- Email: [email protected]
DEFECTIVE BIOTIN ABSORPTION IN MULTIPLE CARBOXYLASE DEFICIENCY
263
MORBIDITY DATA AND SMALL GEOGRAPHICAL AREAS
SIR,-Alderson’ has suggested that further use should be made of data from Hospital Activity Analysis (HAA). In response to the concern that there may be a risk from exposure to high soil levels of cadmium for residents of Shipham Parish District, Somerset,2.4 we have done a survey of this population, using HAA data. Case-notes were examined for all Shipham residents admitted to National Health Service hospitals during the years 1974-78. Standardised admission ratios (SARs) were calculated for International Classification of Diseases categories that are associated with cadmium exposure. For HAA purposes addresses of patients are coded by local authority district. Health problems, however, are often restricted to much smaller geographical areas. Before we could calculate SARs for Shipham, 451 hours of clerical work were required to identify the 201 records of HAA data for Shipham residents from the computer listing of admissions from the local authority district. The need to produce statistics for small areas has been recognised,5and the Office of Population Censuses and Surveys is introducing a postcode system for vital statistics in England and Wales.Small population groups would be much easier to identify if postcodes were also used for inpatients’ addresses. The value of HAA data would also be enhanced by record linkage with other data of the life events. 78 Although HAA codes the patient’s address, the time the patient has been living there cannot be determined. We could not therefore examine the effect of duration of exposure to cadmium. Postcoding of addresses and record linkage would not breach confidentiality provided that detailed study protocols are approved by health district ethical committees. Department of Community Health, University of Bristol, Canynge Hall, Bristol BS8 2PR
R. PHILIPP A. O. HUGHES
A
carboxylase. Organicaciduria typical of propionyl coenzyme (CoA) and methylcrotonyl CoA carboxylase deficiencies appeared under a high protein diet. 12 In addition the three biotin-dependent mitochondrial carboxylase activities (pyruvate, propionyl CoA, and methylcrotonyl CoA carboxylases) were deficient in liver tissue. Our patient was fed a regular infant formula with no raw egg, and no clinical symptoms or laboratory evidence of general malabsorption
were
noted. However, the level of biotin in
plasma
was
significantly decreased before treatment, as measured by the microbiological method (Lactobacillus plantarum). 13 The concentration
was
was 0 - 24 ng/ml; the mean±SD for ten . 59:!:O’ 4 ng/ml. Impaired intestinal
age-matched controls
absorption of biotin was considered as the cause of MCD. To this investigate the child was given increasing daily amounts of biotin possibility mouth. by was sampled 60 min after each oral time for peak concentrations after a administration, the expected single
Blood
plasma biotin concentration remained low
the
dose 14 The patient’ss
(figure).
multiple carboxylase deficiency Plasma aged-matched biotin in patient with (12-36 months). oxy
controls
ase
and in
Increasing amounts of the vitamin were administered each day, orally, after a 12 h period of physiological fasting. Blood samples were 60 min after biotin administration. The number of control values is given in parentheses. All values (patient’s and controls’) are the mean of two determinations.
taken
DEFECTIVE BIOTIN ABSORPTION IN MULTIPLE CARBOXYLASE DEFICIENCY
SIR,-A Lancet editorial9 refers to the suggestion of Thoene et a1.lO that multiple carboxylase deficiency (MCD) with low plasma and urinary biotin could result from a defective transport system of biotin, a cofactor common to four major carboxylases in man. They proposed that the defective transport system could be either limited to intestinal mucosa or common to all tissues. We have described 11,12 a case of MCD in a 12-month-old boy whose clinical presentation (including alopecia, rashes, and neurological symptoms) was similar to that in previous reports9,1O but whose biological disorders mainly consisted of a congenital lacticacidosis due to a deficiency of a biotin-dependent enzyme, pyruvate 1. Alderson M
Hospital Activity Analysis and health information systems. Health Trends
1976, 8: 66-68 2 Carruthers M, Smith B. Evidence of cadmium toxicity in a population living in a zinc mining area. Lancet 1979; 1: 845-47. 3 Harvey TC, Chettle DR, Fremlin JH, Al Haddad IK, Downey SPMJ. Cadmium in Shipham Lancet 1979; i: 551 4. Kraemer DF, Lucas JB, Pahren HR, Ryan JA, Kowal NE. Cadmium toxicity. Lancet 1979, i: 1241-42. 4 Carstairs V. Small area analysis and health service research. Commun Med 1981; 3: 131-39. 6 Brown N Postcodes as a building brick for vital statistics. Popul Trends 1980, no. 20: 17-18 7 Adelstein AM Policies of the Office of Population Censuses and Surveys Philosophy and constraints Br J Prev Soc Med 1976; 30: 1-10. 8 Crown J Area information services. Health Trends 1978; 10: 35-36 9 Editorial Biotin deficiency Lancet 1981; i1195. 10 Thoene J, Baker H, Yoshino M, Sweetman L. Biotin-responsive carboxylase deficiency associated with subnormal plasma and urinary biotin. N Engl J Med 1981; 304: 817-20. 11 Munnich A, Saudubray JM, Coude FX, Charpentier C, Saurat JH, FrézalJ. Fatty acid responsive alopecia in multiple carboxylase deficiency Lancet 1980, i; 1080-81. 12 Munnich A, Saudubray JM, Cotisson A, Coude FX, Ogier H, Charpentier C, Marsac C, Carré G, Bourgeay-Causse M, Frézal J. Biotin dependent multiple carboxylase deficiency presenting as congenital lactic acidosis. Eur J Paediatr (in press).
