts and controversies. In: Aronoff SC, Hughes WT, Kohl S, Speck WT, Wald ER, eds. Advances in pediatric infectious diseases. St Louis: Mosby, 1994: 1–36. 3 Berseth CL, Abrams SA. Special gastrointestinal concerns. In: Taeusch HW, Ballard RA, eds. Avery’s diseases on the newborn. Philadelphia: WB Saunders, 1998: 965–78. 4 NEC outbreak report. Rome: Osservatorio Epidemiologico Regione Lazio and Servizio Igiene Ospedaliera, 1999. 5 NEC revision report. Rome: Policlinico Umberto I Revision Committee, 1999.
Cardiomyopathy in Danish patients with coeliac disease Sir—The understanding of coeliac disease has changed during the past decades. A series of diseases such as primary biliary cirrhosis and type 1 diabetes seem to be associated with coeliac disease.1,2 It has been suggested that the prevalence of coeliac disease in patients with dilated cardiomyopathy has increased; among 52 patients with idiopathic cardiomyopathy, M Curione and co-workers (July 17, p 222)3 found three patients with coeliac disease, which suggests an association with cardiomyopathy. We report the incidence of cardiomyopathy in patients with coeliac disease in a nationwide population-based cohort. The Danish National Registry of Patients (NRP) contains information on virtually all hospital discharges in Denmark since 1977. Each discharge record includes the unique civil registration number given to all citizens Calendar period
Number of Observation patients time (years) with cardiomyopathy
Incidence rate per 100 000 person-years (95% CI)
1977–81 1982–86 1987–92
0 1 3
·· 54 (1–300) 86 (18–251)
733 1859 3488
Number of patients with cardiomyopathy, observation time, and incidence rates of cardiomyopathy by calendar period
THE LANCET • Vol 354 • October 30, 1999
in Denmark at birth. The discharge diagnoses in the NRP were classified according to the Danish version of the International Classification of Diseases, eighth edition (ICD-8) during the study period, from Jan 1, 1977, to Dec 31, 1992. All patients discharged with coeliac disease (ICD 269.00) were included in the study. All other diagnoses registered during the same hospital stay were collected, and cases of cardiomyopathy (ICD 425.99) were identified. We linked patients by their registration number to the Danish Civil Registration System, which contains information on death and emigration. We calculated the risk time for the patients in the cohort from the first discharge with coeliac disease to Dec 31, 1992, or death, whichever was first. We calculated the incidence in calendar periods as the observed number of cases with cardiomyopathy divided by observation time, with 95% CI calculated by exact Poisson limits. 896 patients with coeliac disease were identified in the NRP. Among 893 with a valid civil registration number, four cases of cardiomyopathy were identified. Patients were followed up for a total of 6082 person-years. The incidence rates by calendar periods are shown in the table. We found high incidence rates of cardiomyopathy in patients with coeliac disease, indicating that coeliac disease may be associated with cardiomyopathy. The incidence rates increased during the study period, probably because of a change in diagnostic procedures for cardiomyopathy, since echocardiography was introduced in the last calendar period. Our study was based on discharge diagnoses, which are known to vary in quality. However, Danish data quality studies have shown that gastrointestinal disease and other serious diseases are generally well coded. The rates presented are probably underestimated since comorbid diseases may be underreported in the hospital discharge registries. In conclusion, we found increasing evidence for an association between coeliac disease and cardiomyopathy that should be further examined in analytical studies with appropriate controls. *Kirsten Fonager, Henrik Toft Sørensen, Bente Nørgård, Ane Marie Thulstrup *Department of Epidemiology and Social Medicine, Aarhus University, 8000 Aarhus C, Denmark; Danish Epidemiology Science Centre at the Department of Epidemiology and Social Medicine, Aarhus; and Department of Medicine V, Aarhus University Hospital, Aarhus (e-mail: [email protected])
2
Sørensen HT, Thulstrup AM, Blomquist P, Nørgård B, Fonager K, Ekbom A. Risk of primary biliary liver cirrhosis in patients with coeliac disease: Danish and Swedish cohort data. Gut 1999; 44: 736–38. 3 Curione M, Barbato M, Biase L, Viola F, Russo LL, Cardi E. Prevalence of coeliac disease in idiopathic dilated cardiomyopathy. Lancet 1999; 354: 222–23.
