659
possible failure of a heart-valve prosthesis. Accordingly patients being prepared for this procedure should be patch tested by an experienced dermatologist, and prosthetic materials free of the particular allergen should be used. Patients who are allergic to nickel should be given nickel-free prostheses. Conversely metal allergy should be sought when valve prostheses are unaccountably leaking.
gic
to
metals face
As far as we are aware, this is the first report which attempts to correlate prosthetic-valve dysfunction with allergy to nickel, or indeed to any metal. This is surprising, considering how common allergy to nickel is in the population, and how widely it is used in prostheses. Time will tell whether our patient is unique, or whether
allergy to metal has been overlooked as a culty or failure in heart-valve replacement.
cause
of diffi-
Hypothesis MITOCHONDRIAL INHERITANCE AND DISEASE PAUL E. M. FINE Ross Institute, London School of Hygiene and Tropical Medicine, London WC1E 7HT
of the of mitochondria may be responsible for human disease. Among the prime candidates for such a mitochondrial ætiology are certain drug-induced blood dyscrasias, particularly that due to chloramphenicol. Because mitochondria are generally inherited from the female parent, such disorders should be clustered among matroclinally related individuals. The clinical manifestations of such diseases are a function of the manner in which mitochondria are allocated to somatic cells and tissues during development.
Summary
Spontaneously occurring variants
D.N.A. content
INTRODUCTION
MITOCHONDRIA are essential organelles of all human cells. Interest in the structure and function of mitochondria has increased greatly with the recognition that they contain their own genetic system, which functions to some extent independently of the nuclear chromosomes. Despite the increase in our understanding of the biology of mitochondria, little is known of their role in disease processes, beyond the fact that their morphology is altered in association with severe pathological conditions. I propose here a specific and primary role for mitochondria in certain human diseases, and suggest ways of testing the proposal. FOR, AND IMPLICATIONS OF, THE HYPOTHESIS Certain Essential Information is Coded in Mitochondrial D.NA.-It has long been recognised that mitochondria are at least partly autonomous within their "host" cells, in that they are not synthesised de novo but replicate themselves by binary fission.1-3 That mitochondria contain their own D.N.A. (mtD.N.A.) was first recognised in the early 1960s.4 The amount of mitochondrial structure and function which is coded on EVIDENCE
We are indebted to Mr J. Lawther (Medtronic Ltd) for suggesting the use of the Lillehei-Kaster titanium prosthesis. Requests for reprints should be addressed to A. L., Department of Dermatology, Royal Infirmary, Glasgow G4 OSF. -
REFERENCES 1. Lyell, A., Bain, W. H. Lancet, 1974, i, 408. 2. Stoddart, J. C. ibid. 1960, ii, 741. 3. Kaaber, K., Veien, N. K., Tjell, J. C. Br. J. Derm. 1978, 98, 197. 4. Fisher, A. A. Cutis, 1977, 19, 285. 5. Samitz, M. H., Katz, S. A. Br. J. Derm. 1975, 92, 287. 6. Katz, S.A., Samitz, M.H. Acta derm-vener., Stockh. 1975, 55, 113. 7. Pegum, J. S. Lancet, 1974, i, 674. 8. Pegum, J. S. Personal communication. 9. Evans, E. M., Freeman, M. A. R., Miller, A. J., Vernon-Roberts, B.
J. Bone
Jt Surg. 1974, 56B, 626. 10. Benson, M. K. D., Goodwin, P. G., Brostoff, J. Br. med. J. 1975, iv, 374. 11. Jones, D. A., Lucas, H. K., O’Driscoll, M., Price, C. H. G., Wibberley, B. J. Bone Jt Surg. 1975, 57B, 289. 12. Deutman, R., Mulder, T. J., Brian, R., Nater, J. P. ibid. 1977, 59A, 862. 13. Elves, M. W., Wilson, J. N., Scales, J. T., Kemp, H. B. S. Br. med. J. 1975,
iv, 376.
distinct from nuclear D.N.A. is still uncertain, it is known that some of the structural proteins though of mitochondria are coded in nuclear D.N.A.s-7 The amounts and roles of mitochondrial and nuclear D.N.A. vary between different types of cells, but in general relatively few genes seem to be coded in the D.N.A. of any
mtD.N.A. as
single mitochondrion.89 Maternal Inheritance of Mitochondria.-A tendency for inheritance to occur predominantly through the female line is a distinguishing feature of cytoplasmic material such as mitochondria. This correlates with the great difference in size between maternal and paternal gametes. It has been estimated, for example, that a cow’s ovum may contain 106 mitochondria, in contrast to about 70 mitochondria in a mature spermatid of a bull. 10 Roughly similar numbers are probably applicable to man. There is at least provisional evidence that the inheritance of mitochondria in vertebrates is entirely from the mother. Though the sperm of a rat may introduce a few mitochondria into the zygote, these paternal mitochondria seem to degenerate subsequently.l Furthermore, the only published attempts to trace mitochondrial inheritance in vertebrates, by elegant experiments in frogs and in horses, have revealed no evidence of paternal mtD.N.A. in the progeny. to 12 As the transmission of cytoplasmic material by both parents would permit detrimental cytoplasmic factors to be maintained indefinitely within a population, natural selection may have favoured the strict uniparental inheritance of such material. 6 13 Antibiotic Sensitivity as an Intrinsic Mitochondrial Property.-Various antibiotics are known to be deleterious to certain species or lines of eukaryotic cells in vitro. In several instances this antibiotic sensitivity is known to be due to a mitochondrial genetic factor-for chlorampheniexample, oligomycin, erythromycin, and14-16 col sensitivity in Saccharomyces yeast; erythromycin sensitivity in Parmecium protozoa; 17 and rutamycin and chloramphenicol sensitivity of mouse fibroblasts.18 19 Especially interesting is the recent derivation of human cell lines with strikingly different sensitivity to chloramphenicol, and the demonstration that this sensitivity is coded on the mtD.N.A.20 This is the only mtD.N.A. marker thus far confirmed in human cells. Several antibiotics cause depression of cell activity in certain human tissues, particularly the bone-mar.
