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HLA-DR2 AND DIDMOAD SYNDROME
109
HLA-DR2 AND DIDMOAD SYNDROME SIR.-Dr Monson and Dr Boucher (June 4, p 1286) describe a in which two siblings affected by the DIDMOAD or Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) carry the HLA-DR2 allele. This provides further evidence that the insulin-dependent diabetes mellitus in this syndrome is distinct from classical type I diabetes mellitus (IDDM),
family
because the DR2 allele is uncommon in IDDM. Stanley et all reported three affected siblings, two of whom had two haplotypes in common, but the third two
sibling
shared neither
others, suggesting that the syndrome
however, the
family was not
DR
haplotype
was not
typed.
detail elsewhere,2all siblings, aged 23, 19, and 18, have IDDM and optic atrophy and one of them has partial diabetes insipidus as well. The onset of IDDM occurred in all patients at the age of 5 years; the decrease in visual acuity developed when they were 15, 9, and 8 years old, respectively. The HLA genotypes (see table) were identical in two siblings but different in the third. The HLA identical siblings carried DR2/DR5; the non-identical one carried DR1/DR4. In family R only one child is affected. She is now 16 years old and her three siblings, aged 13, 11, and 7, are symptom-free. When the patient presented at the age of 13 with typical symptoms of IDDM she had a 4 year history of severe optic atrophy, diabetes insipidus, and atony of the urinary tract. Her HLA genotype (A26, Cw7, Bw49, BfS, DR2/A2, Cw6, Bw50, BfFl, DR7) showed a paternal recombination between loci A and C.
family D, reported in
finding of the DR2 allele in patients with DIDMOAD syndrome belonging to three unrelated families needs to be confirmed by further studies. However, the rarity of this allele in IDDM (relative risk 0’ 33) make it unlikely that this finding could have occurred by chance alone. The existence of an association between the DIDMOAD syndrome and DR2 could throw new light on the relation between this syndrome and HLA and on the role of this allele in relation to possible heterogeneity of IDDM. The absence of linkage between Wolfram syndrome and HLA suggested by Stanley et all is confirmed: the segregation of the HLA The
fit with a recessive model since not all the share the same parental haplotypes in the three families reported so far. The genetic control of the may be more complex than the presumed recessive
haplotypes does affected siblings multiplex syndrome
outside the HLA with DR2.
region
and another
one
associated
INSERM Unit 83,
or
interacting
75935 Paris, France
I. DESCHAMPS H. LESTRADET
INSERM Unit 93, Hôpital St Louis, Paris
M. SCHMID J. HORS
Hôpital Hérold,
with the
HLA-linked;
We report here the HLA genotypes of two families with DIDMOAD syndrome in which the affected members also carry HLA DR2. In
mode of inheritance. If an association with DR2 were to be confirmed, a polygenic model might be proposed, including a gene
** In the table accompanying Dr Moson and Dr Boucher’s letter the second entry for sibling C should have been BW44.-ED. L. MALARIA CONTROL AND PRIMARY HEALTH CARE
SIR,-Your editorial of April 30 discussed a strategy for reducing the mortality and morbidity of malaria in Africa. One of the proposals was the provision of chloroquine prophylaxis to high-risk groups such as young children. A similar scheme was undertaken in Papua New Guineal in which amodiaquine was distributed, through unpaid village dispensers, to 2000 pre-school children. Over a two year period the compliance rate was above 70%. At first the parasite rate (mainly Plasmodium falciparum) fell sharply in the children, but subsequently it reverted to pretreatment levels when the P falciparum became mildly to moderately resistant to chloroquine-a phenomenon which occurred simultaneously in many districts outside the prophylaxis area. There was no evidence that the prophylaxis programme accelerated the development of drug resistant P falciparum. The programme
was
terminated because
no
suitable alternative
prophylactic agent was available. The important point is that, although the minor degree of drug resistance did not significantly interfere with the usual 3 day chloroquine treatment of acute attacks of Pfalciparum, it did negate the prophylaxis programme which used a much smaller dose of drug. If drug resistance becomes a problem in Africa, then the chloroquine prophylaxis scheme will be one of the first intervention programmes
to
fail.