This finding suggests that MCD could result from a defective intestinal absorption of biotin. The disorder seems to be limited to the intestinal mucosa since enzyme activities in the patient’s fibroblasts cultured in a biotin-free medium were similar to control values.I2 Little is known about biotin absorption and transport in man. 15 To account for MCD Thoene et al. proposed that the remarkable responsiveness of MCD to pharmacological doses of biotin could be due to a mass-action effect in which large amounts of biotin promote passive absorption across the intestinal mucosa. They also suggested that normal biotin uptake could be the result of two systems-one with low Km and the other with a high Km for biotin, with patients lacking only the low Km system. In our patient plasma biotin was 47070 of control values after a 4 mg biotin loading dose but
only 12%ofnormalaftera0’25mgvitaminadministration,andthis . suggests that the intestinal absorption of the vitamin is selectively impaired in the
range of the low biotin
concentrations. A. MUNNICH
Climque et Unité de Recherches de Génetique Médicale (INSERM U Hôpital des Enfants-Malades, 75 730 Paris, France; et Centre d’Etudes et de Recherches Nutritionnelles, Pasteur, Lyon
Institut
J. M. SAUDUBRAY 12),
G. CARRÉ F. X. COUDE H. OGIER C. CHARPENTIER J. FRÉZAL
Brubacher G. Biotin deficiency in chicks fed a wheat-basewd diet. Int J Vit Nutr Res 1976; 46: 8314-21. 14 Horsburgh J, Gompertz D. A protein-binding assay for measurement of biotin in physiological fluids. Clin Chim Acta 1978; 82: 215-23. 15. Bonjour JP. Biotin in man’s nutrition and therapy: a review. Int J Vit Nutr Res 1977; 47: 107-18. 13.
Frigg M,
MORBIDITY DATA AND SMALL GEOGRAPHICAL AREAS
SIR,-Alderson’ has suggested that further use should be made of data from Hospital Activity Analysis (HAA). In response to the concern that there may be a risk from exposure to high soil levels of cadmium for residents of Shipham Parish District, Somerset,2.4 we have done a survey of this population, using HAA data. Case-notes were examined for all Shipham residents admitted to National Health Service hospitals during the years 1974-78. Standardised admission ratios (SARs) were calculated for International Classification of Diseases categories that are associated with cadmium exposure. For HAA purposes addresses of patients are coded by local authority district. Health problems, however, are often restricted to much smaller geographical areas. Before we could calculate SARs for Shipham, 451 hours of clerical work were required to identify the 201 records of HAA data for Shipham residents from the computer listing of admissions from the local authority district. The need to produce statistics for small areas has been recognised,5and the Office of Population Censuses and Surveys is introducing a postcode system for vital statistics in England and Wales.Small population groups would be much easier to identify if postcodes were also used for inpatients’ addresses. The value of HAA data would also be enhanced by record linkage with other data of the life events. 78 Although HAA codes the patient’s address, the time the patient has been living there cannot be determined. We could not therefore examine the effect of duration of exposure to cadmium. Postcoding of addresses and record linkage would not breach confidentiality provided that detailed study protocols are approved by health district ethical committees. Department of Community Health, University of Bristol, Canynge Hall, Bristol BS8 2PR
R. PHILIPP A. O. HUGHES
A
carboxylase. Organicaciduria typical of propionyl coenzyme (CoA) and methylcrotonyl CoA carboxylase deficiencies appeared under a high protein diet. 12 In addition the three biotin-dependent mitochondrial carboxylase activities (pyruvate, propionyl CoA, and methylcrotonyl CoA carboxylases) were deficient in liver tissue. Our patient was fed a regular infant formula with no raw egg, and no clinical symptoms or laboratory evidence of general malabsorption
were
noted. However, the level of biotin in
plasma
was
significantly decreased before treatment, as measured by the microbiological method (Lactobacillus plantarum). 13 The concentration
was
was 0 - 24 ng/ml; the mean±SD for ten . 59:!:O’ 4 ng/ml. Impaired intestinal
age-matched controls
absorption of biotin was considered as the cause of MCD. To this investigate the child was given increasing daily amounts of biotin possibility mouth. by was sampled 60 min after each oral time for peak concentrations after a administration, the expected single
Blood
plasma biotin concentration remained low
the
dose 14 The patient’ss
(figure).