660 is the total cells which occurs in approximately 1/100 000 persons exposed to chloramphenico1.23-2s In view of the in-vitro evidence for mtD.N.A.-dependent antibiotic sensitivity in cells of several species, including man, it seems reasonable to hypothesise that some of these drug-induced dyscrasias -in particular, that attributed to chloramphenicol are due to the effect of antibiotics on the mitochondria of the hxmatopoietic stem cells. Sensitive individuals would be those whose stem cells contain predominantly, or solely, mitochondria of a sensitive type. The specificity of the drug’s action on the hxmatopoietic system may be due to the high turnover-rate of the stem cells, or to some special metabolic demand which makes these cells particularly susceptible’to mitochondrial disturbance. Predicted Matroclinal Similarity for Drug Sensitivity.-The basic inheritance pattern of mtD.N.A. is illustrated in the schematic mother-father-son-daughter pedigree in the accompanying figure. Germ-line cells are shown with heavy outline, whereas the differentiating lines of somatic cells have a thin outline. Cell nuclei are represented as ovals in the lower right of each cell, and the inheritance of half the nuclear chromosomes from each parent is represented by appropriate shading. Mitochondria are shown as small circles or triangles within the "cytoplasm" of each cell: solid symbols for maternal and open symbols for paternal organelles. These different symbols are meant to represent different mitochondrial "types"-i.e., organelles which differ in their mtD.N.A. constitution. A strict maternal inheritance of mitochondria is illustrated. The possibility of a small paternal contribution of mitochondria could be added to the diagram, if appropriate. Such a diagram could also be extended to describe larger pedigrees. The important point is that each individual is inclined to share mitochondria with his or her mother and all matroclinal relatives-that is, with all individuals in the pedigree who are linked by at least one line which passes only through
row 21 22 The most dramatic inhibition of haematopoietic
example of this
stem
sive generations is dependent upon preservation of the different mtD.N.A. types within the maternal germ-cell line (as in the figure). The mechanism of mitochondrial allocation at cell division is not understood. The mitochondria of some primitive species (e.g., scorpions) are believed to make use of the mitotic spindle and achieve an even distribution between daughter cells; but there is no evidence for such a mechanism in mammals.1-3 In human beings, mitochondrial allocation at cell division is generally considered to occur "at random". In this case, and given a heterogeneous population of mitochondria in the zygote, one would expect there to be some sorting out of different types of mtD.N.A. during the successive cell divisions of an individual’s ontogeny. Such sorting-out has been illustrated in the figure. The two types of mitochondria are shown to be distributed unequally at successive somatic cell divisions within each individual. According to this diagram, some of each individual’s differentiated cell lines eventually become homochondric, despite a heterochondric zygote and maternal germ-cell line. Risk among Carriers is Related to mtD.NA. Heterogeneity.-The implications of mitochondrial heterogeneity and sorting-out in somatic cell lines are important. Clinical evidence of mtD.N.A.-dependent antibiotic sensitivity might arise only if the sorting-out process has led to a cell line which possesses mitochondria predominantly, or solely, of a sensitive type. The probability of this happening should be inversely related to the number of copies of sensitive mtD.N.A.-type mitochondria initially present in the zygote. This quantitative relationship has been examined in simple cell culture systems, but has not yet been extrapolated to the ontogeny of multicellular organisms.34
females.26
Any mitochondrial D.N.A. marker, such as one for drug sensitivity, is expected to be shared by matroclinal relatives of a sensitive proband. The actual risks of drug sensitivity are difficult to assess in practice, since the number exposed in each category of relatives is generally unknown. It is noteworthy, however, that of three recorded familial concordances for acute chloramphenicol sensitivity, two were identical twins and one was in a man and his sister’s daughter.27 211 All are matroclinal ties. /?Mp/!c!07M /br Mitochondrial Heterogeneity.-The hypothesis under consideration implies a variation in mtD.N.A. content of mitochondria in human individuals and populations. There is conflicting evidence as to whether an individual inherits one type or several types of mitochondria (i.e., mitochondria with different mtD.N.A. constitutions). Nor is it clear whether differentiated tissues are naturally "homochondric" or "heterocliondric".29-33 However, given that certain
mtD.N.A.
may
un-
degree of heterogeneity in the mtD.N.A. within single cells, tissues, and individuals, let alone populations, is to be expected. In the absence of paternal transfer of mitochondria to the zygote, the maintenance of mitochondrial heterogeneity in succesdergo mutation,
a
Inheritance pattern of mitochondria
-
This simple pedigree illustrates the pattern of allocation of mitochondrial (A, .,A,O) and nuclear (4m,c=) material to the germ line (heavy outline) and somatic (thin outline) cells of each individual. Strict maternal inheritance of mitochondria is assumed.
661 The actual risk of acute chloramphenicol sensitivity among matroclinal relatives of sensitive individuals is unknown. Considering the widespread use of this antibiotic between 1950 and 1965, the rarity of reports of familial aggregation suggests that this risk is appreciably less than 100%. This may suggest that only a small proportion of the mitochondria of affected individuals are of the sensitive type. Graded Phenotypes with Multiple mtD.N.A. Types.-Given multiple types of mitochondria within cells, which vary in their mtD.N.A. and in their relative numbers, one would expect that any derivative phenotypic traits would vary according to the distribution of types and numbers of mitochondria within the cells, tissues, or organisms. This is consistent with the observed clinical range of antibiotic sensitivity (e.g., to chloramphenicol), which may range from a mild depression to a total shutdown of haematopoiesis.25 It is also consistent with evidence that bone-marrow cells of individuals who have recovered from chloramphenicol-induced anaemia are less sensitive than normal control cells when exposed to chloramphenicol in vitro.35 If the initial exposure des. troys the drug-sensitive mitochondria and those cells which are dependent upon them, then only cells which contain at least some chloramphenicol-resistant mitochondria would be left. Mitochondrial Defects and Other Diseases.-Although special emphasis has been placed here upon the possibility of a mtD.N.A.-dependent mechanism underlying certain antibiotic sensitivities, it should be recognised that, given the importance of mitochondria in energy metabolism and possibly also in cell differentiation, mutations in mtD.N.A. might lead to a broad range of cellular and organismal pathology. TESTING
