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CONCORDANCE IN TWINS AND RECURRENCE IN SIBSHIPS IN MULTIPLE SCLEROSIS
1068 CONCORDANCE IN TWINS AND RECURRENCE IN SIBSHIPS IN MULTIPLE SCLEROSIS
SIR,-Dr James (March 20, p. 690) calculates that the concordance rate for multiple sclerosis (MS) among dizygotic twins is substantially higher than can be accounted for by the raised risk for siblings of index cases. James assumes that the concordance rate for dizygotic twins is at least 15% and that the recurrence rate for MS among siblings ranges from 0-4% to 6 - 0%. He states that his conclusion would be invalid if the concordance rate of 15% is a gross overestimate or if recurrence rate is substantially greater than 6%. There are many problems in studying MS concordance in twins. A major one is that MS has a variable age of onset so that twin pairs who are discordant when first studied may later prove to be concordant. It is therefore more realistic to assume that an estimated concordance rate of 15%2 is an underestimate rather than an overestimate. The reader may, however, question the accuracy of the recurrence rates for MS cited by James. The most recent study cited2 dealt with cases ascertained only until 1965, and many advances 3-5 have been made since that time which help in the diagnosis of MS in the living patient. Therefore, without more recent data, it might be argued that a recurrence rate of 6% is indeed a gross underestimate. In our recent study6 the recurrence rate for MS in siblings of index cases was 2-8±0-9% (n= 1179).. These data further confirm the conclusion drawn by James by showing that a recurrence rate of 6% is probably not a substantial underestimate even in light of advances being made in the diagnosis of MS. Department of Medical Genetics, University of British Columbia, ADELE D. SADOVNICK Vancouver, British Columbia, Canada SIR,-A 1981 Lancet editoria17 and Dr James in his letter in your March 20 issue mention the possibility of ascertainment bias in twin studies on multiple sclerosis (MS). We have studied MS in a total twin population and presented the results at the 12th World Congress of Neurology, held in Kyoto, Japan, in September, 1981. MS twins were ascertained by screening the files and by record linkage in two nationwide registers, the Danish twin register, which carries data on all like-sex twins born in Denmark 1870 to 1930, and the Danish multiple sclerosis register, founded in 1948 and comprising almost all MS cases diagnosed in Denmark. 59 twin probands with clinically definite MS9 from 54 pairs (33 female and 21 male pairs) were ascertained. All co-twins were followed up to death or to the age of at least 50 years, but no additional cases ofMS, definite or possible, were revealed. The diagnosis of MS was based on personal examination by A. H. of 23 twins still alive as well as on hospital records. In the remaining cases the diagnosis was based on hospital records. Zygosity diagnosis was established by the similarity method9 supplemented by extensive blood and serum group determination in 13 pairs (both twins alive in 1980). 6 pairs where the co-twin had died before the age of 50 years without any signs of MS, and one discordant pair with unknown zygosity, were excluded from the analysis. 1. Williams
A, Eldridge R, McFarland H, et al Multiple sclerosis in twins. Neurology 1980; 30: 1139-47. 2. MacKay RP, Myrianthopoulos NC. Multiple sclerosis in twins and their relatives. Arch Neural 1966; 15: 449-62. 3. Schumacher GA, Beebe G, Kibler
RF, et al. Problems of experimental trials of therapy multiple sclerosis. Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis Ann NY Acad Sci 1965; 122: 552-68. 4. Ebers GC, Paty DW. C.S.F. electrophoresis in one thousand patients. Can J Neurol Sci
monozygotic (MZ) and 1 of 28 dizygotic (DZ) twin pairs concordant; this difference is not significant (p=0’ 16). The proband concordance rate was 35% in MZ and 7% in DZ twins. In 24 unrelated MS twins, HLA specificities could be determined. 15 (63%) were DR2 positive against 25% expected from the general population (odds ratio 4-9; p<0-001); only one 4 of 19
were