p53 polymorphism and cervical cancer Sir—Ingeborg Zehbe and colleagues (July 17, p 218)1 report an association between TP53 codon 72 arginine homozygotes and development of cervical cancer, and confirm Storey and colleagues’ findings. 2 Several other groups have failed to confirm this appealing association. Zehbe and coworkers’ results are interesting but surprising. They analysed only a few cases: 28 Italian and 30 Swedish patients with cervical cancer (compared with 24 Italian patients with high-grade cervical intraepithelial neoplasia [HCIN] and 40 Italian controls, 54 Swedish controls with HCIN and 626 Swedish controls). The frequencies among the Swedish controls and HCIN patients are similar to previous reports in Scandinavian populations.3 Were their analyses done on DNA from leucocytes or from tumour tissue samples? Analyses of tumour tissue may affect the results, because a high frequency of loss of heterozygosity in this region may give biased allele frequencies. The statistical power of the study is low. Why Zehbe and co-workers’ results differ from those of previous studies is unclear. These workers refer to some studies and state that the number of cases is small, with an average of 44 patients. The selection of referenced work is surprising, since the average number of cases in the studies to which they do not refer is 130 (range 77–236).3–5 They state that allelespecific PCR is more open to misinterpretation than single-strand confirmation polymorphism (SSCP), which they have used. Hildesheim and co-workers4 also used SSCP, Sonoda et al5 used direct sequencing, and we3 used digestion of a PCR product giving specific products. Several of the uncited studies have precise human papillomavirus data. In our opinion, the discrepancy is still unexplained, and it is difficult to see that the association found by Zehbe et al is other than a coincidental finding that results from the small number of cases. *Åslaug Helland, Anne-Lise Børresen-Dale
1
Feighery C. Coeliac disease. BMJ 1999; 319: 236–39.
Institute of Cancer Research, Norwegian Radiumhospital, N-0310 Oslo, Norway
1561
1
Zehbe I, Voglino G, Wilander E, Genta F, Tommasino M. Codon 72 polymorphism of p53 and its association with cervical cancer. Lancet 1999; 354: 218–19. 2 Storey A, Thomas M, Kalita A, et al. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 1998; 393: 229–34. 3 Helland Å, Langerød A, Johnsen H, et al. p53 polymorphism and risk of cervical cancer. Nature 1998; 396: 530–31. 4 Hildesheim A, Schiffman M, Brinton LA, et al. p53 polymorphism and risk of cervical cancer. Nature 1998; 396: 531–32. 5 Sonoda Y, Saigo PE, Boyd J. p53 and genetic susceptibility to cervical cancer. J Natl Cancer Inst 1999; 91: 557.
Authors’ reply Sir—The analysis of the 53 genotypes was done on DNA from tumour tissue. To exclude loss of heterozygosity in which either the proline or the arginine allele could be lost in heterozygotes during tumour development, normal tissue was microdissected in half the Swedish cancer biopsy specimens. The p53 genotype of the normal tissue was then compared with the genotype of the tumour tissue and no discrepancy was seen. These results are in agreement with those of Storey et al 1 and Minaguchi et al.2 Our data seem to be true because the cases were carefully selected in terms of the histology type (squamous cell carcinomas of the cervix), the interpreter (one pathologist), and the human papillomavirus (HPV) type (HPV 16). In addition, several techniques for the detection of p53 genotypes were tried and SSCP proved the most reliable method. Our results are unlikely to have been coincidental, since the data were obtained in two different populations. Moreover, a similar study done on HPV-16-positive adenocarcinomas in Swedish women showed the same trend as squamous cell carcinoma in Swedish women (Erik Wilander, unpublished data). Whether our initial findings will be confirmed in larger samples remains to be seen. The explanations for the discrepancy were meant to be suggestions and were not the main issue of our letter. The selection of the studies referred to in our investigation was based on scientific criteria. Several genetic factors, which are population-related, may contribute differently to the development of cervical squamous cell carcinoma. For this reason, we have considered only European studies, which automatically excludes references 4 and 5 that Åslaug Helland and Anne-Lise Børresen-Dale cite. The remaining European study by Helland et al was not included because of restrictions of space and numbers of references in Research letters. The inclusion of this Norwegian study3 with