Princess Margaret Hospital for Perth, Western Australia 6001
Children,
J. D. STAGE
not
1. Stanley CA, Spielman RS, Zmijewski CM, Baker L Wolfram syndrome not HLA linked N Engl J Med 1979; 301: 1398-99. 2. Deschamps I, Lestradet H, Schmid M, Hors J HLA-DR2 in two sibships with insulindependent diabetes mellitus. J Med Genet (in press). 3. Deschamps I, Lestradet H, Bonaiti C, et al. HLA genotype studies in juvenile insulindependent diabetes. Diabetologia 1980; 19: 189-93. HLA TYPING IN TWO DIDMOAD FAMILIES
THEOPHYLLINE ASSAY ON DRIED BLOOD SPOTS
SIR,-Recent Lancet correspondence on plasma theophylline measurement2,3 has highlighted the problems of using isolated results to ensure that asthma patients have an adequate theophylline level to prevent symptoms at times when they are particularly susceptible to bronchoconstriction, as in the "early morning dipper". Problems are due to the different pharmacokinetic behaviour of the drug by day and by night, the different characteristics of theophylline preparations,4 and the vagaries of hepatic metabolism in individual patients. A 12 h plasma theophylline level3 can, at best, be only an indirect indicator of the drug’s actual plasma concentration/time profile. It is usually impracticable to obtain samples for standard assay methods when patients have their symptoms. Similar problems occur in patients with diabetes mellitus, and we have successfully monitored therapy by using the glucose concentration on dried blood spots collected by the patient.5This led us to adapt the Ames 4. Cremers CWRJ, Wijdeveld PGAB, Pinckers AJLG
Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atony of the urinary tract and bladder and other abnormalities (Wolfram syndrome). Acta Paediatr Scand 1977; 264 (suppl): 1-16.
Stace JD, Pariwa S. Reduction in malaria parasite ratein young children by distribution of prophylactic amodiaquine through voluntary village workers Papua New Guinea Med J 1981; 24: 254-60. 2. Primrose WR. Asthma at night. Lancet 1983; i: 927. 3. Jonkman JHG, van der Boon WJV. Nocturnal theophylline plasma concentrations. 1.
Lancet 1983; i: 1278-79. M, Hendeles L. Slow release theophylline. Rationale and basis for product selection N Engl J Med 1983, 308: 760-64. 5. Gamlen TR, James HC, Batstone GF. The determination of blood spot glucose concentration using a rapid kinetic assay Scand J Clin Lab Invest 1982; 42: 643-45.
4. Weinberger
’Affec’ed siblings
HLA-DR2 AND DIDMOAD SYNDROME SIR.-Dr Monson and Dr Boucher (June 4, p 1286) describe a in which two siblings affected by the DIDMOAD or Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) carry the HLA-DR2 allele. This provides further evidence that the insulin-dependent diabetes mellitus in this syndrome is distinct from classical type I diabetes mellitus (IDDM),
family
because the DR2 allele is uncommon in IDDM. Stanley et all reported three affected siblings, two of whom had two haplotypes in common, but the third two
sibling
shared neither
others, suggesting that the syndrome
however, the
family was not
DR
haplotype
was not
typed.
detail elsewhere,2all siblings, aged 23, 19, and 18, have IDDM and optic atrophy and one of them has partial diabetes insipidus as well. The onset of IDDM occurred in all patients at the age of 5 years; the decrease in visual acuity developed when they were 15, 9, and 8 years old, respectively. The HLA genotypes (see table) were identical in two siblings but different in the third. The HLA identical siblings carried DR2/DR5; the non-identical one carried DR1/DR4. In family R only one child is affected. She is now 16 years old and her three siblings, aged 13, 11, and 7, are symptom-free. When the patient presented at the age of 13 with typical symptoms of IDDM she had a 4 year history of severe optic atrophy, diabetes insipidus, and atony of the urinary tract. Her HLA genotype (A26, Cw7, Bw49, BfS, DR2/A2, Cw6, Bw50, BfFl, DR7) showed a paternal recombination between loci A and C.
family D, reported in
finding of the DR2 allele in patients with DIDMOAD syndrome belonging to three unrelated families needs to be confirmed by further studies. However, the rarity of this allele in IDDM (relative risk 0’ 33) make it unlikely that this finding could have occurred by chance alone. The existence of an association between the DIDMOAD syndrome and DR2 could throw new light on the relation between this syndrome and HLA and on the role of this allele in relation to possible heterogeneity of IDDM. The absence of linkage between Wolfram syndrome and HLA suggested by Stanley et all is confirmed: the segregation of the HLA The
fit with a recessive model since not all the share the same parental haplotypes in the three families reported so far. The genetic control of the may be more complex than the presumed recessive
haplotypes does affected siblings multiplex syndrome
outside the HLA with DR2.