twin from each of the MS concordant pairs was considered. This twin series is considered to be representative because the probands primarily have been taken from the total Danish twin population; it appears that the MZ/DZ and male/female ratios observed correspond to expectation. Furthermore, the well-known association with HLA-DR2 could be demonstrated. The proband concordance rate in DZ twins, which is comparable with the recurrence risk of ordinary sibs, is similar to risk figures of sibs 10,11 the high heritability estimate 12of about 0 -80 suggests that genetic factors are of major importance for the development of MS. Neurological Department, Copenhagen Municipal Hospital, DK - 1399 Copenhagen
ANNE HELTBERG
Danish Twin Register,
University Institute of Clinical Genetics, Odense
NIELS V. HOLM
DEOXYCHOLIC ACID IN MYOTONIC DYSTROPHY
SIR,-In myotonic dystrophy symptoms may present during the first years of life (early onset) or in adolescence or later. The symptoms in the early onset form are usually more pronounced. In early onset mytonic dystrophy an intrauterine maternal factor has been suggested as being of aetiological importance.’ Tanaka et awl.22 reported increased serum concentrations of deoxycholic acid (DCA) in mothers of children with early onset myotonic dystrophy. Since bile acids cross the placenta and DCA is a cytotoxic agent Tanaka et al. suggested that increased DCA might be the intrauterine maternal factor related to early onset myotonic dystrophy. Even if the association were not causative, Tanaka’s findings, if confirmed, could still improve the basis for genetic counselling. We have measured cholic acid, chenodeoxycholic acid (CDA), and DCA concentrations in the serum and amniotic fluid of women with myotonic dystrophy and healthy controls. Amniotic fluid was obtained by amniocentesis in the 16th week of pregnancy. Controls were either healthy fasting non-pregnant women (serum samples) or healthy pregnant women (amniotic fluid samples). The amniocenteses were done on ordinary indications for prenatal diagnosis. The two women with myotonic dystrophy had asked for amniocentesis for linkage analysis by determination of blood group antigens secreted into the amniotic fluid.3In both cases linkage analysis suggested that the fetus had not inherited the abnormal gene. At birth and up to 6 months of age the children appeared healthy and had a normal psychomotor development. Patients and controls are further specified in the table. Bile acid concentrations were measured by isotope dilution mass spectrometry.4This accurate technique includes deuterated internal standards to compensate for losses during the work-up procedure, which includes saponification and ether extraction. The free bile acids are methylated and converted into trimethylsilyl ethers. The results are given as the sum of conjugated and free forms of each bile acid.55 10.
in
1980; 7: 275-80 5. Eisen A, Purves S, Hoirch M. Central nervous system amplification: Its potential in the diagnosis of early multiple sclerosis. Neurology (Ny) 1982; 32: 359-64. 6. Sadovnick AD, MacLeod PMJ. The familial nature of multiple sclerosis: Empiric recurrence risks for first, second, and third degree relatives of patients. Neurology (Ny) 1981; 31: 1039-41. 7. Editorial. The aetiology of multiple sclerosis. Lancet 1981, i: 1347-48. 8. Hauge M. The Danish twin register In Mednick SA, Baert AE, Bachmann BP, eds. Prospective longitudinal research. an empirical basis for the primary prevention of psycho-social disorders. Oxford: Oxford University Press, 1981; 217-21. 9. Schumacher G, Beebe G, Kibler R, et al. Problems of experimental trials of therapy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann NY Acad Sci 1965; 122: 522-68.
K, Denmark
K Disseminated sclerosis in Denmark distribution. Copenhagen J jørgensen, 1956
Hyllested
Prevalence and
geographical
RP, Myrianthopoulos NC Multiple sclerosis in twins and their relatives, Arch Neurol 1966, 15: 449-62. 12. Smith C. Concordance in twins: Methods and interpretation. Am J Hum Genet 1974, 26: 454-66. 1. Harper PS, Dyken PR. Early-onset dystrophia myotonica: Evidence supporting a maternal environmental factor Lancet 1972; ii. 53-55 2. Tanaka K, Takeshita K, Takita M. Deoxycholic acid, a candidate for the maternal intrauterine factor in early-onset myotonic dystrophy. Lancet 1981, i: 1046-47. 3. Renwick JH, Bundey SE, Ferguson-Smith MA, Izatt MM. Confirmation of linkage of the loci for myotonic dystrophy and ABH secretion. J Med Genet1971; 8: 407-16. 4. Björkhem I. Selective ion monitoring in clinical chemistry. CRC Crit Rev Lab Med 1979; ii: 53-105. 5. Angelin B, Björkhem I. Postprandial serum bile acids in healthy man — evidence for differences in absorptive pattern between individual bile acids. Gut 1977; 18: 606-09 11.
