821
or
biochemical features is specific for the illness.’ Yet these
non-specific individual features are all that one can base the diagnosis on; and failure to make the diagnosis may have fatal consequencesThere may be considerable value in having a sensitive laboratory marker that can confirm, or perhaps even trigger, clinical suspicion of NMS, and that supplements the existing profile of positive and negative findings that is thought to characterise the disorder. Our data suggest that virtually all cases of NMS are associated with profound hypoferraemia; consistently normal concentrations of serum iron would, in our experience, be
unusual. It is in this sense that the serial measurement of serum iron
adjunctive marker in the diagnosis of NMS. We are well aware that a finding of hypoferraemia cannot by itself distinguish, for example, a patient with NMS from one with a neuroleptic-induced extrapyramidal syndrome and concurrent central nervous system infection. We have previously drawn attention to the difficulty of differential diagnosis, and emphasised the importance of microbiology and cerebrospinal fluid studies in the assessment of a patient with suspected NMS.l We do not suggest that measurement of serum iron can substitute for these other investigations. That is why we referred to serum iron as a potentially "helpful adjunct" for the diagnosis of NMS. may be a useful
Departments of Psychiatry and Biomedical Sciences, McMaster University Medical Centre, Hamilton, Ontario L8N 3Z5, Canada
PATRICIA I. ROSEBUSH MICHAEL F. MAZUREK
1. Rosebush PI, Stewart T. A
prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 1989; 146: 717-25. 2. Caroff SN. The neuroleptic malignant syndrome. J Clin Psychol 1980; 41: 79-82.
Dialysis amyloidosis SIR,-Dialysis-related amyloidosis is being seen with increasing frequency in renal replacement programmes. In your Aug 10 editorial you make a plea for early transplantation to prevent this distressing complication, but fail fully to explore other treatments. We agree, and have reported,t that successful transplantation causes
&bgr;2-microglobulin concentrations to return to normal, and we
support efforts to increase organ donation; however, the total acceptance rate onto renal replacement programmes have not yet reached a plateau2 and the number of patients who are either not suitable for transplantation or will spend many years on dialysis is rising, because of previous sensitisation or for other technical reasons.3 Prevention of &bgr;2-microglobulin amyloidosis should therefore be an aim, in parallel with efforts to increase the transplantation rate. We were disappointed that you neglected to discuss the pathophysiology of local &bgr;2-microglobulin deposition-an
understanding of which is critical to the development of strategies for prevention.4 The imaging technique described by Nelson et al5 enables assessment of disease distribution and progression. Serum concentrations of &bgr;2-microglobulin and duration of end-stage renal failure are important variables in the development of amyloidosis,4 but the clear predilection of &bgr;2-microglobulin to deposit at specific sites remains puzzling. Neither the anatomical or physicochemical reasons for this distribution, nor the mechanisms for the variations between individual patients, have been elucidated. The potential interaction with local damage due to renal osteodystrophy has not been widely explored. Until these factors have been investigated, we seem to be left with little other than strategies to lower serum j3z microglobulin. Is there a threshold below which amyloidosis will not arise? Advances in dialysis techniques have enhanced clearance rates, with, for example, the use of glucose polymers in continuous ambulatory peritoneal dialysisl or the more biocompatible highflux dialysis membranes;4 these manoeuvres do not achieve normal serum concentrations, but if used from the beginning of dialysis may prevent the development of this syndrome.4 You do not mention the role of high-flux biocompatible membranes in the treatment of established joint disease. Despite lacking an understanding of the precise mechanism for their effect, it has been our impression that use of these membranes provides
patients with rapid and striking relief from symptoms-perhaps by keeping to a minimum the "inflammatory cascade" unleashed on contact between blood and such membranes as ’Cuprophane’. Specific local measures will remain necessary in the treatment of established joint disease, but your remarks on the treatment of pathological fractures by fixation could be misleading. This may be an inadequate measure where the fracture line passes through amyloid deposits (and it may be difficult to identify that this has occurred with routinely used imaging techniques). We have managed 2 patients with pathological fracture of the femoral neck and widespread dialysis amyloidosis. Despite adequate fixation with good alignment, neither fracture had united after several weeks. Both femoral heads had to be excised and prostheses inserted. Pathological examination of the excised specimens revealed that amyloid tissue was very closely associated with the fracture line, thereby preventing union. Routine radiological studies had not supported our clinical suspicion that this might have been so. The introduction of more sensitive imaging techniques might offer guidance about the most appropriate initial orthopaedic intervention in such patients. DONAL J. O’DONOGHUE Medical Renal Unit, Royal Infirmary of Edinburgh, Edinburgh EH3 9YW, UK
WILLIAM D. PLANT ROBIN J. WINNEY
1.