1562
a sample size of 77 would not have added substantially to our conclusion. Furthermore, no investigation so far has considered all the criteria analysed here in the same study. Our data show a trend for an increased arginine allele in HPV-16positive squamous cell carcinomas of the cervix in two European populations. These findings are in agreement with the in-vitro data of Storey and colleagues,1 which show that both forms of p53 are degraded by E6, although the arginine genotype is a better substrate for E6 than the proline genotype. With these functional data, one would not except more than a weak association between the arginine allele and cervical cancer. *Ingeborg Zehbe, Gianfranco Voglino, Erik Wilander, Franco Genta, Massimo Tommasino *Deutsches Krebsforschungszentrum, Angewandle Tumorvirologie, D-69120 Heidelberg, Germany; Servicio di Anatomie Patologica, Ospedale Sant’Anna, Turin, Italy; and Department of Genetics and Pathology, University Hospital, Uppsala, Sweden (e-mail: [email protected]) 1
Storey A, Thomas M, Kalita A, et al. Role of p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 1998; 393: 229–34. 2 Minaguchi T, Kanamor Y, Matsushima M, et al. No evidence of correlation between polymorphism at codon 72 of p53 and risk of cervical cancer in Japanese patients with human papillomavirus 16/18 infection. Cancer Res 1998; 58: 4585–86. 3 Helland A, Langerød Å, Johnsen H, et al. p53 polymorphism and risk of cervical cancer. Nature 1998; 396: 530–31.
Tetanus and pregnancyrelated mortality Sir—The report by Roger Rochat and Halida Akter (Aug 14, p 545)1 once again highlights a preventable cause of maternal mortality in Bangladesh and, indeed, in many less developed countries. The investigators showed that pregnancy-associated tetanus occurred in a significant number of women as a result of termination of pregnancy, and that about 80% of the deaths were in married women. The recommendations that all 12-year-old girls in Bangladesh be immunised with tetanus toxoid is rather idealistic and utopian, with important implications in terms of costs and logistics for a developing country where tetanus toxoid coverage in pregnant women is just over 50%.1 Since over 80% of these women were married, a failure of contraception or non-use of contraception seems to be the starting point in the chain of events leading to maternal tetanus infection.
The provision of adequate family planning services would thus make an immediate, cost-effective impact on tetanus-associated maternal mortality, and would also provide the additional benefits of planned families. U I Esen South Tyneside District Hospital, South Shields, Tyne & Wear NE34 0PL, UK 1
Rochat R, Akhter H. Tetanus and pregnancy-related mortality in Bangladesh. Lancet 1999; 354: 565.
Sublingual therapy for cobalamin deficiency Sir—Georges Delpre and colleagues (Aug 28, p 740)1 report the use of sublingual cobalamin in cobalamindeficient patients. Cobalamin nuggets are actually chewable, allowing much simpler administration, especially in children and older individuals in whom lack of compliance prevents sublingual use. In fact, the cobalamin nuggets that Delpre and colleagues used are now labelled as chewable instead of sublingual, although the formulation has not changed (personal communication, Joanne DeCandia, Solgar Vitamin and Herb, Leonia, NJ, USA). It is also noteworthy that cobalamin nuggets contain cyanocobalamin and not OHcobalamin (personal communication, Joanne DeCandia). In addition to the indications that Delpre and colleagues mention, OHcobalamin injections are used for the treatment of various inborn errors of metabolism, including cobalaminresponsive methylmalonic acidaemia (MMA; cblA, cblB) and forms of combined MMA and homocysteinuria (cblC, cblD, cblF).2 Most affected patients present in the neonatal period and subsequently have to be treated throughout childhood with regular cobalamin injections. As far as we are aware, there are no data on the use of oral cobalamin in such patients, who have normal plasma cobalamin concentrations but impaired intracellular cobalamin metabolism. *Olaf A F Bodamer, Fernando Scaglia Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 1
Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral cobalamin supplementation. Lancet 1999; 354: 740–41. 2 Fenton WA, Rosenberg LE. Disorders of proprionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease, 7th edn. New York: McGraw Hill, 1995: 1423–49.