THE HYPOTHESIS
Several features of the hypothesis lend themselves to direct investigation. First, the predicted matroclinal tendency may be tested by family-history studies of individuals who have suffered blood dyscrasis attributed to antibiotic therapy. Second, cell lines could be derived from both matroclinal and non-matroclinal relatives of drug-sensitive individuals, in order to assess differences in sensitivity in vitro. Third, there is a need to investigate the possibility and the extent of a paternal contribution to mitochondrial inheritance in man, since this will determine the expected difference in mitochondrial constitution between different classes of relatives.36 Existing restriction endonuclease techniques should make such a study feasible. Fourth, further studies should be pursued on the distribution of mitochondria during human ontogeny. This raises the question of what tissues other than haematopoietic stem cells may be susceptible to mitochondrial toxins. Finally, we need to develop a quantitative theory of mitochondrial genetics in both germ-line and somatic cells of higher
organisms.36 Human family and population studies may make a fundamental contribution to our understanding of the role of the cytoplasm in heredity. Published reports on mitochondrial inheritance deal almost entirely with single-cell organisms or cell cultures. Paramecium and yeast, the early experimental models, have now given place to mammalian cells, studied by’ cell-fusion techniques. These techniques still depend largely upon markers which are expressed in cell-culture systems
-hence the continued emphasis on genes for antibiotic sensitivity in published work on mitochondrial genetics. Such techniques are not directly suited for the study of the role of mtD.N.A. in the development and the function of differentiated cells. Another weakness of the in-vitro methods is their emphasis upon established cell lines in culture, as mitochondrial diversity is very likely to be altered or diluted out with the serial propagation of many standard cell lines.29 For all these reasons, the study of whole organisms and populations has much to contribute to our understanding of mitochondrial inheritance. Several indices discussed here-such as matroclinal excess, variable penetrance, and phenotypic gradations-provide epidemiological tools for the assessment of mitochondrial inheritance in man. A cautionary remark is in order, concerning the inference of cytoplasmic or mitochondrial inheritance in man. Although matroclinal line clustering is to be expected for any trait which is coded in mtD.N.A., various other mechanisms may lead to a similar family-history asymmetry. Many nurtural factors, such as the intrauterine environment, breast milk, or even diet in the home may cause children to resemble their mothers more closely than their fathers. Furthermore, there is a general tendency for women to know their family histories better than do men, and this may lead to a spurious excess in matroclinal lines in retrospective studies.17 38 Finally, the presence of paternal illegitimates in a pedigree may result in an apparent matroclinal clustering of chromosomal, as well as extrachromosomal, traits. Such alternatives to a simple cytoplasmicinheritance hypothesis must be considered in the interpretation of data indicating a matroclinal line clustering in man.
DISCUSSION
Though several disorders of man may ultimately be attributed to aberrant mtD.N.A., particular emphasis is placed here upon the drug-induced blood dyscrasias. That dyscrasias should emerge as prime candidates for such an aetiology may simply reflect the large amount of work which has been done on this aspect of mitochondrial behaviour. And this, in turn, is due to the dependence of most current mitochondrial-genetics techniques upon traits which are expressed in cell culture, and the general need to maintain such cultures under antibiotic cover. But there may be a more intriguing reason for this association. The sensitivity of mitochondria to many antibiotics may reflect a legacy of mitochondria as the evolutionary descendants of bacteria which invaded the primitive pre-eukaryotes xons ago.3This theory of the symbiotic origin of mitochondria has gained considerable credence in recent years, and would explain the similarity of bacteria and mitochondria in their response to antibiotics. Finally, it is noteworthy that the general incidence of aplastic anaemias in man seems to have increased during the present century.21 Could this reflect the mitochondrial toxicity of the broad variety of antibacterial chemicals and drugs in use today? The confirmation of a mitochondrial genetic aetiology for a drug sensitivity, developmental abnormality, or other disease would have immediate practical implications for the use of potentially mitochondriotoxic drugs and in genetic counselling. If mitochondrial inheritance proved to play a role in several human diseases, the implications could be far-reaching indeed. I thank Dr
J. H. Renwick and Dr V. Beral for helpful discussions. implications of paternal illegitimacy were pointed out by Dr J. Ponnighaus.
The
662 Clinical Psychiatry in Primary Care
Reviews of Books
STEVEN L. DUBOVSKY and MICHAEL P. WEISSBERG. Baltimore. Williams and Wilkins. London: Quest. 1978. Pp. 206.$10.95
7.15.
Gynecologic and Obstetric Urology Edited by HERBERT J. BUCHSBAUM and JOSEPH D. SCHMIDT. Philadelphia and London: Saunders, 1978. Pp. 462. /;24.
THIRTY-TWO contributors, of whom two-thirds are gynaecoand one-third urologists, have contributed to this work, which is intended for the clinician "who treats pelvic disease", and which covers a wide range of topics. The interesting historical reviews at the start of most chapters help to preserve continuity. The book is well illustrated, readable, contains much clinical material that will interest both gynxcologists and urologists, and gives adequate, although not always up-todate, references. The chapters on involvement of the urinary tract in gynxcological malignancy and pelvic disease, and urinary-tract infection, are especially good, and the discussion of postoperative bladder drainage is critical and detailed. Unfortunately the accounts of the anatomy of the bladder neck and physiology of continence are out of date. There is little mention of modern urodynamic and urostatic investigations and those which are described need updating. There is controversy over classification of incontinence and the mechanism of
logists
its control, and no particular view prevails. Several topics are repeated and the discussion of asymptomatic bacteriuria in pregnancy could have been included with urinary-tract infections. A chapter on the pharmacology of the lower urinary tract, which would have been complementary to the broad outline of this book, and one on voiding difficulties and retention should have been included.
