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MASON-TYPE DIABETES AND DNA INSERTION POLYMORPHISM
280 STRIATAL GLUTAMATE DECARBOXYLASE VALUES, INDICATIVE OF HOSPITAL WHERE PATIENT DIED
SIR,-Biochemical studies on human brain post mortem have led the observation that glutamic acid decarboxylase (GAD) activity varies with the hospital where the patient died. Of the 78 brains analysed, all from subjects with no known neurological disease, 38 came from a general hospital (CHU Henri Mondor, Creteil) and 40 from a hospice for the elderly (Hopital Charles Foix, Ivry sur Seine). 100 mg samples of the head of the caudate nucleus were immediately homogenised and assayed radioenzymatically for GAD, cholineacetyltransferase (CAT), and tyrosine hydroxylase activities.’ For both groups of patients individual enzyme values were scattered to
but mean TH and CAT values were not significantly different in the two populations (figure). By contrast the mean GAD activity was significantly lower in brains of patients from the general hospital than in those from the hospice (15-1±2-00 and 41 -5±5-33 nmol/h/mg protein, respectively; p <0 - 001). All but 2 striatal GAD activities in the general hospital samples were below the mean for the hospice samples. Thus striatal GAD activity gave an indication, in a few instances a strong one, of the hospital of origin of the
In interpreting post mortem biochemical data not only age and post-mortem delays but also the patient’s condition before death3 must be taken into account. Controls must be selected so that premortem conditions match with those of the abnormal brains under study, and preferably control and pathological brain material should come from the same hospital. Y. AGID A. PLOSKA J. C. MONFORT F. JAVOY-AGID
Laboratory of Experimental Medicine, Faculté de Médecine Pitié - Salpêtrière, 75634
Paris, France
(figure),
sample. Post mortem (hospice 7’6±0’77 h, general hospital 9-9±0-66 h; p <0-01) can not account for a difference of 60% in mean GAD values. Nor does age: the greater age of the hospice patients (82± I -2vs 65-t2 -5) would lead us to predict a lower, not a higher, mean GAD activity in the hospice group. Diseases and treatments varied and are not likely to have been responsible for the discrepant GAD values. The difference is probably related to the extreme sensitivity of GAD to anoxia and hypovolaemia3 and to protracted terminal illness.All the patients who died in the general hospital had been under intensive treatment just before death (and 20 had been in an intensive care unit). None of the hospice patients had been under such treatment.
dela
1.
Puymirat J, Javoy-Agid F, Gaspar P, Ploska A, Prochiantz A, Agid Y Post mortem stability and storage in the cold of brain enzymes. J Neurochem 1979; 32: 449-54.
2. Bowen DM, Smith CB, White P, Davison AN. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 1976, 99: 459-96. 3. Monfort JC, Ploska A, Javoy-Agid F, Agid Y. GAD activity as a marker for GABAergic systems in control and parkinsonian patients: Influence of pre-mortem conditions. 4.
Unpublished. Perry, EK, Perry RH, Tomlinsson BE. The influence of agonal status on some neurochemical activities of postmortem human brain tissue. Neurosci Lett 1982; 29: 303-08.
MASON-TYPE DIABETES AND DNA INSERTION POLYMORPHISM
SIR,-Mason-type diabetes is a diabetes characterised by early
form of non-insulin-dependent age of onset and apparently autosomal dominant inheritance.5 Most such diabetics show the this may be a marker for chlorpropamide alcohol flush (CPAF), this type of diabetes in some families. Population studies of noninsulin-dependent diabetics in general have suggested an association between this type of diabetes and a large DNA sequence adjacent to the 5’ end of the human insulin gene.This region shows polymorphism resulting from the insertion of DNA sequences of different sizes. Large (U) and small (L) insertions appear to be inherited in a mendelian manner as separate alleles. We now report six families with Mason-type diabetes associated with CPAF in which there was no association between the diabetes and the large DNA insertion. The criteria for inclusion were that the proband in each of the six families should have had diabetes diagnosed under the age of 25, have been controlled without insulin for at least 2 years, and have a family history consistent with autosomal dominant inheritance. Non-diabetic members had a normal random blood glucose and haemoglobin A,. Analysis for insulin gene fragments was done by the method previously described.The CPAF test was done in the diabetics; 7 days of 250 mg chlorpropamide were given before ethanol challenge (8 g pure ethanol in fruit juice). Flushing was recorded when it was reported by the subject and accompanied by a rise in facial temperature of at least 1°C. There was a strong association between CPAF and diabetes in these families. Of 10 diabetics tested all showed CPAF. An association between CPAF and a large base insertion is, however, unlikely ; of2sibs with CPAF one had a large DNA insertion and the other did not. There was no linkage between a particular DNA sequence and Mason-type diabetes. Of 12 diabetics 9 were UL heterozygoxes and3 LL homozygotes. Of 11 non-diabetics 6 had UL and 5 had LL insertions. Moreover, in one family the Uallele in the diabetics was inherited from the non-diabetic father and not from the diabetic mother. In conclusion, our study of 6 families, taken with the reports of 2 other families with Mason-type diabetes,8,9 strongly suggests that a large DNA insertion is not associated with this form of non-insulin
and
dependent diabetes. C. JOHNSTON
Diabetic Clinic, King’s College Hospital, London SE5 9RS; and Steno Memorial Hospital, Gentofte, Copenhagen,