Mistry CD, O’Donoghue DJ, Nelson S, Gokal R, Ballardie FW. Kinetic and clinical studies of beta-2 microglobulin m continuous ambulatory peritoneal dialysis. influence of renal and enhanced peritoneal clearances using glucose polymer. Nephrol Dial Transplant 1990; 5: 513-19 2. Feest TG, Mistry CD, Grimes DS, Mallick NP. Incidence of advanced chronic renal failure and the need for end stage renal replacement therapy. Br Med J 1990; 301: 897-900. 3 Keown PA. The highly sensitised patient: aetiology, impact and management. Transplant Proc 1987; 19: 74-78. 4. Zingraff J, Drueke T. Can the nephrologist prevent dialysis-related amyloidosis? Am J
Kidney Dis 1991; 18: 1-11. SR, Hawkins PN, Richardson S, et al. Imaging of haemodialysis-associated amyloidosis with 123I-serum amyloid P component. Lancet 1991; 338: 335-39.
5. Nelson
Manic-depression locus on X chromosome SIR,-We would like to update some of the conclusions from our study on the linkage of a putative manic-depression (MDI) locus with coagulation factor IX on the X chromosome.1 This study was initiated on the basis that families showing a transmission of MDII compatible with linkage to the X chromosome displayed linkage with colour blindness and glucose-6-phosphate dehydrogenase (G6PD).2 At that time, the markers available in this region of the X chromosome were few; they included the factor IX gene, so linkage was sought between MDI and factor IX in a series of pedigrees, and it was found (lod score 31, recombination fraction 0.11). Two facts have since altered our confidence in this conclusion. Further mapping of the X chromosome has demonstrated the absence of significant linkage between the factor IX locus and the factor VIII/G6PD/colour blindness cluster.3 Therefore, either linkage of MDI with factor IX or with colour blindness (or both) has to be wrong. Also we have become aware that family no 5 had been misclassified. Besides symptoms of MDI the affected individuals had fragile X syndrome (for which linkage with factor IX has been described). Although this family contributed only 0-095 to the final lod score of 3-1, the fact is worth mentioning. We feel that the genetics of affective illness is enough of a puzzle not to miss any opportunity for clarification. Departments of Medical Genetics and Gynaecology and Obstetrics, University of Brussels, Campus Erasme, 1070 Brussels, Belgium
GILBERT VASSART PHILIPPE SIMON
Sevy S, et al. Polymorphic DNA marker on X chromosome and manic depression. Lancet 1987; i: 1230-32. 2. Mendlewicz J, Fleiss JL, Fieve RR. Evidence for X-linkage in the transmission m manic-depressive illness. JAMA 1972; 222: 1624-27. 3. Human gene mapping 10. Cytogenet Cell Genet 1989; 51: 1148. 4. Camerino G, Mattel MG, Mattel JF, Jaye M, Mandel JL. Close linkage of fragile X-mental retardation syndrome to haemophilia B and transmission through a normal male. Nature 1983, 306: 701-04. 1. Mendlewicz J, Simon P,
or
biochemical features is specific for the illness.’ Yet these
non-specific individual features are all that one can base the diagnosis on; and failure to make the diagnosis may have fatal consequencesThere may be considerable value in having a sensitive laboratory marker that can confirm, or perhaps even trigger, clinical suspicion of NMS, and that supplements the existing profile of positive and negative findings that is thought to characterise the disorder. Our data suggest that virtually all cases of NMS are associated with profound hypoferraemia; consistently normal concentrations of serum iron would, in our experience, be
unusual. It is in this sense that the serial measurement of serum iron
adjunctive marker in the diagnosis of NMS. We are well aware that a finding of hypoferraemia cannot by itself distinguish, for example, a patient with NMS from one with a neuroleptic-induced extrapyramidal syndrome and concurrent central nervous system infection. We have previously drawn attention to the difficulty of differential diagnosis, and emphasised the importance of microbiology and cerebrospinal fluid studies in the assessment of a patient with suspected NMS.l We do not suggest that measurement of serum iron can substitute for these other investigations. That is why we referred to serum iron as a potentially "helpful adjunct" for the diagnosis of NMS. may be a useful