MacKay
SIR,-Dr James (March 20, p. 690) calculates that the concordance rate for multiple sclerosis (MS) among dizygotic twins is substantially higher than can be accounted for by the raised risk for siblings of index cases. James assumes that the concordance rate for dizygotic twins is at least 15% and that the recurrence rate for MS among siblings ranges from 0-4% to 6 - 0%. He states that his conclusion would be invalid if the concordance rate of 15% is a gross overestimate or if recurrence rate is substantially greater than 6%. There are many problems in studying MS concordance in twins. A major one is that MS has a variable age of onset so that twin pairs who are discordant when first studied may later prove to be concordant. It is therefore more realistic to assume that an estimated concordance rate of 15%2 is an underestimate rather than an overestimate. The reader may, however, question the accuracy of the recurrence rates for MS cited by James. The most recent study cited2 dealt with cases ascertained only until 1965, and many advances 3-5 have been made since that time which help in the diagnosis of MS in the living patient. Therefore, without more recent data, it might be argued that a recurrence rate of 6% is indeed a gross underestimate. In our recent study6 the recurrence rate for MS in siblings of index cases was 2-8±0-9% (n= 1179).. These data further confirm the conclusion drawn by James by showing that a recurrence rate of 6% is probably not a substantial underestimate even in light of advances being made in the diagnosis of MS. Department of Medical Genetics, University of British Columbia, ADELE D. SADOVNICK Vancouver, British Columbia, Canada SIR,-A 1981 Lancet editoria17 and Dr James in his letter in your March 20 issue mention the possibility of ascertainment bias in twin studies on multiple sclerosis (MS). We have studied MS in a total twin population and presented the results at the 12th World Congress of Neurology, held in Kyoto, Japan, in September, 1981. MS twins were ascertained by screening the files and by record linkage in two nationwide registers, the Danish twin register, which carries data on all like-sex twins born in Denmark 1870 to 1930, and the Danish multiple sclerosis register, founded in 1948 and comprising almost all MS cases diagnosed in Denmark. 59 twin probands with clinically definite MS9 from 54 pairs (33 female and 21 male pairs) were ascertained. All co-twins were followed up to death or to the age of at least 50 years, but no additional cases ofMS, definite or possible, were revealed. The diagnosis of MS was based on personal examination by A. H. of 23 twins still alive as well as on hospital records. In the remaining cases the diagnosis was based on hospital records. Zygosity diagnosis was established by the similarity method9 supplemented by extensive blood and serum group determination in 13 pairs (both twins alive in 1980). 6 pairs where the co-twin had died before the age of 50 years without any signs of MS, and one discordant pair with unknown zygosity, were excluded from the analysis. 1. Williams
A, Eldridge R, McFarland H, et al Multiple sclerosis in twins. Neurology 1980; 30: 1139-47. 2. MacKay RP, Myrianthopoulos NC. Multiple sclerosis in twins and their relatives. Arch Neural 1966; 15: 449-62. 3. Schumacher GA, Beebe G, Kibler
RF, et al. Problems of experimental trials of therapy multiple sclerosis. Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis Ann NY Acad Sci 1965; 122: 552-68. 4. Ebers GC, Paty DW. C.S.F. electrophoresis in one thousand patients. Can J Neurol Sci
monozygotic (MZ) and 1 of 28 dizygotic (DZ) twin pairs concordant; this difference is not significant (p=0’ 16). The proband concordance rate was 35% in MZ and 7% in DZ twins. In 24 unrelated MS twins, HLA specificities could be determined. 15 (63%) were DR2 positive against 25% expected from the general population (odds ratio 4-9; p<0-001); only one 4 of 19
were
twin from each of the MS concordant pairs was considered. This twin series is considered to be representative because the probands primarily have been taken from the total Danish twin population; it appears that the MZ/DZ and male/female ratios observed correspond to expectation. Furthermore, the well-known association with HLA-DR2 could be demonstrated. The proband concordance rate in DZ twins, which is comparable with the recurrence risk of ordinary sibs, is similar to risk figures of sibs 10,11 the high heritability estimate 12of about 0 -80 suggests that genetic factors are of major importance for the development of MS. Neurological Department, Copenhagen Municipal Hospital, DK - 1399 Copenhagen
