- Email: [email protected]
HORMONAL ACTIVITY AND END-ORGAN RESPONSE
510
drowsy and grossly oliguric, and later comatose. Arrangements were made to carry out a second pig-liver perfusion but unfortunately, only 30 minutes before the pig liver could be brought to him, he developed another haematemesis and died. Necropsy showed a very soft and shrunken liver which on histological examination revealed extensive hepatic necrosis and other features of acute viral hepatitis. There was a myriad of minute gastric and small-bowel erosions. The mortality from hepatic coma due to acute hepatic necrosis is exceedingly high,9 10 and when accompanied by oliguria and uraemia there is very often a fatal outcome.ll Nevertheless, owing to the enormous capacity of the liver for regeneration, the hepatic damage may be regarded as potentially reversible. It follows therefore that, if some form of effective temporary and repeated hepatic support can be provided for these patients, the inevitable gloomy outcome might be prevented. With exchange blood-transfusion some salvage has been reported by Berger et all and Saunders,t3 though Jones a1.14 had no survivors among seven cases thus treated. In view of the complexities of liver functions only a normal liver can be substituted for another which has failed, and for this reason the use of a healthy extracorporeal liver, we believe, is the rational method of therapy. The effectiveness of such a liver is very well demonstrated in this case. The clinical improvement in this patient after 51/2 hours of perfusion was very striking, and in parallel with this were the dramatic hmmatological and biochemical changes. Unfortunately, the patient in coma from acute hepatic necrosis develops other very serious complications—namely, renal failure, haemorrhage, hypoglycxmia, respiratory failure, and electrolyte imbalance. Gastrointestinal haemorrhage seems to be the commonest terminal complication, as in this case. et
C.M. ABOUNA R. GARRY C. HULL J. KIRKLEY D. N. WALDER.
The Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP
COPROPORPHYRINURIA AND HUMAN HEART TRANSPLANTATION wish to draw attention to a disturbance in urinary SiR,ŇI porphyrin excretion observed in two patients after cardiac transplantation and to express the hope that other cardiactransplant teams will be encouraged to undertake serial studies of porphyrin excretion. Both patients developed pronounced coproporphyrinuria. Uroporphyrin excretion was unaffected. 8-aminolaevulinic acid (A.L.A.) and porphobilinogen (P.B.G.) excretion showed little if any deviation from normal except for a preterminal rise in urinary A.L.A. in the first patient. Both patients had a temporary mild increase in urinary coproporphyrin soon after operation; about the 10th post-operative day the coproporphyrin increased again to reach initial peak values of 500 g. and 596 g. per day respectively. In the first patient the peak excretion of 500 g. was reached on the 12th postoperative day, 5 days before his death from a fulminant Klebsiella-Pseudomonas pneumonia. In the second patient, the initial peak value was reached on the 18th postoperative day. Thereafter the urinary coproporphyrin excretion (mainly isomer III) remained well above normal and only approached 150-200 ;jtg. per day 4 days before his discharge from hospital on the 74th postoperative day. The fall in coproporphyrin output was evanescent and, despite striking physical improvement, the level rose sharply again and has remained raised since then, isomer III constituting 48-58% of the copro9. 10.
Cook, G. C., Sherlock, S. Lancet, 1965, i, 175. Chalmers, T. C. in The Liver (edited by A. E. Read); p. 287. London, 1967. 1121.