Departments of Psychiatry and Biomedical Sciences, McMaster University Medical Centre, Hamilton, Ontario L8N 3Z5, Canada
PATRICIA I. ROSEBUSH MICHAEL F. MAZUREK
1. Rosebush PI, Stewart T. A
prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 1989; 146: 717-25. 2. Caroff SN. The neuroleptic malignant syndrome. J Clin Psychol 1980; 41: 79-82.
Dialysis amyloidosis SIR,-Dialysis-related amyloidosis is being seen with increasing frequency in renal replacement programmes. In your Aug 10 editorial you make a plea for early transplantation to prevent this distressing complication, but fail fully to explore other treatments. We agree, and have reported,t that successful transplantation causes
&bgr;2-microglobulin concentrations to return to normal, and we
support efforts to increase organ donation; however, the total acceptance rate onto renal replacement programmes have not yet reached a plateau2 and the number of patients who are either not suitable for transplantation or will spend many years on dialysis is rising, because of previous sensitisation or for other technical reasons.3 Prevention of &bgr;2-microglobulin amyloidosis should therefore be an aim, in parallel with efforts to increase the transplantation rate. We were disappointed that you neglected to discuss the pathophysiology of local &bgr;2-microglobulin deposition-an
understanding of which is critical to the development of strategies for prevention.4 The imaging technique described by Nelson et al5 enables assessment of disease distribution and progression. Serum concentrations of &bgr;2-microglobulin and duration of end-stage renal failure are important variables in the development of amyloidosis,4 but the clear predilection of &bgr;2-microglobulin to deposit at specific sites remains puzzling. Neither the anatomical or physicochemical reasons for this distribution, nor the mechanisms for the variations between individual patients, have been elucidated. The potential interaction with local damage due to renal osteodystrophy has not been widely explored. Until these factors have been investigated, we seem to be left with little other than strategies to lower serum j3z microglobulin. Is there a threshold below which amyloidosis will not arise? Advances in dialysis techniques have enhanced clearance rates, with, for example, the use of glucose polymers in continuous ambulatory peritoneal dialysisl or the more biocompatible highflux dialysis membranes;4 these manoeuvres do not achieve normal serum concentrations, but if used from the beginning of dialysis may prevent the development of this syndrome.4 You do not mention the role of high-flux biocompatible membranes in the treatment of established joint disease. Despite lacking an understanding of the precise mechanism for their effect, it has been our impression that use of these membranes provides
patients with rapid and striking relief from symptoms-perhaps by keeping to a minimum the "inflammatory cascade" unleashed on contact between blood and such membranes as ’Cuprophane’. Specific local measures will remain necessary in the treatment of established joint disease, but your remarks on the treatment of pathological fractures by fixation could be misleading. This may be an inadequate measure where the fracture line passes through amyloid deposits (and it may be difficult to identify that this has occurred with routinely used imaging techniques). We have managed 2 patients with pathological fracture of the femoral neck and widespread dialysis amyloidosis. Despite adequate fixation with good alignment, neither fracture had united after several weeks. Both femoral heads had to be excised and prostheses inserted. Pathological examination of the excised specimens revealed that amyloid tissue was very closely associated with the fracture line, thereby preventing union. Routine radiological studies had not supported our clinical suspicion that this might have been so. The introduction of more sensitive imaging techniques might offer guidance about the most appropriate initial orthopaedic intervention in such patients. DONAL J. O’DONOGHUE Medical Renal Unit, Royal Infirmary of Edinburgh, Edinburgh EH3 9YW, UK
WILLIAM D. PLANT ROBIN J. WINNEY
1.
