706
225). I note, however, that he refers to "glucocorticosteroids" five times and "glucocorticoids" six times, and that the terms are used interchangeably as adjectives and nouns. To the best of my knowledge there is no such word as glucocorticosteroid ; is there some distinction between this and glucocorticoid ? If not, then in the interest of decreasing the plethora of polysyllabics in current medical writing and, more importantly, out of respect to Prof. Hans Selye, who, I believe, coined the term and elucidated the significance of "glucocorticoids" thirty or forty years ago, we should adhere to accepted nomenclature. p.
patterns:
124 Park Avenue, Yonkers, N.Y. 10703, U.S.A.
PAUL
J. ROSCH
AMINOCYCLITOL
SIR,—DR Cargill (Jan. 29, p. 260) takes exception to the coclassification of streptomycin and spectinomycin as aminocyclitols. Both of these antibiotics-besides the neomycins, kanamycins, and gentamicins--contain a cyclic aminopolyol (aminocyclitol) glycosidically linked to a sugar or sugars, and this is the basis of the nomenclature.l Spectinomycin differs from the other antibiotics mentioned above in the absence of an aminosugar (hence it is not an aminoglycoside) and in the stereochemistry of the aminocyclitol unit (actinaminenot streptamine). Either or both of these variations could account for differences in biological properties, particularly the absence of ototoxicity. Streptomycin and spectinomycin may be grouped under the name aminocyclitol on the basis of structural similarities. of Infectious Diseases, Pharmaceutical Research and Development
be assumed to present no signs of iron overload, although a few might have minor disorders. Thus the absence of metabolic disorder in 4 subjects having one haplotype and the presence of minor anomalies of iron metabolism in 2 subjects with the other haplotype could be chance findings and cannot prove that the two haplotypes are markers of two different genes. On theoretical grounds, since chromosome 6 represents only 1/18 of the human genome, it seems unlikely that it would carry two presumably different genes coding for the same disease. In thirteen families where each of 72 subjects had one of the two I.H. marking haplotypes we found the following serum-iron in eleven families members with the same I.H. marking haplotype had different serum-iron levels or those with dif. ferent I.H. marking haplotypes had similar iron concentrations ; and there was no difference in serum-iron between those with A3 alone or associated with B14 and those without A3. Certainly, an oligogenic heredity, a possibility which we have already proposed,45cannot be excluded. All the same the absence of metabolic differences according to marking haplotypes makes it more reasonable to speculate that different HLA haplotypes may serve as markers of the same i.H. allele, thus representing a classical recessive mode of inheritance. It is not impossible that facilitating genes may exist on other chromosomes and that environmental factors may play an important role in the expression of the sixth chromosome I.H. allele. Médicale A, Unité U. 49 de l’ I.N.S.E.R.M., et Centre Régional de Transfusion Sanguine,
Clinique
Hôpital Pontchaillou, 35043
Rennes, France
M. SIMON M. BOUREL B. GENETET R. FAUCHET
Department
Division,
Upjohn Company, Kalamazoo, Michigan 49001, U.S.A.
LONG-TERM LEVODOPA IN PARKINSON’S DISEASE
HERMAN HOEKSEMA
SIR,—The results of long-term treatment of Parkinson’s diswith levodopa reported by Professor Marsden and Dr Parkes (Feb. 12, p. 345) parallel those we presented at the Vth International Symposium on Parkinson’s Disease in Vienna in September, 1975.1 Both reports reveal a gradual loss of efficacy, beginning two to three years after treatment started, Marsden and Parkes attribute this loss of benefit primarily to progression of the underlying disease process. There is evidence to support the concept of progression of the disease pro2 cess during levodopa therapy,’ but I do not believe that it fully explains the loss of response to the drug. An analysis of our follow-up data, with regard to severity of disease, is shown in the accompanying figure. The assessment at the start of treatment is based on a rating scale-stage I (mild) to stage v (most severe)-introduced by us in 19673 and in general use in many clinics throughout the world. These data indicate that, regardless of the initial level of therapeutic response and pretreatment severity of the Parkinson process, the benefit of levodopa on Parkinson symptoms begins to decrease after three years of treatment. Although initially the differing levels of response can be explained in terms of severity of the disease, it seems unlikely that the subsequent fall-off can be completely accounted for by progression of the underlying disease process, To claim this one would have to assume a uniform rate of progression, which would be highly unlikely. Rather it would seem that levodopa has a finite period of usefulness which is related to the drug’s pharmacodynamic properties. Much is yet to be learned about the effects of the long-term administration of various aromatic aminoacids on the central nervous system in respect of their own metabolism and interaction with that of other neurotransmitters. Such data may ease
HEREDITY OF IDIOPATHIC HÆMOCHROMATOSIS
SIR,—On the basis of 10 patients in