THE LANCET • Vol 354 • October 30, 1999
Lev MH, Rhea JT, Bramson RT. Avoidance of variability and error in radiology. Lancet 1999; 354: 272. 2 Faix RG, Adams JT. Neonatal necrotizing enterocolitis: current concepts and controversies. In: Aronoff SC, Hughes WT, Kohl S, Speck WT, Wald ER, eds. Advances in pediatric infectious diseases. St Louis: Mosby, 1994: 1–36. 3 Berseth CL, Abrams SA. Special gastrointestinal concerns. In: Taeusch HW, Ballard RA, eds. Avery’s diseases on the newborn. Philadelphia: WB Saunders, 1998: 965–78. 4 NEC outbreak report. Rome: Osservatorio Epidemiologico Regione Lazio and Servizio Igiene Ospedaliera, 1999. 5 NEC revision report. Rome: Policlinico Umberto I Revision Committee, 1999.
Cardiomyopathy in Danish patients with coeliac disease Sir—The understanding of coeliac disease has changed during the past decades. A series of diseases such as primary biliary cirrhosis and type 1 diabetes seem to be associated with coeliac disease.1,2 It has been suggested that the prevalence of coeliac disease in patients with dilated cardiomyopathy has increased; among 52 patients with idiopathic cardiomyopathy, M Curione and co-workers (July 17, p 222)3 found three patients with coeliac disease, which suggests an association with cardiomyopathy. We report the incidence of cardiomyopathy in patients with coeliac disease in a nationwide population-based cohort. The Danish National Registry of Patients (NRP) contains information on virtually all hospital discharges in Denmark since 1977. Each discharge record includes the unique civil registration number given to all citizens Calendar period
Number of Observation patients time (years) with cardiomyopathy
Incidence rate per 100 000 person-years (95% CI)
1977–81 1982–86 1987–92
0 1 3
·· 54 (1–300) 86 (18–251)
733 1859 3488
Number of patients with cardiomyopathy, observation time, and incidence rates of cardiomyopathy by calendar period
THE LANCET • Vol 354 • October 30, 1999
in Denmark at birth. The discharge diagnoses in the NRP were classified according to the Danish version of the International Classification of Diseases, eighth edition (ICD-8) during the study period, from Jan 1, 1977, to Dec 31, 1992. All patients discharged with coeliac disease (ICD 269.00) were included in the study. All other diagnoses registered during the same hospital stay were collected, and cases of cardiomyopathy (ICD 425.99) were identified. We linked patients by their registration number to the Danish Civil Registration System, which contains information on death and emigration. We calculated the risk time for the patients in the cohort from the first discharge with coeliac disease to Dec 31, 1992, or death, whichever was first. We calculated the incidence in calendar periods as the observed number of cases with cardiomyopathy divided by observation time, with 95% CI calculated by exact Poisson limits. 896 patients with coeliac disease were identified in the NRP. Among 893 with a valid civil registration number, four cases of cardiomyopathy were identified. Patients were followed up for a total of 6082 person-years. The incidence rates by calendar periods are shown in the table. We found high incidence rates of cardiomyopathy in patients with coeliac disease, indicating that coeliac disease may be associated with cardiomyopathy. The incidence rates increased during the study period, probably because of a change in diagnostic procedures for cardiomyopathy, since echocardiography was introduced in the last calendar period. Our study was based on discharge diagnoses, which are known to vary in quality. However, Danish data quality studies have shown that gastrointestinal disease and other serious diseases are generally well coded. The rates presented are probably underestimated since comorbid diseases may be underreported in the hospital discharge registries. In conclusion, we found increasing evidence for an association between coeliac disease and cardiomyopathy that should be further examined in analytical studies with appropriate controls. *Kirsten Fonager, Henrik Toft Sørensen, Bente Nørgård, Ane Marie Thulstrup *Department of Epidemiology and Social Medicine, Aarhus University, 8000 Aarhus C, Denmark; Danish Epidemiology Science Centre at the Department of Epidemiology and Social Medicine, Aarhus; and Department of Medicine V, Aarhus University Hospital, Aarhus (e-mail: [email protected])
2
Sørensen HT, Thulstrup AM, Blomquist P, Nørgård B, Fonager K, Ekbom A. Risk of primary biliary liver cirrhosis in patients with coeliac disease: Danish and Swedish cohort data. Gut 1999; 44: 736–38. 3 Curione M, Barbato M, Biase L, Viola F, Russo LL, Cardi E. Prevalence of coeliac disease in idiopathic dilated cardiomyopathy. Lancet 1999; 354: 222–23.