D. OWERBACH R. D. G. LESLIE D. A. PYKE J. NERUP
Denmark
5. Tattersall RB. Mild familial diabetes with dominant inheritance.
acetyltransferase (CAT), tyrosine hydroxylase (TH), and glutamic acid decarboxylase (GAD) in caudate nucleus of patients who had died in the hospice (0) or in the general hospital (8).
Choline
*
p <0001.
Quart J Med 1974;
43: 339-57. 6. Pyke DA, Leslie RDG. Chlorpropamide-alcohol flushing: a definition of its relation to non-insulin dependent diabetes. Br MedJ 1978; n: 1519-21. 7. Owerbach D, Nerup J. Restriction fragment length polymorphism of the insulin gene in diabetes mellitus. Diabetes 1982; 31: 275-77. 8. Owerbach D, Thomsen B, Johansen K, Lamm LV, Nerup J. DNA insertion sequences near the insulin gene are not associated with maturity-onset diabetes of young
people. Diabetologia 1983; 25: 18-20. 9. Bell JI, Wainscoat JS, Old JM, Chlouverakis
diabetes of the young 1983; 286: 590-92.
Maturity-onset
C, Keen H, Turner RC, Weatherall DJ. linked to the insulin gene. Br Med J
is not
SIR,-Biochemical studies on human brain post mortem have led the observation that glutamic acid decarboxylase (GAD) activity varies with the hospital where the patient died. Of the 78 brains analysed, all from subjects with no known neurological disease, 38 came from a general hospital (CHU Henri Mondor, Creteil) and 40 from a hospice for the elderly (Hopital Charles Foix, Ivry sur Seine). 100 mg samples of the head of the caudate nucleus were immediately homogenised and assayed radioenzymatically for GAD, cholineacetyltransferase (CAT), and tyrosine hydroxylase activities.’ For both groups of patients individual enzyme values were scattered to
but mean TH and CAT values were not significantly different in the two populations (figure). By contrast the mean GAD activity was significantly lower in brains of patients from the general hospital than in those from the hospice (15-1±2-00 and 41 -5±5-33 nmol/h/mg protein, respectively; p <0 - 001). All but 2 striatal GAD activities in the general hospital samples were below the mean for the hospice samples. Thus striatal GAD activity gave an indication, in a few instances a strong one, of the hospital of origin of the
In interpreting post mortem biochemical data not only age and post-mortem delays but also the patient’s condition before death3 must be taken into account. Controls must be selected so that premortem conditions match with those of the abnormal brains under study, and preferably control and pathological brain material should come from the same hospital. Y. AGID A. PLOSKA J. C. MONFORT F. JAVOY-AGID
Laboratory of Experimental Medicine, Faculté de Médecine Pitié - Salpêtrière, 75634
Paris, France
(figure),
sample. Post mortem (hospice 7’6±0’77 h, general hospital 9-9±0-66 h; p <0-01) can not account for a difference of 60% in mean GAD values. Nor does age: the greater age of the hospice patients (82± I -2vs 65-t2 -5) would lead us to predict a lower, not a higher, mean GAD activity in the hospice group. Diseases and treatments varied and are not likely to have been responsible for the discrepant GAD values. The difference is probably related to the extreme sensitivity of GAD to anoxia and hypovolaemia3 and to protracted terminal illness.All the patients who died in the general hospital had been under intensive treatment just before death (and 20 had been in an intensive care unit). None of the hospice patients had been under such treatment.
dela
1.