11. Hecker, R., Sherlock, S. Lancet, 1956, ii, 12. Berger, R. L., Liverage, R. M., Chalmers, T. C., Graham, J. H., McGoldrick, D. M., Stohlman, F. New Engl. J. Med. 1966, 274, 497. 13. Saunders, S. J. in The Liver (edited by A. E. Read); p. 289. London, 1967. 14. Jones, E. A., Clain, D., Clink, H. M., MacGillivray, M., Sherlock, S. Lancet, 1967, ii, 169.
increases (up to 835 (Lg. per day) have accompanied complications such as deterioration in cardiac function, development of a septicaemia with meningitis, hepatitis, and suspected pulmonary embolism and pneumonia. In view of the multiplicity of factors influencing the progress following organ transplantation, the precise aetiology of the porphyrinuria is difficult to establish. Among the factors to be considered early in the course after transplantation are the post-
porphyrin. Striking
operative
metabolic response, the effects of
cardiopulmonary
bypass, and the pericardial and myocardial reaction with or without congestive heart-failure. Later, other factors supervene : the toxicity of prolonged immunosuppressive therapy, the effects of tissue damage due to rejection, infection, or pulmonary embolism, and hepatic dysfunction due to liver congestion. Haemolytic anaemia, sometimes a cause of copro-
porphyrinuria, also needs to be excluded. Of some help in interpretation was the observation that two other patients undergoing open-heart surgery with cardiopulmonary bypass showed no disturbance in serial porphyrin excretion. Patients with myocardial infarction had only an immediate, short-lived, mild disturbance. Two patients on immunosuppressive therapy after renal transplantation also showed no abnormality of urinary porphyrin excretion even during rejection episodes. In the first of the two cardiac-transplant patients the coproporphyrinuria can reasonably be related to the severe pneumonic infection. In the second patient, however, many of the abovementioned factors need to be considered, including myocardial and pericardial involvement at a time when there was no evidence of infection, liver disease, or congestive heart-failure. Hasmolytic anaemia was seriously considered in view of a persistent reticulocytosis but there was no other supporting evidence, although later increased osmotic fragility developed. However, variations in therapy, meningitis, hepatitis, poor tissue perfusion, and suspected pulmonary embolism probably all contributed to the disturbance in porphyrin excretion. This multiplicity made correlation with other clinical, biochemical, and serological features difficult. For these reasons it is important that more patients be carefully studied, so as to evaluate the role of coproporphyrin excretion in assessing the progress of the patient after heart University of Cape Town, Department of Medicine, Observatory, Cape, South Africa.
transplantation. LENNOX EALES.
HORMONAL ACTIVITY AND END-ORGAN RESPONSE
SiR,ŇThe responsiveness of peripheral receptor-sites to hormonal action, and its role in the determination of the endocrine status of the individual, is again in the limelight as shown by a wealth of recent experimental studies and clinical observations on the subject, and recently by the paper by Dr. Merimee and his co-workers (July 27, p. 191). These workers found, in a male dwarf, abnormally raised levels of growth hormone (H.G.H.) with subresponsiveness of the peripheral tissues to exogenous H.G.H. They tentatively suggest that the underlying defect was abnormal responsiveness of the end-organs rather than abnormal secretion of the pituitary gland. The role played by the peripheral tissues in the pathogenesis of endocrine disease has concerned me for a long time, and from the early 1920s onwards I have approached the problem from various angles, though with less refined and elegant laboratory techniques than are used today. On the strength of clinical observations and simple model experiments revealing the significance of the pH, ionic environment, and other environmental factors for hormonal activity at the cell membrane,! I formulated in 1924 my peripheral theory "2 and I am happy to find that my postulate has been amply confirmed by elaborate physical and histochemical techniques. 1. Zondek, H., Reiter, T. Klin. Wschr. 1923, 2, 1344. Zondek, H., Ucko, H. "
ibid. 1924, 29, 1752; Hoppe-Seyler’s Z. physiol. Chem. 1925, 148, 8. Zondek, H., Bansi, H. Klin. Wschr. 1927, 6; Biochem. Z. 1928, 195, 376. 2. Zondek, H. Dt. med. Wschr. 1924, 50, 364.