two families, of which Dr Bomford and his colleagues (Feb. 12, p. 327) suggest that idiopathic hæmochromatosis (i.H.) could be caused by two different genes carried by the sixth chromosome. Such hypotheses are difficult, to prove. In a study of iron overload in first-degree relatives in over a hundred families3 4 we found that major forms of I.H. were significantly more common in the generation of siblings compared age for age with the children, whereas minor forms were found in all generations. This is a strong argument in favour of recessive inheritance with heterozygotes sometimes expressing minor forms (intermediate heredity), although oligogenic heredity cannot be eliminated. We have found a relation between I.H. and HLA A3 and B14, suggesting that these antigens were simply markers of an I.H. gene situated on chromosome 6 near the A locus.5 In seven families, each with at least one affected sibling besides the proband,4 Ne found that affected siblings often had both HLA haplotypes in common. This suggests that two genetic entities linked to the HLA system must be inherited, one each from each parent, if I.H. is to develop. If the maternal and paternal entities are the same heredity is recessive or intermediate. 46 If they are different inheritance is oligogenic. On both theories, individuals carrying just one gene could one
had 2 affected
siblings,
1. Rinehart, K. L., Jr. J. infect. Dis. 1969, 119, 345. 2. Wiley, P. F., Argoudelis, A. D., Hoeksema, H. J. Am. chem. Soc. 1963, 85, 2652. 3. Simon, M., Alexandre, J. L., Bourel, M., Le Marec, B., Scordia, C. Clin. Genet. (in the press). 4. Simon, M., Bourel, M., Alexandre, J. L., Brissot, P., Hita de Nercy, Y., Scordia, C., Fauchet, R., Genetet, N., Genetet, B. Nouv. Presse méd. 1976,
5, 1762. M., Bourel, M., Fauchet, R., Genetet, B. Gut, 1976, 17, 332. M., Bourel, M., Fauchet, R., Genetet, B. Lancet, 1976, ii, 973.
5. Simon, 6. Simon,
1. Yahr, M. D. in Recent Advances in the Research of Parkinsonism (edited by W. Birkmayer). Basle (in the press). 2. Sweet, R. D., McDowell, F. H. Ann. intern. Med. 1975, 83, 456. 3. Yahr, M. D., Wolf, A., Antunes, J.-L., Miyoshi, K., Duffy, P. Neurology.
4.
1972, 22, 56. Hoehn, M., Yahr, M. D. ibid. 1967, 17, 427.
225). I note, however, that he refers to "glucocorticosteroids" five times and "glucocorticoids" six times, and that the terms are used interchangeably as adjectives and nouns. To the best of my knowledge there is no such word as glucocorticosteroid ; is there some distinction between this and glucocorticoid ? If not, then in the interest of decreasing the plethora of polysyllabics in current medical writing and, more importantly, out of respect to Prof. Hans Selye, who, I believe, coined the term and elucidated the significance of "glucocorticoids" thirty or forty years ago, we should adhere to accepted nomenclature. p.
patterns:
124 Park Avenue, Yonkers, N.Y. 10703, U.S.A.
PAUL
J. ROSCH
AMINOCYCLITOL
SIR,—DR Cargill (Jan. 29, p. 260) takes exception to the coclassification of streptomycin and spectinomycin as aminocyclitols. Both of these antibiotics-besides the neomycins, kanamycins, and gentamicins--contain a cyclic aminopolyol (aminocyclitol) glycosidically linked to a sugar or sugars, and this is the basis of the nomenclature.l Spectinomycin differs from the other antibiotics mentioned above in the absence of an aminosugar (hence it is not an aminoglycoside) and in the stereochemistry of the aminocyclitol unit (actinaminenot streptamine). Either or both of these variations could account for differences in biological properties, particularly the absence of ototoxicity. Streptomycin and spectinomycin may be grouped under the name aminocyclitol on the basis of structural similarities. of Infectious Diseases, Pharmaceutical Research and Development
be assumed to present no signs of iron overload, although a few might have minor disorders. Thus the absence of metabolic disorder in 4 subjects having one haplotype and the presence of minor anomalies of iron metabolism in 2 subjects with the other haplotype could be chance findings and cannot prove that the two haplotypes are markers of two different genes. On theoretical grounds, since chromosome 6 represents only 1/18 of the human genome, it seems unlikely that it would carry two presumably different genes coding for the same disease. In thirteen families where each of 72 subjects had one of the two I.H. marking haplotypes we found the following serum-iron in eleven families members with the same I.H. marking haplotype had different serum-iron levels or those with dif. ferent I.H. marking haplotypes had similar iron concentrations ; and there was no difference in serum-iron between those with A3 alone or associated with B14 and those without A3. Certainly, an oligogenic heredity, a possibility which we have already proposed,45cannot be excluded. All the same the absence of metabolic differences according to marking haplotypes makes it more reasonable to speculate that different HLA haplotypes may serve as markers of the same i.H. allele, thus representing a classical recessive mode of inheritance. It is not impossible that facilitating genes may exist on other chromosomes and that environmental factors may play an important role in the expression of the sixth chromosome I.H. allele. Médicale A, Unité U. 49 de l’ I.N.S.E.R.M., et Centre Régional de Transfusion Sanguine,
Clinique
Hôpital Pontchaillou, 35043
Rennes, France
M. SIMON M. BOUREL B. GENETET R. FAUCHET
Department
Division,
Upjohn Company, Kalamazoo, Michigan 49001, U.S.A.