multiple carboxylase deficiency Plasma aged-matched biotin in patient with (12-36 months). oxy
controls
ase
and in
Increasing amounts of the vitamin were administered each day, orally, after a 12 h period of physiological fasting. Blood samples were 60 min after biotin administration. The number of control values is given in parentheses. All values (patient’s and controls’) are the mean of two determinations.
taken
DEFECTIVE BIOTIN ABSORPTION IN MULTIPLE CARBOXYLASE DEFICIENCY
SIR,-A Lancet editorial9 refers to the suggestion of Thoene et a1.lO that multiple carboxylase deficiency (MCD) with low plasma and urinary biotin could result from a defective transport system of biotin, a cofactor common to four major carboxylases in man. They proposed that the defective transport system could be either limited to intestinal mucosa or common to all tissues. We have described 11,12 a case of MCD in a 12-month-old boy whose clinical presentation (including alopecia, rashes, and neurological symptoms) was similar to that in previous reports9,1O but whose biological disorders mainly consisted of a congenital lacticacidosis due to a deficiency of a biotin-dependent enzyme, pyruvate 1. Alderson M
Hospital Activity Analysis and health information systems. Health Trends
1976, 8: 66-68 2 Carruthers M, Smith B. Evidence of cadmium toxicity in a population living in a zinc mining area. Lancet 1979; 1: 845-47. 3 Harvey TC, Chettle DR, Fremlin JH, Al Haddad IK, Downey SPMJ. Cadmium in Shipham Lancet 1979; i: 551 4. Kraemer DF, Lucas JB, Pahren HR, Ryan JA, Kowal NE. Cadmium toxicity. Lancet 1979, i: 1241-42. 4 Carstairs V. Small area analysis and health service research. Commun Med 1981; 3: 131-39. 6 Brown N Postcodes as a building brick for vital statistics. Popul Trends 1980, no. 20: 17-18 7 Adelstein AM Policies of the Office of Population Censuses and Surveys Philosophy and constraints Br J Prev Soc Med 1976; 30: 1-10. 8 Crown J Area information services. Health Trends 1978; 10: 35-36 9 Editorial Biotin deficiency Lancet 1981; i1195. 10 Thoene J, Baker H, Yoshino M, Sweetman L. Biotin-responsive carboxylase deficiency associated with subnormal plasma and urinary biotin. N Engl J Med 1981; 304: 817-20. 11 Munnich A, Saudubray JM, Coude FX, Charpentier C, Saurat JH, FrézalJ. Fatty acid responsive alopecia in multiple carboxylase deficiency Lancet 1980, i; 1080-81. 12 Munnich A, Saudubray JM, Cotisson A, Coude FX, Ogier H, Charpentier C, Marsac C, Carré G, Bourgeay-Causse M, Frézal J. Biotin dependent multiple carboxylase deficiency presenting as congenital lactic acidosis. Eur J Paediatr (in press).
This finding suggests that MCD could result from a defective intestinal absorption of biotin. The disorder seems to be limited to the intestinal mucosa since enzyme activities in the patient’s fibroblasts cultured in a biotin-free medium were similar to control values.I2 Little is known about biotin absorption and transport in man. 15 To account for MCD Thoene et al. proposed that the remarkable responsiveness of MCD to pharmacological doses of biotin could be due to a mass-action effect in which large amounts of biotin promote passive absorption across the intestinal mucosa. They also suggested that normal biotin uptake could be the result of two systems-one with low Km and the other with a high Km for biotin, with patients lacking only the low Km system. In our patient plasma biotin was 47070 of control values after a 4 mg biotin loading dose but
only 12%ofnormalaftera0’25mgvitaminadministration,andthis . suggests that the intestinal absorption of the vitamin is selectively impaired in the
range of the low biotin
concentrations. A. MUNNICH
Climque et Unité de Recherches de Génetique Médicale (INSERM U Hôpital des Enfants-Malades, 75 730 Paris, France; et Centre d’Etudes et de Recherches Nutritionnelles, Pasteur, Lyon
Institut
J. M. SAUDUBRAY 12),
G. CARRÉ F. X. COUDE H. OGIER C. CHARPENTIER J. FRÉZAL
Brubacher G. Biotin deficiency in chicks fed a wheat-basewd diet. Int J Vit Nutr Res 1976; 46: 8314-21. 14 Horsburgh J, Gompertz D. A protein-binding assay for measurement of biotin in physiological fluids. Clin Chim Acta 1978; 82: 215-23. 15. Bonjour JP. Biotin in man’s nutrition and therapy: a review. Int J Vit Nutr Res 1977; 47: 107-18. 13.
Frigg M,