511 This is
to
remind my fellow-endocrinologists that clinical
observation should be the beginning and the end of endocrine research. With regard to H.G.H. the role played by the target tissues can now be extensively investigated, as borne out by the paper of Dr. Merimee and his associates. Yet more than 40 years ago the occurrence of " partial acromegaly " (that is, excessive growth of isolated acra) proved to me the same point. I wrote in 1926 3: " The peripheral tissues must possess a certain physico-chemical constellation so as to permit abnormal effects of the pituitary (growth) hormone. This must be due either to the loss of factors normally inhibiting, or to the presence of factors enhancing such hormonal influences. The pituitary gland may remain morphologically and functionally
intact." Jerusalem, Israel.
HERMANN ZONDEK.
ESSENTIAL FATTY ACIDS AND ATHEROMA SIR,-Mr. McCullagh (Aug. 10, p. 353) states that Dr. Crawford4 misrepresents the facts about the development of atheromatous lesions in elephant populations living in " disturbed " habitats in East Africa, and he does not accept that the lesions described by Dr. S. K. Sikes5 resemble atheroma in man. Although Dr. Sikes has described the calcified lesions of the media to which Mr. McCullagh refers, she also found fatty intimal lesions in elephants from " disturbed " scrubland habitats which, in the opinion of a number of experts who examined them, are similar to human atheroma. Dr. Sikes does not necessarily attribute these either to essential-fatty-acid deficiency or to other nutritional factors. A full account of Dr. Sikes’ studies over some four years will be published in the Transactions of the Zoological Society at the end of the year, when it will be possible to give them proper appraisal, in the light of the evidence she presents and the authorities who have given her assistance. Meanwhile, she is in Canada and inaccessible; hence this letter is sent by the writer, as head of the department in which she worked. Department of Pathology, Nuffield Institute of Comparative Medicine, The Zoological Society of London, Regent’s Park, London N.W.1.
R. N. FIENNES.
AORTIC RECONSTRUCTION FOR CLAUDICATION SIR,-We support, in general, the views expressed by Mr. Dyde (Aug. 10, p. 326) on the question of reconstruction of the aortic bifurcation in claudicating patients who have a coexisting block of the femoral artery. Certainly superficial-femoralartery occlusion rarely gives rise to significant symptoms provided that the aorto-iliac segment and profunda femoris are normal. This view, which has principally been championed by Wesolowski, and is confirmed by our own experience in 23 cases, is gaining ground among vascular surgeons. It is an important concept, because reconstruction of the large arterial trunks above the inguinal ligament is a much simpler and more satisfactory operation than direct attack on the blocked femoral artery. There are, however, as Mr. Dyde mentions, patients who continue to claudicate in spite of a successful clearance of the aorto-iliac region, and these cases cannot reliably be diagnosed on a preoperative aortogram. It is here that strain-gauge plethysmography is of the greatest help, since the presence of a significant pressure gradient between thigh and calf implies that additional surgery to the femoropopliteal segment may be
required. Our practice differs from that of Mr. Dyde in that we consider it unnecessary, and indeed possibly unwise, to excise the aortic bifurcation. In our experience a satisfactory result can always be obtained by endarterectomy (if the external iliac 3.
H. Die Krankheiten der Endokrinen Druesen, p. 251, Berlin, 1926; The Diseases of the Endocrine Glands; p. 327. London, 1944. 4. Crawford, M. A. Lancet, 1968, i, 1329. 5. Sikes, S. K. Symp. Zool. Soc. Lond. 1968, no. 21, p. 251.
trunk is normal),’Dacron ’ bypass graft, or combination of the two. In our view, excision of the Leriche lesion unnecessarily prolongs the operating-time and carries the disadvantage of sacrificing the lumbar arteries, which may be valuable collaterals, especially to the spinal cord. Department of Surgical Studies, The Middlesex Hospital, London W.1.
ADRIAN MARSTON H. W. S. PIGOTT.