LONG-TERM LEVODOPA IN PARKINSON’S DISEASE
HERMAN HOEKSEMA
SIR,—The results of long-term treatment of Parkinson’s diswith levodopa reported by Professor Marsden and Dr Parkes (Feb. 12, p. 345) parallel those we presented at the Vth International Symposium on Parkinson’s Disease in Vienna in September, 1975.1 Both reports reveal a gradual loss of efficacy, beginning two to three years after treatment started, Marsden and Parkes attribute this loss of benefit primarily to progression of the underlying disease process. There is evidence to support the concept of progression of the disease pro2 cess during levodopa therapy,’ but I do not believe that it fully explains the loss of response to the drug. An analysis of our follow-up data, with regard to severity of disease, is shown in the accompanying figure. The assessment at the start of treatment is based on a rating scale-stage I (mild) to stage v (most severe)-introduced by us in 19673 and in general use in many clinics throughout the world. These data indicate that, regardless of the initial level of therapeutic response and pretreatment severity of the Parkinson process, the benefit of levodopa on Parkinson symptoms begins to decrease after three years of treatment. Although initially the differing levels of response can be explained in terms of severity of the disease, it seems unlikely that the subsequent fall-off can be completely accounted for by progression of the underlying disease process, To claim this one would have to assume a uniform rate of progression, which would be highly unlikely. Rather it would seem that levodopa has a finite period of usefulness which is related to the drug’s pharmacodynamic properties. Much is yet to be learned about the effects of the long-term administration of various aromatic aminoacids on the central nervous system in respect of their own metabolism and interaction with that of other neurotransmitters. Such data may ease
HEREDITY OF IDIOPATHIC HÆMOCHROMATOSIS
SIR,—On the basis of 10 patients in
two families, of which Dr Bomford and his colleagues (Feb. 12, p. 327) suggest that idiopathic hæmochromatosis (i.H.) could be caused by two different genes carried by the sixth chromosome. Such hypotheses are difficult, to prove. In a study of iron overload in first-degree relatives in over a hundred families3 4 we found that major forms of I.H. were significantly more common in the generation of siblings compared age for age with the children, whereas minor forms were found in all generations. This is a strong argument in favour of recessive inheritance with heterozygotes sometimes expressing minor forms (intermediate heredity), although oligogenic heredity cannot be eliminated. We have found a relation between I.H. and HLA A3 and B14, suggesting that these antigens were simply markers of an I.H. gene situated on chromosome 6 near the A locus.5 In seven families, each with at least one affected sibling besides the proband,4 Ne found that affected siblings often had both HLA haplotypes in common. This suggests that two genetic entities linked to the HLA system must be inherited, one each from each parent, if I.H. is to develop. If the maternal and paternal entities are the same heredity is recessive or intermediate. 46 If they are different inheritance is oligogenic. On both theories, individuals carrying just one gene could one
had 2 affected
siblings,
1. Rinehart, K. L., Jr. J. infect. Dis. 1969, 119, 345. 2. Wiley, P. F., Argoudelis, A. D., Hoeksema, H. J. Am. chem. Soc. 1963, 85, 2652. 3. Simon, M., Alexandre, J. L., Bourel, M., Le Marec, B., Scordia, C. Clin. Genet. (in the press). 4. Simon, M., Bourel, M., Alexandre, J. L., Brissot, P., Hita de Nercy, Y., Scordia, C., Fauchet, R., Genetet, N., Genetet, B. Nouv. Presse méd. 1976,
5, 1762. M., Bourel, M., Fauchet, R., Genetet, B. Gut, 1976, 17, 332. M., Bourel, M., Fauchet, R., Genetet, B. Lancet, 1976, ii, 973.
5. Simon, 6. Simon,
1. Yahr, M. D. in Recent Advances in the Research of Parkinsonism (edited by W. Birkmayer). Basle (in the press). 2. Sweet, R. D., McDowell, F. H. Ann. intern. Med. 1975, 83, 456. 3. Yahr, M. D., Wolf, A., Antunes, J.-L., Miyoshi, K., Duffy, P. Neurology.
4.
1972, 22, 56. Hoehn, M., Yahr, M. D. ibid. 1967, 17, 427.