Wilson, E. B. The Cell in Development and Heredity. New York, 1925. Jinks, J. L. Extrachromosonal Inheritance. Englewood Cliffs, 1964. 3. Margulis, L. Origin of Eukaryotic Cells. New Haven, 1970. 4. Nass, M. M. K., Nass S. J. Cell Biol. 1963, 19, 593. 5. Sager, R. Cytoplasmic Genes and Organelles. New York, 1972. 6. Grun, P. Cytoplasmic Genetics and Evolution. New York, 1976. 7. Beale, G., Knowles, J. Extranuclear Genetics. London, 1978. 8. Nass, M.M. K. Proc. natn. Acad. Sci., U.S.A. 1966, 56, 1215. 9. Saccone, C., Kroon, A. M. (editors) The Genetic Function of Mitochondrial DNA. Amsterdam, 1976. 10. Hutchison, C. A., Newbold, J. E., Potter, S. S., Edgell, M. H. Nature, 1974, 251, 536. 11. Szollosi, D. J. exp. Zool. 1965, 159, 367. 12. Dawid, J. B., Blackler, A. W. Devl. Biol. 1972, 29, 152. 13. Fine, P.E.M. Ann. N.Y. Acad. Sci. 1975, 266, 173. 14. Wilkie, D. Symp. Soc. Exp. Biol. 1970, 24, 71. 15. Rank, G. H., Bech Hansen, V. T. Genetics, 1972, 72,1. 16. Rank, G. H. Heredity, 1973, 30, 265. 17. Beale, G. H., Knowles, J. K. C., Tait, A. Nature, 1972, 235, 396. 18. Lichtor, T., Getz, G. S. Proc. natn. Acad. Sci., U.S.A. 1978, 75, 324. 19. Bunn, C. L., Wallace, D. C., Eisenstadt, J. M. ibid. 1974, 71, 1681. 20. Wallace, D. C., Bunn, C. L., Eisenstadt, J. M. J. Cell Biol. 1975, 67, 174. 21. Bithell, T. C., Wintrobe, M. M. Semin. Hemat. 1967, 4, 194. 22. Bottinger, L. E., Westerholme, B. Br. med. J. 1973, iii, 339. 23. Best, W. R. J. Am. med. Ass. 1967, 201, 181. 24. Wallerstein, R. O., Condit, P. K., Kasper, C. K., Brown, J. W., Morrison, F. R. ibid. 1969, 208, 2045. 25. Weinstein, L. in The Pharmacological Basis of Therapeutics (edited by L. S. Goodman and A. Gilman). London, 1975. 26. Lancet, 1978, 1, 592. 27. Nagao, T., Mauer, A. M. New Engl J. Med. 1969, 281, 7. 28. Rosenthal, R. L., Blackman, A.J. Am. med. Ass. 1965,191, 136. 29. Gordon, M. W., Deanin, G. G. J. biol. Chem. 1968, 243, 4222. 30. Potter, S. S., Newbold, J. E., Hutchison, C. A., Edgell, M. H. Proc. natn. Acad. Sci., U.S.A. 1975, 72, 4496. 31. Skinnider, L. F., Ghadially, F. N. Archs Pathol. Lab. Med. 1976, 100, 601. 32. Sun, C.N., White, H.J.J. Cell Biol. 1974, 63, 339a. 33. Woods, M. W., Du Buy, H. G. J. Natn. Cancer Inst. 1951, 11, 1105. 34. Wallace, D. C., Bunn, C. L., Eisenstadt, J. M. Somat. Cell Genet. 1977, 3, 1. 2.
93. 35. Howell, A., Andrews, T. M., Watts, R. W. E. Lancet, 1975,
i, 65; ibid. 1975, ii, 81. 36. Fine, P. E. M. J. med. Genet. 1977, 14, 399. 37. Murphy, D. P., Abbey, N. Cancer in Families. Cambridge, 1959. 38. Klimt, C. R., Meinert, C. L., Ho, I. P., Briese, F. W. Diabetes, 1967, 16, 40.
THE title is appealing but the format and the type style do not impress. The Introduction, said to be on page xi, is on page xv and the interview with the hypochondriac on page 4 is naive. However, after this bad start, the book is a goldmine of useful advice and information. The layout is unusual, but the language is precise and free from the mumbo-jumbo of psychi-. atry. The introduction explains how this volume, which can be read as a whole or used for reference, provides a novel way of
learning practical psychiatry and patient management. The everyday problems of neuropsychiatric illness, as they appear to the general physician, are listed. Various approaches and attitudes, some bad, some good, are described, and very practical advice (e.g., some simple tests for abnormal cerebration of patients suffering from organic brain syndromes and downto-earth methods of tackling certain forms of sexual dysfunctions). As is the trend in American psychiatry today, the use of E.C.T. is all but ignored; on the other hand, there is a detailed description of how to apply an instrument of restraint, not commonly seen in Britain for some forty years. This book can certainly be recommended to primary-care physiciansreaders are urged to go through the introduction carefully. Clinics in Haematology Vol. P7/.—Edited by J. V. SIMONE. London and Saunders. 1978. Pp. 427. 8.25.
ACUTE leukaemia continues
to
present
a
Philadelphia:
formidable chal-
lenge. Although progress has been rather slow, there have been sufficient changes recently in the clinical management and in laboratory aspects of the disease to justify a second issue in this series. Sound appraisals of the present treatment of acute leukxmia in adults and children are preceded by a helpful guide to the mysteries of clinical trials. Accounts of bone-marrow transplantation for acute leukaemia and blood-component therapy emphasise the change in approach that has occurred in quite a short time, whilst immunotherapy is given a cautious and balanced appraisal. The study of cell kinetics in leukmmia is important but it is a great pity that it is not contributing more to the practical management of leukaemia. The prospect of cell-kinetic studies being used to help individual patients by indicating modifications in treatment, or by aiding the "fine tuning" of the drug regimen used, is seen as dismal. Generally, the study of kinetics is considered to have helped in the improvement of the design of treatment schedules. Dr Simone says that the subjects to watch are cytogenetics and leukxmiaassociated antigens. It will be interesting to see if he is right in five or six years time.
New Editions
Microbiology in Patient Care.-2nd ed. By H. 1. Winner. London: Hodder & Stoughton. 1978. Pp. 175. 3.95. Textbook of Immunology.-3rd ed. By James T. Barrett. St. Louis: Mosby. London: Kimpton. 1978. Pp. 505. 11.95. Bone Tumors.-3rd ed. By David C. Dahlin. Illinois: Charles C. Thomas. 1978. Pp. 445.$32.75. Towards Earlier Diagnosis in Primary Care.-4th ed. By Keith Hodgkin. Edinburgh: Churchill Livingstone. 1978. Pp. 623. k8.59. Patients, Practitioners medical Care.-2nd ed. By David Robinson. London: Heinemann. 1978. Pp. 185. £3.25. Basic Surgical Techniques.-2nd ed. By R. M. Kirk. Edinburgh: Churchill Livingstone. 1978. Pp. 168. /:2.95. Clinical Radiology of the Ear, Nose & Throat.-2nd ed. By Eric Samuel and Glyn A. S. Lloyd. London: Lewis. 1978. Pp. 262. /;15.00. Handbook of Medical Emergencies.-2nd ed. Edited by Jay H. Sanders and Lawrence B. Gardner. St. Louis: Mosby. London: Kimpton. 1978. Pp. 384./;9.00.