BIOCHEMICAL DIAGNOSIS OF AN X-LINKED DISEASE IN UTERO SIR,-We wish to report the identification in utero of a human foetus heterozygous for an X-linked heritable metabolic disease. The disorder, first described by Lesch and Nyhan, is characterised by spasticity, choreoathetosis, psychomotor retardation, and compulsive automutilation of lips and fingers, and is associated with hyperuricsemia and excessive uric-acid production.! The latter metabolic abnormality often results in haematuria and crystalluria and, occasionally, renal colic and progressive renal failure. This disorder occurs only in males, and to date all pedigrees are compatible with an X-linked mode of inheritance.2 Cells of patients with this syndrome have virtually no activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (H.G.P.R.T.).3 Skin-fibroblast cultures derived from six mothers of affected children consisted of two cell populations, one with and one without H.G.P.R.T. activity, as demonstrated by a radioautographic technique.4 In addition, cellular clones, with and without H.G.P.R.T. activity, have been isolated from skin-fibroblast cultures from obligate heterozygotes.5 Such mosaicism in cells cultured from heterozygotes for X-linked defects is in keeping with the random inactivation of one of the two X-chromosomes of female somatic cells at an early stage of somatic development, as proposed in the Lyon hypothesis.Demonstration of mosaicism in fibroblast cultures is the most convenient method at present for detecting heterozygotes for this disorder. Cell cultures derived from foetal cells present in amniotic fluid exhibit activity for the enzymes which are deficient in patients with some of the inborn errors of metabolism.7 We have now found that cells cultured from amniotic fluid have H.G.P.R.T. activity. This was shown by the radioautographic technique and by a quantitative assay for H.G.P.R.T. activity, which measures the incorporation of [14C]-hypoxanthine into inosinic acid and inosine in extracts of such cells. The amount of activity was similar to that in control skin fibroblasts.8 These findings suggested that the radioautographic determination of H.G.P.R.T. activity in amniotic-fluid-cell cultures from women heterozygous for deficiency of this enzyme might be helpful in their genetic counselling. Case-report and Enzyme Studies The first pregnancy at risk for H.G.P.R.T. deficiency that we encountered was that of a 24-year-old housewife, who was a first cousin of an affected male (related through the mothers). Her three previous pregnancies had produced two daughters and a normal son. On March 27, 1968, during her 13th 1. 2.
3. 4. 5.
6. 7.
Zonkek,
8.
Lesch, M., Nyhan, W. L. Am. J. Med. 1964, 36, 561. Hoefnagel, D., Andrew, E. D., Mireault, N. G., Berndt, W. O. New Engl. J. Med. 1965, 273, 130. Shapiro, S. L., Sheppard, B. L., Jr., Dreifuss, F. E., Newcombe, D. S. Proc. Soc. exp. Biol. Med. 1966, 122, 609. Nyhan, W. L., Pesek, J., Sweetman, L., Carpenter, D. G., Carter, C. H. Pediat. Res. 1967, 1, 5. Seegmiller, J. E., Rosenbloom, F. M., Kelley, W. N. Science, N.Y. 1967, 155, 1682. Rosenbloom, F. M., Kelley, W. N., Henderson, J. F., Seegmiller, J. E. Lancet, 1967, ii, 305. Fujimoto, W. Y., Seegmiller, J. E. Unpublished. Migeon, B. R., der Kaloustian, V. M., Nyhan, W. L., Young, W. L., Childs, B. Science, N. Y. 1968, 160, 425. Salzmann, J., De Mars, R. Benke, P. Proc. natn. Acad. Sci. U.S. 1968, 60, 545. Lyon, M. F. Nature, Lond. 1961, 190, 372. Uhlendorf, B. W., Mudd, S. H. Science, N.Y. 1968, 160, 1007. Nadler, H. L. Abstract of the Annual Meeting of the American Society of Human Genetics, Toronto, Canada, Dec. 1-3, 1967. Uhlendorf, B. W., Jacobson, C. B., Sloan, H. R., Mudd, S. H., Herndon, J. H., Brady, R. O., Seegmiller, J. E., Fujimoto, W. Y. In vitro (in the press). Uhlendorf, B. W., Fujimoto, W. Y., Jacobson, C. B., Seegmiller, J. E.