ANNE HELTBERG
Danish Twin Register,
University Institute of Clinical Genetics, Odense
NIELS V. HOLM
DEOXYCHOLIC ACID IN MYOTONIC DYSTROPHY
SIR,-In myotonic dystrophy symptoms may present during the first years of life (early onset) or in adolescence or later. The symptoms in the early onset form are usually more pronounced. In early onset mytonic dystrophy an intrauterine maternal factor has been suggested as being of aetiological importance.’ Tanaka et awl.22 reported increased serum concentrations of deoxycholic acid (DCA) in mothers of children with early onset myotonic dystrophy. Since bile acids cross the placenta and DCA is a cytotoxic agent Tanaka et al. suggested that increased DCA might be the intrauterine maternal factor related to early onset myotonic dystrophy. Even if the association were not causative, Tanaka’s findings, if confirmed, could still improve the basis for genetic counselling. We have measured cholic acid, chenodeoxycholic acid (CDA), and DCA concentrations in the serum and amniotic fluid of women with myotonic dystrophy and healthy controls. Amniotic fluid was obtained by amniocentesis in the 16th week of pregnancy. Controls were either healthy fasting non-pregnant women (serum samples) or healthy pregnant women (amniotic fluid samples). The amniocenteses were done on ordinary indications for prenatal diagnosis. The two women with myotonic dystrophy had asked for amniocentesis for linkage analysis by determination of blood group antigens secreted into the amniotic fluid.3In both cases linkage analysis suggested that the fetus had not inherited the abnormal gene. At birth and up to 6 months of age the children appeared healthy and had a normal psychomotor development. Patients and controls are further specified in the table. Bile acid concentrations were measured by isotope dilution mass spectrometry.4This accurate technique includes deuterated internal standards to compensate for losses during the work-up procedure, which includes saponification and ether extraction. The free bile acids are methylated and converted into trimethylsilyl ethers. The results are given as the sum of conjugated and free forms of each bile acid.55 10.
in
1980; 7: 275-80 5. Eisen A, Purves S, Hoirch M. Central nervous system amplification: Its potential in the diagnosis of early multiple sclerosis. Neurology (Ny) 1982; 32: 359-64. 6. Sadovnick AD, MacLeod PMJ. The familial nature of multiple sclerosis: Empiric recurrence risks for first, second, and third degree relatives of patients. Neurology (Ny) 1981; 31: 1039-41. 7. Editorial. The aetiology of multiple sclerosis. Lancet 1981, i: 1347-48. 8. Hauge M. The Danish twin register In Mednick SA, Baert AE, Bachmann BP, eds. Prospective longitudinal research. an empirical basis for the primary prevention of psycho-social disorders. Oxford: Oxford University Press, 1981; 217-21. 9. Schumacher G, Beebe G, Kibler R, et al. Problems of experimental trials of therapy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann NY Acad Sci 1965; 122: 522-68.
K, Denmark
K Disseminated sclerosis in Denmark distribution. Copenhagen J jørgensen, 1956
Hyllested
Prevalence and
geographical
RP, Myrianthopoulos NC Multiple sclerosis in twins and their relatives, Arch Neurol 1966, 15: 449-62. 12. Smith C. Concordance in twins: Methods and interpretation. Am J Hum Genet 1974, 26: 454-66. 1. Harper PS, Dyken PR. Early-onset dystrophia myotonica: Evidence supporting a maternal environmental factor Lancet 1972; ii. 53-55 2. Tanaka K, Takeshita K, Takita M. Deoxycholic acid, a candidate for the maternal intrauterine factor in early-onset myotonic dystrophy. Lancet 1981, i: 1046-47. 3. Renwick JH, Bundey SE, Ferguson-Smith MA, Izatt MM. Confirmation of linkage of the loci for myotonic dystrophy and ABH secretion. J Med Genet1971; 8: 407-16. 4. Björkhem I. Selective ion monitoring in clinical chemistry. CRC Crit Rev Lab Med 1979; ii: 53-105. 5. Angelin B, Björkhem I. Postprandial serum bile acids in healthy man — evidence for differences in absorptive pattern between individual bile acids. Gut 1977; 18: 606-09 11.
MacKay