possible failure of a heart-valve prosthesis. Accordingly patients being prepared for this procedure should be patch tested by an experienced dermatologist, and prosthetic materials free of the particular allergen should be used. Patients who are allergic to nickel should be given nickel-free prostheses. Conversely metal allergy should be sought when valve prostheses are unaccountably leaking.
gic
to
metals face
As far as we are aware, this is the first report which attempts to correlate prosthetic-valve dysfunction with allergy to nickel, or indeed to any metal. This is surprising, considering how common allergy to nickel is in the population, and how widely it is used in prostheses. Time will tell whether our patient is unique, or whether
allergy to metal has been overlooked as a culty or failure in heart-valve replacement.
cause
of diffi-
Hypothesis MITOCHONDRIAL INHERITANCE AND DISEASE PAUL E. M. FINE Ross Institute, London School of Hygiene and Tropical Medicine, London WC1E 7HT
of the of mitochondria may be responsible for human disease. Among the prime candidates for such a mitochondrial ætiology are certain drug-induced blood dyscrasias, particularly that due to chloramphenicol. Because mitochondria are generally inherited from the female parent, such disorders should be clustered among matroclinally related individuals. The clinical manifestations of such diseases are a function of the manner in which mitochondria are allocated to somatic cells and tissues during development.
Summary
Spontaneously occurring variants
D.N.A. content
INTRODUCTION
MITOCHONDRIA are essential organelles of all human cells. Interest in the structure and function of mitochondria has increased greatly with the recognition that they contain their own genetic system, which functions to some extent independently of the nuclear chromosomes. Despite the increase in our understanding of the biology of mitochondria, little is known of their role in disease processes, beyond the fact that their morphology is altered in association with severe pathological conditions. I propose here a specific and primary role for mitochondria in certain human diseases, and suggest ways of testing the proposal. FOR, AND IMPLICATIONS OF, THE HYPOTHESIS Certain Essential Information is Coded in Mitochondrial D.NA.-It has long been recognised that mitochondria are at least partly autonomous within their "host" cells, in that they are not synthesised de novo but replicate themselves by binary fission.1-3 That mitochondria contain their own D.N.A. (mtD.N.A.) was first recognised in the early 1960s.4 The amount of mitochondrial structure and function which is coded on EVIDENCE
We are indebted to Mr J. Lawther (Medtronic Ltd) for suggesting the use of the Lillehei-Kaster titanium prosthesis. Requests for reprints should be addressed to A. L., Department of Dermatology, Royal Infirmary, Glasgow G4 OSF. -
REFERENCES 1. Lyell, A., Bain, W. H. Lancet, 1974, i, 408. 2. Stoddart, J. C. ibid. 1960, ii, 741. 3. Kaaber, K., Veien, N. K., Tjell, J. C. Br. J. Derm. 1978, 98, 197. 4. Fisher, A. A. Cutis, 1977, 19, 285. 5. Samitz, M. H., Katz, S. A. Br. J. Derm. 1975, 92, 287. 6. Katz, S.A., Samitz, M.H. Acta derm-vener., Stockh. 1975, 55, 113. 7. Pegum, J. S. Lancet, 1974, i, 674. 8. Pegum, J. S. Personal communication. 9. Evans, E. M., Freeman, M. A. R., Miller, A. J., Vernon-Roberts, B.
J. Bone
Jt Surg. 1974, 56B, 626. 10. Benson, M. K. D., Goodwin, P. G., Brostoff, J. Br. med. J. 1975, iv, 374. 11. Jones, D. A., Lucas, H. K., O’Driscoll, M., Price, C. H. G., Wibberley, B. J. Bone Jt Surg. 1975, 57B, 289. 12. Deutman, R., Mulder, T. J., Brian, R., Nater, J. P. ibid. 1977, 59A, 862. 13. Elves, M. W., Wilson, J. N., Scales, J. T., Kemp, H. B. S. Br. med. J. 1975,
iv, 376.
distinct from nuclear D.N.A. is still uncertain, it is known that some of the structural proteins though of mitochondria are coded in nuclear D.N.A.s-7 The amounts and roles of mitochondrial and nuclear D.N.A. vary between different types of cells, but in general relatively few genes seem to be coded in the D.N.A. of any
mtD.N.A. as
single mitochondrion.89 Maternal Inheritance of Mitochondria.-A tendency for inheritance to occur predominantly through the female line is a distinguishing feature of cytoplasmic material such as mitochondria. This correlates with the great difference in size between maternal and paternal gametes. It has been estimated, for example, that a cow’s ovum may contain 106 mitochondria, in contrast to about 70 mitochondria in a mature spermatid of a bull. 10 Roughly similar numbers are probably applicable to man. There is at least provisional evidence that the inheritance of mitochondria in vertebrates is entirely from the mother. Though the sperm of a rat may introduce a few mitochondria into the zygote, these paternal mitochondria seem to degenerate subsequently.l Furthermore, the only published attempts to trace mitochondrial inheritance in vertebrates, by elegant experiments in frogs and in horses, have revealed no evidence of paternal mtD.N.A. in the progeny. to 12 As the transmission of cytoplasmic material by both parents would permit detrimental cytoplasmic factors to be maintained indefinitely within a population, natural selection may have favoured the strict uniparental inheritance of such material. 6 13 Antibiotic Sensitivity as an Intrinsic Mitochondrial Property.-Various antibiotics are known to be deleterious to certain species or lines of eukaryotic cells in vitro. In several instances this antibiotic sensitivity is known to be due to a mitochondrial genetic factor-for chlorampheniexample, oligomycin, erythromycin, and14-16 col sensitivity in Saccharomyces yeast; erythromycin sensitivity in Parmecium protozoa; 17 and rutamycin and chloramphenicol sensitivity of mouse fibroblasts.18 19 Especially interesting is the recent derivation of human cell lines with strikingly different sensitivity to chloramphenicol, and the demonstration that this sensitivity is coded on the mtD.N.A.20 This is the only mtD.N.A. marker thus far confirmed in human cells. Several antibiotics cause depression of cell activity in certain human tissues, particularly the bone-mar.