Unpublished.
drowsy and grossly oliguric, and later comatose. Arrangements were made to carry out a second pig-liver perfusion but unfortunately, only 30 minutes before the pig liver could be brought to him, he developed another haematemesis and died. Necropsy showed a very soft and shrunken liver which on histological examination revealed extensive hepatic necrosis and other features of acute viral hepatitis. There was a myriad of minute gastric and small-bowel erosions. The mortality from hepatic coma due to acute hepatic necrosis is exceedingly high,9 10 and when accompanied by oliguria and uraemia there is very often a fatal outcome.ll Nevertheless, owing to the enormous capacity of the liver for regeneration, the hepatic damage may be regarded as potentially reversible. It follows therefore that, if some form of effective temporary and repeated hepatic support can be provided for these patients, the inevitable gloomy outcome might be prevented. With exchange blood-transfusion some salvage has been reported by Berger et all and Saunders,t3 though Jones a1.14 had no survivors among seven cases thus treated. In view of the complexities of liver functions only a normal liver can be substituted for another which has failed, and for this reason the use of a healthy extracorporeal liver, we believe, is the rational method of therapy. The effectiveness of such a liver is very well demonstrated in this case. The clinical improvement in this patient after 51/2 hours of perfusion was very striking, and in parallel with this were the dramatic hmmatological and biochemical changes. Unfortunately, the patient in coma from acute hepatic necrosis develops other very serious complications—namely, renal failure, haemorrhage, hypoglycxmia, respiratory failure, and electrolyte imbalance. Gastrointestinal haemorrhage seems to be the commonest terminal complication, as in this case. et
C.M. ABOUNA R. GARRY C. HULL J. KIRKLEY D. N. WALDER.
The Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP
COPROPORPHYRINURIA AND HUMAN HEART TRANSPLANTATION wish to draw attention to a disturbance in urinary SiR,ŇI porphyrin excretion observed in two patients after cardiac transplantation and to express the hope that other cardiactransplant teams will be encouraged to undertake serial studies of porphyrin excretion. Both patients developed pronounced coproporphyrinuria. Uroporphyrin excretion was unaffected. 8-aminolaevulinic acid (A.L.A.) and porphobilinogen (P.B.G.) excretion showed little if any deviation from normal except for a preterminal rise in urinary A.L.A. in the first patient. Both patients had a temporary mild increase in urinary coproporphyrin soon after operation; about the 10th post-operative day the coproporphyrin increased again to reach initial peak values of 500 g. and 596 g. per day respectively. In the first patient the peak excretion of 500 g. was reached on the 12th postoperative day, 5 days before his death from a fulminant Klebsiella-Pseudomonas pneumonia. In the second patient, the initial peak value was reached on the 18th postoperative day. Thereafter the urinary coproporphyrin excretion (mainly isomer III) remained well above normal and only approached 150-200 ;jtg. per day 4 days before his discharge from hospital on the 74th postoperative day. The fall in coproporphyrin output was evanescent and, despite striking physical improvement, the level rose sharply again and has remained raised since then, isomer III constituting 48-58% of the copro9. 10.
Cook, G. C., Sherlock, S. Lancet, 1965, i, 175. Chalmers, T. C. in The Liver (edited by A. E. Read); p. 287. London, 1967. 1121.
11. Hecker, R., Sherlock, S. Lancet, 1956, ii, 12. Berger, R. L., Liverage, R. M., Chalmers, T. C., Graham, J. H., McGoldrick, D. M., Stohlman, F. New Engl. J. Med. 1966, 274, 497. 13. Saunders, S. J. in The Liver (edited by A. E. Read); p. 289. London, 1967. 14. Jones, E. A., Clain, D., Clink, H. M., MacGillivray, M., Sherlock, S. Lancet, 1967, ii, 169.