p53 polymorphism and cervical cancer Sir—Ingeborg Zehbe and colleagues (July 17, p 218)1 report an association between TP53 codon 72 arginine homozygotes and development of cervical cancer, and confirm Storey and colleagues’ findings. 2 Several other groups have failed to confirm this appealing association. Zehbe and coworkers’ results are interesting but surprising. They analysed only a few cases: 28 Italian and 30 Swedish patients with cervical cancer (compared with 24 Italian patients with high-grade cervical intraepithelial neoplasia [HCIN] and 40 Italian controls, 54 Swedish controls with HCIN and 626 Swedish controls). The frequencies among the Swedish controls and HCIN patients are similar to previous reports in Scandinavian populations.3 Were their analyses done on DNA from leucocytes or from tumour tissue samples? Analyses of tumour tissue may affect the results, because a high frequency of loss of heterozygosity in this region may give biased allele frequencies. The statistical power of the study is low. Why Zehbe and co-workers’ results differ from those of previous studies is unclear. These workers refer to some studies and state that the number of cases is small, with an average of 44 patients. The selection of referenced work is surprising, since the average number of cases in the studies to which they do not refer is 130 (range 77–236).3–5 They state that allelespecific PCR is more open to misinterpretation than single-strand confirmation polymorphism (SSCP), which they have used. Hildesheim and co-workers4 also used SSCP, Sonoda et al5 used direct sequencing, and we3 used digestion of a PCR product giving specific products. Several of the uncited studies have precise human papillomavirus data. In our opinion, the discrepancy is still unexplained, and it is difficult to see that the association found by Zehbe et al is other than a coincidental finding that results from the small number of cases. *Åslaug Helland, Anne-Lise Børresen-Dale
1
Feighery C. Coeliac disease. BMJ 1999; 319: 236–39.
Institute of Cancer Research, Norwegian Radiumhospital, N-0310 Oslo, Norway
1561
1
Zehbe I, Voglino G, Wilander E, Genta F, Tommasino M. Codon 72 polymorphism of p53 and its association with cervical cancer. Lancet 1999; 354: 218–19. 2 Storey A, Thomas M, Kalita A, et al. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 1998; 393: 229–34. 3 Helland Å, Langerød A, Johnsen H, et al. p53 polymorphism and risk of cervical cancer. Nature 1998; 396: 530–31. 4 Hildesheim A, Schiffman M, Brinton LA, et al. p53 polymorphism and risk of cervical cancer. Nature 1998; 396: 531–32. 5 Sonoda Y, Saigo PE, Boyd J. p53 and genetic susceptibility to cervical cancer. J Natl Cancer Inst 1999; 91: 557.
Authors’ reply Sir—The analysis of the 53 genotypes was done on DNA from tumour tissue. To exclude loss of heterozygosity in which either the proline or the arginine allele could be lost in heterozygotes during tumour development, normal tissue was microdissected in half the Swedish cancer biopsy specimens. The p53 genotype of the normal tissue was then compared with the genotype of the tumour tissue and no discrepancy was seen. These results are in agreement with those of Storey et al 1 and Minaguchi et al.2 Our data seem to be true because the cases were carefully selected in terms of the histology type (squamous cell carcinomas of the cervix), the interpreter (one pathologist), and the human papillomavirus (HPV) type (HPV 16). In addition, several techniques for the detection of p53 genotypes were tried and SSCP proved the most reliable method. Our results are unlikely to have been coincidental, since the data were obtained in two different populations. Moreover, a similar study done on HPV-16-positive adenocarcinomas in Swedish women showed the same trend as squamous cell carcinoma in Swedish women (Erik Wilander, unpublished data). Whether our initial findings will be confirmed in larger samples remains to be seen. The explanations for the discrepancy were meant to be suggestions and were not the main issue of our letter. The selection of the studies referred to in our investigation was based on scientific criteria. Several genetic factors, which are population-related, may contribute differently to the development of cervical squamous cell carcinoma. For this reason, we have considered only European studies, which automatically excludes references 4 and 5 that Åslaug Helland and Anne-Lise Børresen-Dale cite. The remaining European study by Helland et al was not included because of restrictions of space and numbers of references in Research letters. The inclusion of this Norwegian study3 with