660 is the total cells which occurs in approximately 1/100 000 persons exposed to chloramphenico1.23-2s In view of the in-vitro evidence for mtD.N.A.-dependent antibiotic sensitivity in cells of several species, including man, it seems reasonable to hypothesise that some of these drug-induced dyscrasias -in particular, that attributed to chloramphenicol are due to the effect of antibiotics on the mitochondria of the hxmatopoietic stem cells. Sensitive individuals would be those whose stem cells contain predominantly, or solely, mitochondria of a sensitive type. The specificity of the drug’s action on the hxmatopoietic system may be due to the high turnover-rate of the stem cells, or to some special metabolic demand which makes these cells particularly susceptible’to mitochondrial disturbance. Predicted Matroclinal Similarity for Drug Sensitivity.-The basic inheritance pattern of mtD.N.A. is illustrated in the schematic mother-father-son-daughter pedigree in the accompanying figure. Germ-line cells are shown with heavy outline, whereas the differentiating lines of somatic cells have a thin outline. Cell nuclei are represented as ovals in the lower right of each cell, and the inheritance of half the nuclear chromosomes from each parent is represented by appropriate shading. Mitochondria are shown as small circles or triangles within the "cytoplasm" of each cell: solid symbols for maternal and open symbols for paternal organelles. These different symbols are meant to represent different mitochondrial "types"-i.e., organelles which differ in their mtD.N.A. constitution. A strict maternal inheritance of mitochondria is illustrated. The possibility of a small paternal contribution of mitochondria could be added to the diagram, if appropriate. Such a diagram could also be extended to describe larger pedigrees. The important point is that each individual is inclined to share mitochondria with his or her mother and all matroclinal relatives-that is, with all individuals in the pedigree who are linked by at least one line which passes only through
row 21 22 The most dramatic inhibition of haematopoietic
example of this
stem
sive generations is dependent upon preservation of the different mtD.N.A. types within the maternal germ-cell line (as in the figure). The mechanism of mitochondrial allocation at cell division is not understood. The mitochondria of some primitive species (e.g., scorpions) are believed to make use of the mitotic spindle and achieve an even distribution between daughter cells; but there is no evidence for such a mechanism in mammals.1-3 In human beings, mitochondrial allocation at cell division is generally considered to occur "at random". In this case, and given a heterogeneous population of mitochondria in the zygote, one would expect there to be some sorting out of different types of mtD.N.A. during the successive cell divisions of an individual’s ontogeny. Such sorting-out has been illustrated in the figure. The two types of mitochondria are shown to be distributed unequally at successive somatic cell divisions within each individual. According to this diagram, some of each individual’s differentiated cell lines eventually become homochondric, despite a heterochondric zygote and maternal germ-cell line. Risk among Carriers is Related to mtD.NA. Heterogeneity.-The implications of mitochondrial heterogeneity and sorting-out in somatic cell lines are important. Clinical evidence of mtD.N.A.-dependent antibiotic sensitivity might arise only if the sorting-out process has led to a cell line which possesses mitochondria predominantly, or solely, of a sensitive type. The probability of this happening should be inversely related to the number of copies of sensitive mtD.N.A.-type mitochondria initially present in the zygote. This quantitative relationship has been examined in simple cell culture systems, but has not yet been extrapolated to the ontogeny of multicellular organisms.34
females.26
Any mitochondrial D.N.A. marker, such as one for drug sensitivity, is expected to be shared by matroclinal relatives of a sensitive proband. The actual risks of drug sensitivity are difficult to assess in practice, since the number exposed in each category of relatives is generally unknown. It is noteworthy, however, that of three recorded familial concordances for acute chloramphenicol sensitivity, two were identical twins and one was in a man and his sister’s daughter.27 211 All are matroclinal ties. /?Mp/!c!07M /br Mitochondrial Heterogeneity.-The hypothesis under consideration implies a variation in mtD.N.A. content of mitochondria in human individuals and populations. There is conflicting evidence as to whether an individual inherits one type or several types of mitochondria (i.e., mitochondria with different mtD.N.A. constitutions). Nor is it clear whether differentiated tissues are naturally "homochondric" or "heterocliondric".29-33 However, given that certain
mtD.N.A.
may
un-
degree of heterogeneity in the mtD.N.A. within single cells, tissues, and individuals, let alone populations, is to be expected. In the absence of paternal transfer of mitochondria to the zygote, the maintenance of mitochondrial heterogeneity in succesdergo mutation,
a
Inheritance pattern of mitochondria
-
This simple pedigree illustrates the pattern of allocation of mitochondrial (A, .,A,O) and nuclear (4m,c=) material to the germ line (heavy outline) and somatic (thin outline) cells of each individual. Strict maternal inheritance of mitochondria is assumed.
661 The actual risk of acute chloramphenicol sensitivity among matroclinal relatives of sensitive individuals is unknown. Considering the widespread use of this antibiotic between 1950 and 1965, the rarity of reports of familial aggregation suggests that this risk is appreciably less than 100%. This may suggest that only a small proportion of the mitochondria of affected individuals are of the sensitive type. Graded Phenotypes with Multiple mtD.N.A. Types.-Given multiple types of mitochondria within cells, which vary in their mtD.N.A. and in their relative numbers, one would expect that any derivative phenotypic traits would vary according to the distribution of types and numbers of mitochondria within the cells, tissues, or organisms. This is consistent with the observed clinical range of antibiotic sensitivity (e.g., to chloramphenicol), which may range from a mild depression to a total shutdown of haematopoiesis.25 It is also consistent with evidence that bone-marrow cells of individuals who have recovered from chloramphenicol-induced anaemia are less sensitive than normal control cells when exposed to chloramphenicol in vitro.35 If the initial exposure des. troys the drug-sensitive mitochondria and those cells which are dependent upon them, then only cells which contain at least some chloramphenicol-resistant mitochondria would be left. Mitochondrial Defects and Other Diseases.-Although special emphasis has been placed here upon the possibility of a mtD.N.A.-dependent mechanism underlying certain antibiotic sensitivities, it should be recognised that, given the importance of mitochondria in energy metabolism and possibly also in cell differentiation, mutations in mtD.N.A. might lead to a broad range of cellular and organismal pathology. TESTING