Mistry CD, O’Donoghue DJ, Nelson S, Gokal R, Ballardie FW. Kinetic and clinical studies of beta-2 microglobulin m continuous ambulatory peritoneal dialysis. influence of renal and enhanced peritoneal clearances using glucose polymer. Nephrol Dial Transplant 1990; 5: 513-19 2. Feest TG, Mistry CD, Grimes DS, Mallick NP. Incidence of advanced chronic renal failure and the need for end stage renal replacement therapy. Br Med J 1990; 301: 897-900. 3 Keown PA. The highly sensitised patient: aetiology, impact and management. Transplant Proc 1987; 19: 74-78. 4. Zingraff J, Drueke T. Can the nephrologist prevent dialysis-related amyloidosis? Am J
Kidney Dis 1991; 18: 1-11. SR, Hawkins PN, Richardson S, et al. Imaging of haemodialysis-associated amyloidosis with 123I-serum amyloid P component. Lancet 1991; 338: 335-39.
5. Nelson
Manic-depression locus on X chromosome SIR,-We would like to update some of the conclusions from our study on the linkage of a putative manic-depression (MDI) locus with coagulation factor IX on the X chromosome.1 This study was initiated on the basis that families showing a transmission of MDII compatible with linkage to the X chromosome displayed linkage with colour blindness and glucose-6-phosphate dehydrogenase (G6PD).2 At that time, the markers available in this region of the X chromosome were few; they included the factor IX gene, so linkage was sought between MDI and factor IX in a series of pedigrees, and it was found (lod score 31, recombination fraction 0.11). Two facts have since altered our confidence in this conclusion. Further mapping of the X chromosome has demonstrated the absence of significant linkage between the factor IX locus and the factor VIII/G6PD/colour blindness cluster.3 Therefore, either linkage of MDI with factor IX or with colour blindness (or both) has to be wrong. Also we have become aware that family no 5 had been misclassified. Besides symptoms of MDI the affected individuals had fragile X syndrome (for which linkage with factor IX has been described). Although this family contributed only 0-095 to the final lod score of 3-1, the fact is worth mentioning. We feel that the genetics of affective illness is enough of a puzzle not to miss any opportunity for clarification. Departments of Medical Genetics and Gynaecology and Obstetrics, University of Brussels, Campus Erasme, 1070 Brussels, Belgium
GILBERT VASSART PHILIPPE SIMON
Sevy S, et al. Polymorphic DNA marker on X chromosome and manic depression. Lancet 1987; i: 1230-32. 2. Mendlewicz J, Fleiss JL, Fieve RR. Evidence for X-linkage in the transmission m manic-depressive illness. JAMA 1972; 222: 1624-27. 3. Human gene mapping 10. Cytogenet Cell Genet 1989; 51: 1148. 4. Camerino G, Mattel MG, Mattel JF, Jaye M, Mandel JL. Close linkage of fragile X-mental retardation syndrome to haemophilia B and transmission through a normal male. Nature 1983, 306: 701-04. 1. Mendlewicz J, Simon P,