1562
a sample size of 77 would not have added substantially to our conclusion. Furthermore, no investigation so far has considered all the criteria analysed here in the same study. Our data show a trend for an increased arginine allele in HPV-16positive squamous cell carcinomas of the cervix in two European populations. These findings are in agreement with the in-vitro data of Storey and colleagues,1 which show that both forms of p53 are degraded by E6, although the arginine genotype is a better substrate for E6 than the proline genotype. With these functional data, one would not except more than a weak association between the arginine allele and cervical cancer. *Ingeborg Zehbe, Gianfranco Voglino, Erik Wilander, Franco Genta, Massimo Tommasino *Deutsches Krebsforschungszentrum, Angewandle Tumorvirologie, D-69120 Heidelberg, Germany; Servicio di Anatomie Patologica, Ospedale Sant’Anna, Turin, Italy; and Department of Genetics and Pathology, University Hospital, Uppsala, Sweden (e-mail: [email protected]) 1
Storey A, Thomas M, Kalita A, et al. Role of p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 1998; 393: 229–34. 2 Minaguchi T, Kanamor Y, Matsushima M, et al. No evidence of correlation between polymorphism at codon 72 of p53 and risk of cervical cancer in Japanese patients with human papillomavirus 16/18 infection. Cancer Res 1998; 58: 4585–86. 3 Helland A, Langerød Å, Johnsen H, et al. p53 polymorphism and risk of cervical cancer. Nature 1998; 396: 530–31.
Tetanus and pregnancyrelated mortality Sir—The report by Roger Rochat and Halida Akter (Aug 14, p 545)1 once again highlights a preventable cause of maternal mortality in Bangladesh and, indeed, in many less developed countries. The investigators showed that pregnancy-associated tetanus occurred in a significant number of women as a result of termination of pregnancy, and that about 80% of the deaths were in married women. The recommendations that all 12-year-old girls in Bangladesh be immunised with tetanus toxoid is rather idealistic and utopian, with important implications in terms of costs and logistics for a developing country where tetanus toxoid coverage in pregnant women is just over 50%.1 Since over 80% of these women were married, a failure of contraception or non-use of contraception seems to be the starting point in the chain of events leading to maternal tetanus infection.
The provision of adequate family planning services would thus make an immediate, cost-effective impact on tetanus-associated maternal mortality, and would also provide the additional benefits of planned families. U I Esen South Tyneside District Hospital, South Shields, Tyne & Wear NE34 0PL, UK 1
Rochat R, Akhter H. Tetanus and pregnancy-related mortality in Bangladesh. Lancet 1999; 354: 565.
Sublingual therapy for cobalamin deficiency Sir—Georges Delpre and colleagues (Aug 28, p 740)1 report the use of sublingual cobalamin in cobalamindeficient patients. Cobalamin nuggets are actually chewable, allowing much simpler administration, especially in children and older individuals in whom lack of compliance prevents sublingual use. In fact, the cobalamin nuggets that Delpre and colleagues used are now labelled as chewable instead of sublingual, although the formulation has not changed (personal communication, Joanne DeCandia, Solgar Vitamin and Herb, Leonia, NJ, USA). It is also noteworthy that cobalamin nuggets contain cyanocobalamin and not OHcobalamin (personal communication, Joanne DeCandia). In addition to the indications that Delpre and colleagues mention, OHcobalamin injections are used for the treatment of various inborn errors of metabolism, including cobalaminresponsive methylmalonic acidaemia (MMA; cblA, cblB) and forms of combined MMA and homocysteinuria (cblC, cblD, cblF).2 Most affected patients present in the neonatal period and subsequently have to be treated throughout childhood with regular cobalamin injections. As far as we are aware, there are no data on the use of oral cobalamin in such patients, who have normal plasma cobalamin concentrations but impaired intracellular cobalamin metabolism. *Olaf A F Bodamer, Fernando Scaglia Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 1
Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral cobalamin supplementation. Lancet 1999; 354: 740–41. 2 Fenton WA, Rosenberg LE. Disorders of proprionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease, 7th edn. New York: McGraw Hill, 1995: 1423–49.
THE LANCET • Vol 354 • October 30, 1999