THE HYPOTHESIS
Several features of the hypothesis lend themselves to direct investigation. First, the predicted matroclinal tendency may be tested by family-history studies of individuals who have suffered blood dyscrasis attributed to antibiotic therapy. Second, cell lines could be derived from both matroclinal and non-matroclinal relatives of drug-sensitive individuals, in order to assess differences in sensitivity in vitro. Third, there is a need to investigate the possibility and the extent of a paternal contribution to mitochondrial inheritance in man, since this will determine the expected difference in mitochondrial constitution between different classes of relatives.36 Existing restriction endonuclease techniques should make such a study feasible. Fourth, further studies should be pursued on the distribution of mitochondria during human ontogeny. This raises the question of what tissues other than haematopoietic stem cells may be susceptible to mitochondrial toxins. Finally, we need to develop a quantitative theory of mitochondrial genetics in both germ-line and somatic cells of higher
organisms.36 Human family and population studies may make a fundamental contribution to our understanding of the role of the cytoplasm in heredity. Published reports on mitochondrial inheritance deal almost entirely with single-cell organisms or cell cultures. Paramecium and yeast, the early experimental models, have now given place to mammalian cells, studied by’ cell-fusion techniques. These techniques still depend largely upon markers which are expressed in cell-culture systems
-hence the continued emphasis on genes for antibiotic sensitivity in published work on mitochondrial genetics. Such techniques are not directly suited for the study of the role of mtD.N.A. in the development and the function of differentiated cells. Another weakness of the in-vitro methods is their emphasis upon established cell lines in culture, as mitochondrial diversity is very likely to be altered or diluted out with the serial propagation of many standard cell lines.29 For all these reasons, the study of whole organisms and populations has much to contribute to our understanding of mitochondrial inheritance. Several indices discussed here-such as matroclinal excess, variable penetrance, and phenotypic gradations-provide epidemiological tools for the assessment of mitochondrial inheritance in man. A cautionary remark is in order, concerning the inference of cytoplasmic or mitochondrial inheritance in man. Although matroclinal line clustering is to be expected for any trait which is coded in mtD.N.A., various other mechanisms may lead to a similar family-history asymmetry. Many nurtural factors, such as the intrauterine environment, breast milk, or even diet in the home may cause children to resemble their mothers more closely than their fathers. Furthermore, there is a general tendency for women to know their family histories better than do men, and this may lead to a spurious excess in matroclinal lines in retrospective studies.17 38 Finally, the presence of paternal illegitimates in a pedigree may result in an apparent matroclinal clustering of chromosomal, as well as extrachromosomal, traits. Such alternatives to a simple cytoplasmicinheritance hypothesis must be considered in the interpretation of data indicating a matroclinal line clustering in man.
DISCUSSION
Though several disorders of man may ultimately be attributed to aberrant mtD.N.A., particular emphasis is placed here upon the drug-induced blood dyscrasias. That dyscrasias should emerge as prime candidates for such an aetiology may simply reflect the large amount of work which has been done on this aspect of mitochondrial behaviour. And this, in turn, is due to the dependence of most current mitochondrial-genetics techniques upon traits which are expressed in cell culture, and the general need to maintain such cultures under antibiotic cover. But there may be a more intriguing reason for this association. The sensitivity of mitochondria to many antibiotics may reflect a legacy of mitochondria as the evolutionary descendants of bacteria which invaded the primitive pre-eukaryotes xons ago.3This theory of the symbiotic origin of mitochondria has gained considerable credence in recent years, and would explain the similarity of bacteria and mitochondria in their response to antibiotics. Finally, it is noteworthy that the general incidence of aplastic anaemias in man seems to have increased during the present century.21 Could this reflect the mitochondrial toxicity of the broad variety of antibacterial chemicals and drugs in use today? The confirmation of a mitochondrial genetic aetiology for a drug sensitivity, developmental abnormality, or other disease would have immediate practical implications for the use of potentially mitochondriotoxic drugs and in genetic counselling. If mitochondrial inheritance proved to play a role in several human diseases, the implications could be far-reaching indeed. I thank Dr
J. H. Renwick and Dr V. Beral for helpful discussions. implications of paternal illegitimacy were pointed out by Dr J. Ponnighaus.
The
662 Clinical Psychiatry in Primary Care
Reviews of Books
STEVEN L. DUBOVSKY and MICHAEL P. WEISSBERG. Baltimore. Williams and Wilkins. London: Quest. 1978. Pp. 206.$10.95
7.15.
Gynecologic and Obstetric Urology Edited by HERBERT J. BUCHSBAUM and JOSEPH D. SCHMIDT. Philadelphia and London: Saunders, 1978. Pp. 462. /;24.
THIRTY-TWO contributors, of whom two-thirds are gynaecoand one-third urologists, have contributed to this work, which is intended for the clinician "who treats pelvic disease", and which covers a wide range of topics. The interesting historical reviews at the start of most chapters help to preserve continuity. The book is well illustrated, readable, contains much clinical material that will interest both gynxcologists and urologists, and gives adequate, although not always up-todate, references. The chapters on involvement of the urinary tract in gynxcological malignancy and pelvic disease, and urinary-tract infection, are especially good, and the discussion of postoperative bladder drainage is critical and detailed. Unfortunately the accounts of the anatomy of the bladder neck and physiology of continence are out of date. There is little mention of modern urodynamic and urostatic investigations and those which are described need updating. There is controversy over classification of incontinence and the mechanism of
logists
its control, and no particular view prevails. Several topics are repeated and the discussion of asymptomatic bacteriuria in pregnancy could have been included with urinary-tract infections. A chapter on the pharmacology of the lower urinary tract, which would have been complementary to the broad outline of this book, and one on voiding difficulties and retention should have been included.