increases (up to 835 (Lg. per day) have accompanied complications such as deterioration in cardiac function, development of a septicaemia with meningitis, hepatitis, and suspected pulmonary embolism and pneumonia. In view of the multiplicity of factors influencing the progress following organ transplantation, the precise aetiology of the porphyrinuria is difficult to establish. Among the factors to be considered early in the course after transplantation are the post-
porphyrin. Striking
operative
metabolic response, the effects of
cardiopulmonary
bypass, and the pericardial and myocardial reaction with or without congestive heart-failure. Later, other factors supervene : the toxicity of prolonged immunosuppressive therapy, the effects of tissue damage due to rejection, infection, or pulmonary embolism, and hepatic dysfunction due to liver congestion. Haemolytic anaemia, sometimes a cause of copro-
porphyrinuria, also needs to be excluded. Of some help in interpretation was the observation that two other patients undergoing open-heart surgery with cardiopulmonary bypass showed no disturbance in serial porphyrin excretion. Patients with myocardial infarction had only an immediate, short-lived, mild disturbance. Two patients on immunosuppressive therapy after renal transplantation also showed no abnormality of urinary porphyrin excretion even during rejection episodes. In the first of the two cardiac-transplant patients the coproporphyrinuria can reasonably be related to the severe pneumonic infection. In the second patient, however, many of the abovementioned factors need to be considered, including myocardial and pericardial involvement at a time when there was no evidence of infection, liver disease, or congestive heart-failure. Hasmolytic anaemia was seriously considered in view of a persistent reticulocytosis but there was no other supporting evidence, although later increased osmotic fragility developed. However, variations in therapy, meningitis, hepatitis, poor tissue perfusion, and suspected pulmonary embolism probably all contributed to the disturbance in porphyrin excretion. This multiplicity made correlation with other clinical, biochemical, and serological features difficult. For these reasons it is important that more patients be carefully studied, so as to evaluate the role of coproporphyrin excretion in assessing the progress of the patient after heart University of Cape Town, Department of Medicine, Observatory, Cape, South Africa.
transplantation. LENNOX EALES.
HORMONAL ACTIVITY AND END-ORGAN RESPONSE
SiR,ŇThe responsiveness of peripheral receptor-sites to hormonal action, and its role in the determination of the endocrine status of the individual, is again in the limelight as shown by a wealth of recent experimental studies and clinical observations on the subject, and recently by the paper by Dr. Merimee and his co-workers (July 27, p. 191). These workers found, in a male dwarf, abnormally raised levels of growth hormone (H.G.H.) with subresponsiveness of the peripheral tissues to exogenous H.G.H. They tentatively suggest that the underlying defect was abnormal responsiveness of the end-organs rather than abnormal secretion of the pituitary gland. The role played by the peripheral tissues in the pathogenesis of endocrine disease has concerned me for a long time, and from the early 1920s onwards I have approached the problem from various angles, though with less refined and elegant laboratory techniques than are used today. On the strength of clinical observations and simple model experiments revealing the significance of the pH, ionic environment, and other environmental factors for hormonal activity at the cell membrane,! I formulated in 1924 my peripheral theory "2 and I am happy to find that my postulate has been amply confirmed by elaborate physical and histochemical techniques. 1. Zondek, H., Reiter, T. Klin. Wschr. 1923, 2, 1344. Zondek, H., Ucko, H. "
ibid. 1924, 29, 1752; Hoppe-Seyler’s Z. physiol. Chem. 1925, 148, 8. Zondek, H., Bansi, H. Klin. Wschr. 1927, 6; Biochem. Z. 1928, 195, 376. 2. Zondek, H. Dt. med. Wschr. 1924, 50, 364.
511 This is
to
remind my fellow-endocrinologists that clinical
observation should be the beginning and the end of endocrine research. With regard to H.G.H. the role played by the target tissues can now be extensively investigated, as borne out by the paper of Dr. Merimee and his associates. Yet more than 40 years ago the occurrence of " partial acromegaly " (that is, excessive growth of isolated acra) proved to me the same point. I wrote in 1926 3: " The peripheral tissues must possess a certain physico-chemical constellation so as to permit abnormal effects of the pituitary (growth) hormone. This must be due either to the loss of factors normally inhibiting, or to the presence of factors enhancing such hormonal influences. The pituitary gland may remain morphologically and functionally
intact." Jerusalem, Israel.