Puymirat J, Javoy-Agid F, Gaspar P, Ploska A, Prochiantz A, Agid Y Post mortem stability and storage in the cold of brain enzymes. J Neurochem 1979; 32: 449-54.
2. Bowen DM, Smith CB, White P, Davison AN. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 1976, 99: 459-96. 3. Monfort JC, Ploska A, Javoy-Agid F, Agid Y. GAD activity as a marker for GABAergic systems in control and parkinsonian patients: Influence of pre-mortem conditions. 4.
Unpublished. Perry, EK, Perry RH, Tomlinsson BE. The influence of agonal status on some neurochemical activities of postmortem human brain tissue. Neurosci Lett 1982; 29: 303-08.
MASON-TYPE DIABETES AND DNA INSERTION POLYMORPHISM
SIR,-Mason-type diabetes is a diabetes characterised by early
form of non-insulin-dependent age of onset and apparently autosomal dominant inheritance.5 Most such diabetics show the this may be a marker for chlorpropamide alcohol flush (CPAF), this type of diabetes in some families. Population studies of noninsulin-dependent diabetics in general have suggested an association between this type of diabetes and a large DNA sequence adjacent to the 5’ end of the human insulin gene.This region shows polymorphism resulting from the insertion of DNA sequences of different sizes. Large (U) and small (L) insertions appear to be inherited in a mendelian manner as separate alleles. We now report six families with Mason-type diabetes associated with CPAF in which there was no association between the diabetes and the large DNA insertion. The criteria for inclusion were that the proband in each of the six families should have had diabetes diagnosed under the age of 25, have been controlled without insulin for at least 2 years, and have a family history consistent with autosomal dominant inheritance. Non-diabetic members had a normal random blood glucose and haemoglobin A,. Analysis for insulin gene fragments was done by the method previously described.The CPAF test was done in the diabetics; 7 days of 250 mg chlorpropamide were given before ethanol challenge (8 g pure ethanol in fruit juice). Flushing was recorded when it was reported by the subject and accompanied by a rise in facial temperature of at least 1°C. There was a strong association between CPAF and diabetes in these families. Of 10 diabetics tested all showed CPAF. An association between CPAF and a large base insertion is, however, unlikely ; of2sibs with CPAF one had a large DNA insertion and the other did not. There was no linkage between a particular DNA sequence and Mason-type diabetes. Of 12 diabetics 9 were UL heterozygoxes and3 LL homozygotes. Of 11 non-diabetics 6 had UL and 5 had LL insertions. Moreover, in one family the Uallele in the diabetics was inherited from the non-diabetic father and not from the diabetic mother. In conclusion, our study of 6 families, taken with the reports of 2 other families with Mason-type diabetes,8,9 strongly suggests that a large DNA insertion is not associated with this form of non-insulin
and
dependent diabetes. C. JOHNSTON
Diabetic Clinic, King’s College Hospital, London SE5 9RS; and Steno Memorial Hospital, Gentofte, Copenhagen,
D. OWERBACH R. D. G. LESLIE D. A. PYKE J. NERUP
Denmark
5. Tattersall RB. Mild familial diabetes with dominant inheritance.
acetyltransferase (CAT), tyrosine hydroxylase (TH), and glutamic acid decarboxylase (GAD) in caudate nucleus of patients who had died in the hospice (0) or in the general hospital (8).
Choline
*
p <0001.
Quart J Med 1974;
43: 339-57. 6. Pyke DA, Leslie RDG. Chlorpropamide-alcohol flushing: a definition of its relation to non-insulin dependent diabetes. Br MedJ 1978; n: 1519-21. 7. Owerbach D, Nerup J. Restriction fragment length polymorphism of the insulin gene in diabetes mellitus. Diabetes 1982; 31: 275-77. 8. Owerbach D, Thomsen B, Johansen K, Lamm LV, Nerup J. DNA insertion sequences near the insulin gene are not associated with maturity-onset diabetes of young
people. Diabetologia 1983; 25: 18-20. 9. Bell JI, Wainscoat JS, Old JM, Chlouverakis
diabetes of the young 1983; 286: 590-92.
Maturity-onset
C, Keen H, Turner RC, Weatherall DJ. linked to the insulin gene. Br Med J
is not