region
and another
one
associated
INSERM Unit 83,
or
interacting
75935 Paris, France
I. DESCHAMPS H. LESTRADET
INSERM Unit 93, Hôpital St Louis, Paris
M. SCHMID J. HORS
Hôpital Hérold,
with the
HLA-linked;
We report here the HLA genotypes of two families with DIDMOAD syndrome in which the affected members also carry HLA DR2. In
mode of inheritance. If an association with DR2 were to be confirmed, a polygenic model might be proposed, including a gene
** In the table accompanying Dr Moson and Dr Boucher’s letter the second entry for sibling C should have been BW44.-ED. L. MALARIA CONTROL AND PRIMARY HEALTH CARE
SIR,-Your editorial of April 30 discussed a strategy for reducing the mortality and morbidity of malaria in Africa. One of the proposals was the provision of chloroquine prophylaxis to high-risk groups such as young children. A similar scheme was undertaken in Papua New Guineal in which amodiaquine was distributed, through unpaid village dispensers, to 2000 pre-school children. Over a two year period the compliance rate was above 70%. At first the parasite rate (mainly Plasmodium falciparum) fell sharply in the children, but subsequently it reverted to pretreatment levels when the P falciparum became mildly to moderately resistant to chloroquine-a phenomenon which occurred simultaneously in many districts outside the prophylaxis area. There was no evidence that the prophylaxis programme accelerated the development of drug resistant P falciparum. The programme
was
terminated because
no
suitable alternative
prophylactic agent was available. The important point is that, although the minor degree of drug resistance did not significantly interfere with the usual 3 day chloroquine treatment of acute attacks of Pfalciparum, it did negate the prophylaxis programme which used a much smaller dose of drug. If drug resistance becomes a problem in Africa, then the chloroquine prophylaxis scheme will be one of the first intervention programmes
to
fail.
Princess Margaret Hospital for Perth, Western Australia 6001
Children,
J. D. STAGE
not
1. Stanley CA, Spielman RS, Zmijewski CM, Baker L Wolfram syndrome not HLA linked N Engl J Med 1979; 301: 1398-99. 2. Deschamps I, Lestradet H, Schmid M, Hors J HLA-DR2 in two sibships with insulindependent diabetes mellitus. J Med Genet (in press). 3. Deschamps I, Lestradet H, Bonaiti C, et al. HLA genotype studies in juvenile insulindependent diabetes. Diabetologia 1980; 19: 189-93. HLA TYPING IN TWO DIDMOAD FAMILIES
THEOPHYLLINE ASSAY ON DRIED BLOOD SPOTS
SIR,-Recent Lancet correspondence on plasma theophylline measurement2,3 has highlighted the problems of using isolated results to ensure that asthma patients have an adequate theophylline level to prevent symptoms at times when they are particularly susceptible to bronchoconstriction, as in the "early morning dipper". Problems are due to the different pharmacokinetic behaviour of the drug by day and by night, the different characteristics of theophylline preparations,4 and the vagaries of hepatic metabolism in individual patients. A 12 h plasma theophylline level3 can, at best, be only an indirect indicator of the drug’s actual plasma concentration/time profile. It is usually impracticable to obtain samples for standard assay methods when patients have their symptoms. Similar problems occur in patients with diabetes mellitus, and we have successfully monitored therapy by using the glucose concentration on dried blood spots collected by the patient.5This led us to adapt the Ames 4. Cremers CWRJ, Wijdeveld PGAB, Pinckers AJLG
Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atony of the urinary tract and bladder and other abnormalities (Wolfram syndrome). Acta Paediatr Scand 1977; 264 (suppl): 1-16.
Stace JD, Pariwa S. Reduction in malaria parasite ratein young children by distribution of prophylactic amodiaquine through voluntary village workers Papua New Guinea Med J 1981; 24: 254-60. 2. Primrose WR. Asthma at night. Lancet 1983; i: 927. 3. Jonkman JHG, van der Boon WJV. Nocturnal theophylline plasma concentrations. 1.
Lancet 1983; i: 1278-79. M, Hendeles L. Slow release theophylline. Rationale and basis for product selection N Engl J Med 1983, 308: 760-64. 5. Gamlen TR, James HC, Batstone GF. The determination of blood spot glucose concentration using a rapid kinetic assay Scand J Clin Lab Invest 1982; 42: 643-45.
4. Weinberger
’Affec’ed siblings