HERMANN ZONDEK.
ESSENTIAL FATTY ACIDS AND ATHEROMA SIR,-Mr. McCullagh (Aug. 10, p. 353) states that Dr. Crawford4 misrepresents the facts about the development of atheromatous lesions in elephant populations living in " disturbed " habitats in East Africa, and he does not accept that the lesions described by Dr. S. K. Sikes5 resemble atheroma in man. Although Dr. Sikes has described the calcified lesions of the media to which Mr. McCullagh refers, she also found fatty intimal lesions in elephants from " disturbed " scrubland habitats which, in the opinion of a number of experts who examined them, are similar to human atheroma. Dr. Sikes does not necessarily attribute these either to essential-fatty-acid deficiency or to other nutritional factors. A full account of Dr. Sikes’ studies over some four years will be published in the Transactions of the Zoological Society at the end of the year, when it will be possible to give them proper appraisal, in the light of the evidence she presents and the authorities who have given her assistance. Meanwhile, she is in Canada and inaccessible; hence this letter is sent by the writer, as head of the department in which she worked. Department of Pathology, Nuffield Institute of Comparative Medicine, The Zoological Society of London, Regent’s Park, London N.W.1.
R. N. FIENNES.
AORTIC RECONSTRUCTION FOR CLAUDICATION SIR,-We support, in general, the views expressed by Mr. Dyde (Aug. 10, p. 326) on the question of reconstruction of the aortic bifurcation in claudicating patients who have a coexisting block of the femoral artery. Certainly superficial-femoralartery occlusion rarely gives rise to significant symptoms provided that the aorto-iliac segment and profunda femoris are normal. This view, which has principally been championed by Wesolowski, and is confirmed by our own experience in 23 cases, is gaining ground among vascular surgeons. It is an important concept, because reconstruction of the large arterial trunks above the inguinal ligament is a much simpler and more satisfactory operation than direct attack on the blocked femoral artery. There are, however, as Mr. Dyde mentions, patients who continue to claudicate in spite of a successful clearance of the aorto-iliac region, and these cases cannot reliably be diagnosed on a preoperative aortogram. It is here that strain-gauge plethysmography is of the greatest help, since the presence of a significant pressure gradient between thigh and calf implies that additional surgery to the femoropopliteal segment may be
required. Our practice differs from that of Mr. Dyde in that we consider it unnecessary, and indeed possibly unwise, to excise the aortic bifurcation. In our experience a satisfactory result can always be obtained by endarterectomy (if the external iliac 3.
H. Die Krankheiten der Endokrinen Druesen, p. 251, Berlin, 1926; The Diseases of the Endocrine Glands; p. 327. London, 1944. 4. Crawford, M. A. Lancet, 1968, i, 1329. 5. Sikes, S. K. Symp. Zool. Soc. Lond. 1968, no. 21, p. 251.
trunk is normal),’Dacron ’ bypass graft, or combination of the two. In our view, excision of the Leriche lesion unnecessarily prolongs the operating-time and carries the disadvantage of sacrificing the lumbar arteries, which may be valuable collaterals, especially to the spinal cord. Department of Surgical Studies, The Middlesex Hospital, London W.1.
ADRIAN MARSTON H. W. S. PIGOTT.