Wilson, E. B. The Cell in Development and Heredity. New York, 1925. Jinks, J. L. Extrachromosonal Inheritance. Englewood Cliffs, 1964. 3. Margulis, L. Origin of Eukaryotic Cells. New Haven, 1970. 4. Nass, M. M. K., Nass S. J. Cell Biol. 1963, 19, 593. 5. Sager, R. Cytoplasmic Genes and Organelles. New York, 1972. 6. Grun, P. Cytoplasmic Genetics and Evolution. New York, 1976. 7. Beale, G., Knowles, J. Extranuclear Genetics. London, 1978. 8. Nass, M.M. K. Proc. natn. Acad. Sci., U.S.A. 1966, 56, 1215. 9. Saccone, C., Kroon, A. M. (editors) The Genetic Function of Mitochondrial DNA. Amsterdam, 1976. 10. Hutchison, C. A., Newbold, J. E., Potter, S. S., Edgell, M. H. Nature, 1974, 251, 536. 11. Szollosi, D. J. exp. Zool. 1965, 159, 367. 12. Dawid, J. B., Blackler, A. W. Devl. Biol. 1972, 29, 152. 13. Fine, P.E.M. Ann. N.Y. Acad. Sci. 1975, 266, 173. 14. Wilkie, D. Symp. Soc. Exp. Biol. 1970, 24, 71. 15. Rank, G. H., Bech Hansen, V. T. Genetics, 1972, 72,1. 16. Rank, G. H. Heredity, 1973, 30, 265. 17. Beale, G. H., Knowles, J. K. C., Tait, A. Nature, 1972, 235, 396. 18. Lichtor, T., Getz, G. S. Proc. natn. Acad. Sci., U.S.A. 1978, 75, 324. 19. Bunn, C. L., Wallace, D. C., Eisenstadt, J. M. ibid. 1974, 71, 1681. 20. Wallace, D. C., Bunn, C. L., Eisenstadt, J. M. J. Cell Biol. 1975, 67, 174. 21. Bithell, T. C., Wintrobe, M. M. Semin. Hemat. 1967, 4, 194. 22. Bottinger, L. E., Westerholme, B. Br. med. J. 1973, iii, 339. 23. Best, W. R. J. Am. med. Ass. 1967, 201, 181. 24. Wallerstein, R. O., Condit, P. K., Kasper, C. K., Brown, J. W., Morrison, F. R. ibid. 1969, 208, 2045. 25. Weinstein, L. in The Pharmacological Basis of Therapeutics (edited by L. S. Goodman and A. Gilman). London, 1975. 26. Lancet, 1978, 1, 592. 27. Nagao, T., Mauer, A. M. New Engl J. Med. 1969, 281, 7. 28. Rosenthal, R. L., Blackman, A.J. Am. med. Ass. 1965,191, 136. 29. Gordon, M. W., Deanin, G. G. J. biol. Chem. 1968, 243, 4222. 30. Potter, S. S., Newbold, J. E., Hutchison, C. A., Edgell, M. H. Proc. natn. Acad. Sci., U.S.A. 1975, 72, 4496. 31. Skinnider, L. F., Ghadially, F. N. Archs Pathol. Lab. Med. 1976, 100, 601. 32. Sun, C.N., White, H.J.J. Cell Biol. 1974, 63, 339a. 33. Woods, M. W., Du Buy, H. G. J. Natn. Cancer Inst. 1951, 11, 1105. 34. Wallace, D. C., Bunn, C. L., Eisenstadt, J. M. Somat. Cell Genet. 1977, 3, 1. 2.
93. 35. Howell, A., Andrews, T. M., Watts, R. W. E. Lancet, 1975,
i, 65; ibid. 1975, ii, 81. 36. Fine, P. E. M. J. med. Genet. 1977, 14, 399. 37. Murphy, D. P., Abbey, N. Cancer in Families. Cambridge, 1959. 38. Klimt, C. R., Meinert, C. L., Ho, I. P., Briese, F. W. Diabetes, 1967, 16, 40.
THE title is appealing but the format and the type style do not impress. The Introduction, said to be on page xi, is on page xv and the interview with the hypochondriac on page 4 is naive. However, after this bad start, the book is a goldmine of useful advice and information. The layout is unusual, but the language is precise and free from the mumbo-jumbo of psychi-. atry. The introduction explains how this volume, which can be read as a whole or used for reference, provides a novel way of
learning practical psychiatry and patient management. The everyday problems of neuropsychiatric illness, as they appear to the general physician, are listed. Various approaches and attitudes, some bad, some good, are described, and very practical advice (e.g., some simple tests for abnormal cerebration of patients suffering from organic brain syndromes and downto-earth methods of tackling certain forms of sexual dysfunctions). As is the trend in American psychiatry today, the use of E.C.T. is all but ignored; on the other hand, there is a detailed description of how to apply an instrument of restraint, not commonly seen in Britain for some forty years. This book can certainly be recommended to primary-care physiciansreaders are urged to go through the introduction carefully. Clinics in Haematology Vol. P7/.—Edited by J. V. SIMONE. London and Saunders. 1978. Pp. 427. 8.25.
ACUTE leukaemia continues
to
present
a
Philadelphia:
formidable chal-
lenge. Although progress has been rather slow, there have been sufficient changes recently in the clinical management and in laboratory aspects of the disease to justify a second issue in this series. Sound appraisals of the present treatment of acute leukxmia in adults and children are preceded by a helpful guide to the mysteries of clinical trials. Accounts of bone-marrow transplantation for acute leukaemia and blood-component therapy emphasise the change in approach that has occurred in quite a short time, whilst immunotherapy is given a cautious and balanced appraisal. The study of cell kinetics in leukmmia is important but it is a great pity that it is not contributing more to the practical management of leukaemia. The prospect of cell-kinetic studies being used to help individual patients by indicating modifications in treatment, or by aiding the "fine tuning" of the drug regimen used, is seen as dismal. Generally, the study of kinetics is considered to have helped in the improvement of the design of treatment schedules. Dr Simone says that the subjects to watch are cytogenetics and leukxmiaassociated antigens. It will be interesting to see if he is right in five or six years time.
New Editions
Microbiology in Patient Care.-2nd ed. By H. 1. Winner. London: Hodder & Stoughton. 1978. Pp. 175. 3.95. Textbook of Immunology.-3rd ed. By James T. Barrett. St. Louis: Mosby. London: Kimpton. 1978. Pp. 505. 11.95. Bone Tumors.-3rd ed. By David C. Dahlin. Illinois: Charles C. Thomas. 1978. Pp. 445.$32.75. Towards Earlier Diagnosis in Primary Care.-4th ed. By Keith Hodgkin. Edinburgh: Churchill Livingstone. 1978. Pp. 623. k8.59. Patients, Practitioners medical Care.-2nd ed. By David Robinson. London: Heinemann. 1978. Pp. 185. £3.25. Basic Surgical Techniques.-2nd ed. By R. M. Kirk. Edinburgh: Churchill Livingstone. 1978. Pp. 168. /:2.95. Clinical Radiology of the Ear, Nose & Throat.-2nd ed. By Eric Samuel and Glyn A. S. Lloyd. London: Lewis. 1978. Pp. 262. /;15.00. Handbook of Medical Emergencies.-2nd ed. Edited by Jay H. Sanders and Lawrence B. Gardner. St. Louis: Mosby. London: Kimpton. 1978. Pp. 384./;9.00.