BIOCHEMICAL DIAGNOSIS OF AN X-LINKED DISEASE IN UTERO SIR,-We wish to report the identification in utero of a human foetus heterozygous for an X-linked heritable metabolic disease. The disorder, first described by Lesch and Nyhan, is characterised by spasticity, choreoathetosis, psychomotor retardation, and compulsive automutilation of lips and fingers, and is associated with hyperuricsemia and excessive uric-acid production.! The latter metabolic abnormality often results in haematuria and crystalluria and, occasionally, renal colic and progressive renal failure. This disorder occurs only in males, and to date all pedigrees are compatible with an X-linked mode of inheritance.2 Cells of patients with this syndrome have virtually no activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (H.G.P.R.T.).3 Skin-fibroblast cultures derived from six mothers of affected children consisted of two cell populations, one with and one without H.G.P.R.T. activity, as demonstrated by a radioautographic technique.4 In addition, cellular clones, with and without H.G.P.R.T. activity, have been isolated from skin-fibroblast cultures from obligate heterozygotes.5 Such mosaicism in cells cultured from heterozygotes for X-linked defects is in keeping with the random inactivation of one of the two X-chromosomes of female somatic cells at an early stage of somatic development, as proposed in the Lyon hypothesis.Demonstration of mosaicism in fibroblast cultures is the most convenient method at present for detecting heterozygotes for this disorder. Cell cultures derived from foetal cells present in amniotic fluid exhibit activity for the enzymes which are deficient in patients with some of the inborn errors of metabolism.7 We have now found that cells cultured from amniotic fluid have H.G.P.R.T. activity. This was shown by the radioautographic technique and by a quantitative assay for H.G.P.R.T. activity, which measures the incorporation of [14C]-hypoxanthine into inosinic acid and inosine in extracts of such cells. The amount of activity was similar to that in control skin fibroblasts.8 These findings suggested that the radioautographic determination of H.G.P.R.T. activity in amniotic-fluid-cell cultures from women heterozygous for deficiency of this enzyme might be helpful in their genetic counselling. Case-report and Enzyme Studies The first pregnancy at risk for H.G.P.R.T. deficiency that we encountered was that of a 24-year-old housewife, who was a first cousin of an affected male (related through the mothers). Her three previous pregnancies had produced two daughters and a normal son. On March 27, 1968, during her 13th 1. 2.
3. 4. 5.
6. 7.
Zonkek,
8.
Lesch, M., Nyhan, W. L. Am. J. Med. 1964, 36, 561. Hoefnagel, D., Andrew, E. D., Mireault, N. G., Berndt, W. O. New Engl. J. Med. 1965, 273, 130. Shapiro, S. L., Sheppard, B. L., Jr., Dreifuss, F. E., Newcombe, D. S. Proc. Soc. exp. Biol. Med. 1966, 122, 609. Nyhan, W. L., Pesek, J., Sweetman, L., Carpenter, D. G., Carter, C. H. Pediat. Res. 1967, 1, 5. Seegmiller, J. E., Rosenbloom, F. M., Kelley, W. N. Science, N.Y. 1967, 155, 1682. Rosenbloom, F. M., Kelley, W. N., Henderson, J. F., Seegmiller, J. E. Lancet, 1967, ii, 305. Fujimoto, W. Y., Seegmiller, J. E. Unpublished. Migeon, B. R., der Kaloustian, V. M., Nyhan, W. L., Young, W. L., Childs, B. Science, N. Y. 1968, 160, 425. Salzmann, J., De Mars, R. Benke, P. Proc. natn. Acad. Sci. U.S. 1968, 60, 545. Lyon, M. F. Nature, Lond. 1961, 190, 372. Uhlendorf, B. W., Mudd, S. H. Science, N.Y. 1968, 160, 1007. Nadler, H. L. Abstract of the Annual Meeting of the American Society of Human Genetics, Toronto, Canada, Dec. 1-3, 1967. Uhlendorf, B. W., Jacobson, C. B., Sloan, H. R., Mudd, S. H., Herndon, J. H., Brady, R. O., Seegmiller, J. E., Fujimoto, W. Y. In vitro (in the press). Uhlendorf, B. W., Fujimoto, W. Y., Jacobson, C. B., Seegmiller, J. E.
Unpublished.